Chem Biol Drug Des 2014 Research Article
Synthesis, Biological Evaluation, and Molecular Docking Studies of Xanthone Sulfonamides as ACAT Inhibitors Xiang Li, Yan Zou, Qingjie Zhao, Yan Yang, Maocheng Wu, Ting Huang, Honggang Hu* and Qiuye Wu* Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China *Corresponding authors: Honggang Hu, [email protected]; Qiuye Wu, [email protected] Xiang Li and Yan Zou contributed equally to this work. Three series of xanthone sulfonamides were synthesized, and their inhibitory activities against acyl-CoA: cholesterol acyltransferase (ACAT) were evaluated. Results showed that most of the title compounds exhibited strong inhibitory activity against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Computational docking experiments indicated that the interaction between inhibitors and ACAT contained the H-bond interaction, the hydrophobic interaction, and the narrow hydrophobic cleft. Key words: ACAT, docking, Structure–activity relationship, sulfonamide, xanthone Received 6 May 2014, revised 24 July 2014 and accepted for publication 13 August 2014
Arteriosclerosis, as the most common sclerosis, has become the underlying cause of most myocardial infractions. Arteriosclerosis is usually caused by an excess accumulation of cholesteryl esters in macrophages and smooth muscle cells in the arterial wall (1–3). Thus, hypercholesterolemia has been identified as an independent risk factor for coronary heart disease. Recent studies have demonstrated that controlling the level of serum cholesterol is an effective way in the treatment of atherosclerosis (4–6). As Acyl-CoA: cholesterol acyltransferase (EC 2.3.1.26, ACAT), which plays a key role in the absorption and metabolism of cholesterol, is principally responsible for the intracellular esterification of cholesterol. The inhibition of ACAT is expected to reduce plasma lipid levels by inhibiting ª 2014 John Wiley & Sons A/S. doi: 10.1111/cbdd.12419
intestinal cholesterol absorption and thus to prevent progression of atherosclerotic lesions (7–9). Therefore, ACAT has become an important target enzyme in the treatment of the arteriosclerosis (10–12). In this area, considerable efforts have been made directly to the development of potent ACAT inhibitors in recent years (13–20). Our group has always focused on the study of the xanthone compounds, including synthesizing novel xanthone compounds and evaluating the inhibitory activities against ACAT. In our previous study, a series of 1,3,6,7tetramethoxyxanthone-4-sulfonamide derivatives were successfully synthesized as potent ACAT inhibitors for the first time, of which compound 14, shown in Figure 1, was proved to be more potent than the positive control Sandoz 58-035 (21) (an ACAT inhibitor, from Sigma). In an effort to develop new xanthone derivatives with potent ACAT inhibitory effect, further optimization and modification have been conducted. Based on the previous study, the present work had focused on introducing different groups to the xanthone sulfonamide framework to further study the structure and activity relationships. As shown in Figure 2, three series of 1,3-Dimethoxyxanthone4-sulfonamide derivatives were designed, synthesized, and evaluated for their ACAT inhibitory activities. In addition, a docking study of these compounds was performed in an attempt to understand their mechanism of action on the ACAT-2, an expected target enzyme of hypercholesterolemia and atherosclerosis.
Experimental Chemistry The synthetic route designed for the novel xanthone sulfonamides was shown in Scheme 1. Three key intermediates 8–10 were prepared from the substituted salicylic acid. Herein, Eaton’s reagent (phosphorus pentoxide in methanesulfonic acid) was successfully used to promote the cyclization in high yield under mild conditions. This method was inexpensive and Eaton’s reagent could be destroyed conveniently with water, thus avoiding the usage of PPA (Polyphosphoric acid) in the traditional Grover, Shah and Shah reaction (22). Compounds 11–13 were obtained by the sulfonylation of 8–10 using chlorosulfonic acid in high yield. Finally, nucleophilic substitutions of 11–13 with 1
Li et al.
Figure 1: The structure of xanthone sulfonamide 14 in our previous study.
the corresponding substituted aryl piperazines furnished the target compounds 1a–1k, 2a–2j, and 3a–3k. All new compounds were characterized by NMR and MS.
Fluorescent ACAT assay HepG2 cells were cultured in low-glucose DMEM supplement with 100 U/mL streptomycin and penicillin. Twenty thousand cells were plated per well on 96-well culture plates and grew overnight at 37 °C. Cells were incubated in medium containing either different samples, Sandoz 58-035 (positive control) or without sample (negative control and blank control) for 1 h. Then, NBD-cholesterol with final concentration of 2 lg/mL was added into the medium except for blank control and incubated overnight. NBDcholesterol was added from a 1 mg/mL stock in ethanol, and ethanol concentrations did not exceed 0.1%. After incubation, medium was removed, and the cells were washed three times with 20 lL PBS buffer. Plates were read fluorescence from the bottom using WALLAC Victor 2 plate reader (PerkinElmer, Waltham, MA, USA) equipped with 485-nm excitation and 535-nm emission filters. The inhibition rate was calculated based on fluorescence as the FSamfollowing equation: Inhibition % = (FNegative FBlank) 9 100%. ple FBlank)/(FNegative
Molecular docking All the molecular modeling calculations were performed using SYBYL 6.9 version (Tripos International, St. Louis, MO, USA). And the structures of the compounds were €ckle partial atomic charges. assigned with Gasteiger–Hu Energy minimization was performed using the Tripos force field, Powell optimization method, and MAXIMIN2 minimizer with a convergence criterion 0.001 Kcal/mol A. Simulated annealing was then performed. The system was heated to 1000 K for 1.0 ps and then annealed to 250 K for 1.5 ps. The annealing function was exponential; 50 such cycles of annealing were run and the resulting 50 conformers were optimized using methods described above. The lowest energy conformation was selected. All the other parameters were default value.
Chemistry: general procedures Melting points were measured on a Yamato MP-21 melting point apparatus and were uncorrected. NMR spectra were recorded in CDCl3 or DMSO-d6 unless otherwise indicated with a Bruker spectrometer (Bruker Biospin Inc., Zurich, Switzerland), using TMS as internal standard. ESI mass spectra were performed on an API-3000 LC-MS spectrometer (Applied Biosystems Inc., Foster City, CA, USA). Elemental analysis was undertaken with an Italian MOD 1106 analyzer (CarloErba., Italian, Milan, Italy) at the Analysis Center of Shanghai Institute of Pharmaceutical Industry. Column chromatography was carried out on silica gel (200–300 mesh). The solvents and reagents were used as received or dried prior to use as needed. All reactions were monitored using thin-layer chromatography (TLC) on silica gel plates. Detection was effected by examination under UV light.
1,3-Dimethoxy-7-nitro-9H-xanthen-9-one (8) 2-Hydroxy-5-nitrobenzoic acid (9.1 g, 0.050 mol) and 1,3,5-trimethoxybenzene (8.5 g, 0.055 mol) were added in a three-necked flask (500 mL) and then dropped the fresh
Figure 2: The structures of all the compounds we designed and synthesized.
2
Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors
Scheme 1: Reagents and conditions: (a) P2O5/CH3SO3H, 110 °C, 2.5 h, 78.2–83.74%; (b) HSO3Cl, 0 °C, 4 h, 78.9–82.1%; and (c) 1,4-dioxane, K2CO3, piperazine, r.t., overnight, 53.3–78.9%.
Eaton’s reagent (100 mL) slowly by a constant pressure dropping funnel. The reaction mixture was kept at 110 °C for 2.5 h. When it was cooled, the mixture was quenched by adding ice water mixture, and then the mixture was stirred for 2 h to give a precipitate which was filtered, washed with water until it was deemed neutral. At last, the precipitate was recrystallized from methanol to give a yellow solid with yield of 78.2%. 1H NMR (300 MHz, DMSO-d6, TMS) d 9.14 (d, J = 2.4 Hz, 1H, Ar), 8.47 (dd, J = 9.6, 3.0 Hz, 1H, Ar), 7.50 (d, J = 6.6 Hz, 1H, Ar), 6.55 (d, J = 1.8 Hz, 1H, Ar), 6.42 (d, J = 1.8 Hz, 1H, Ar), 4.01 (s, 3H, OCH3), 3.95 (s, 3H, OCH3); ESI-MS, Calcd. for C15H12NO6+, [M + H]+, 302; Anal. Calcd for C15H11NO6: C, 59.80; H, 3.68; N, 4.65; Found, C, 59.72; H, 3.58; N, 4.77. Compounds 9 and 10 were prepared using the same procedure as compound 8 described above.
1,3-Dimethoxy-6-methyl-9H-xanthen-9-one (9) The starting material was 2-hydroxy-4-methylbenzoic acid. Yield: 81.7%. 1H NMR (300 MHz, DMSO-d6, TMS) d 8.17 (d, J = 7.8 Hz, 1H, Ar), 7.16–7.13 (m, 2H, Ar), 6.48 (d, J = 2.4 Hz, 1H, Ar), 6.34 (d, 1H, J = 2.4 Hz, Ar), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 2.48 (s, 3H, CH3); ESI-MS, Calcd. for C16H15O4+, [M + H]+, 271; Anal. Calcd for C16H14O4: C, 71.10; H, 5.22; Found, C, 71.22; H, 5.25.
7-bromo-1,3-Dimethoxy-9H-xanthen-9-one (10) The starting material was 5-bromo-2-hydroxybenzoic acid. Yield: 83.4%. 1H NMR (300 MHz, DMSO-d6, TMS) d 8.38 (d, J = 1.8 Hz, 1H, Ar), 7.70 (dd, J = 8.7, 2.4 Hz, 1H, Ar), 7.25 (t, J = 3.6 Hz, 1H, Ar), 6.49 (d, J = 2.4 Hz, 1H, Ar), 6.35 (d, J = 2.4 Hz, 1H, Ar), 4.12 (s, 3H, OCH3), 3.96 (s, 3H, OCH3); ESI-MS, Calcd. for C15H12BrO4+, [M + H]+, 335; Anal. Calcd for C15H11BrO4: C, 53.76; H, 3.31; Found, C, 53.88; H, 3.19. Chem Biol Drug Des 2014
1,3-Dimethoxy-7-nitro-9-oxo-9H-xanthene-4sulfonyl chloride (11) To a stirred solution of 1,3-Dimethoxy-7-nitro-9H-xanthen9-one (8) (3.1 g, 0.011 mol) dissolved in dichloromethane (20 mL), chlorosulfonic acid (20 mL) was dropped slowly. The temperature was kept at 25 °C about 2.5 h, and the reaction was deemed completely by TLC analysis. Then the product was poured into the ice water slowly and extracted with ethyl acetate (4 9 100 mL). The combined organic layers were washed with brine (2 9 100 mL), dried over anhydrous sodium sulfate, and removed under vacuum to give the crude product, which was recrystallized from ethyl acetate to give the pure product with yield of 82.1%. The obtained product was used in next reaction immediately. 1H NMR (300 MHz, DMSO-d6, TMS) d 8.72 (d, J = 2.7 Hz, 1H, Ar), 8.53 (dd, J = 9.1, 2.9 Hz, 1H, Ar), 7.67 (dd, J = 33.3, 9.1 Hz, 1H, Ar), 6.92–6.45 (m, 1H, Ar), 3.93 (dd, J = 15.5, 7.4 Hz, 6H, OCH3); 13C NMR (75 MHz, DMSO-d6, TMS) d 174.53, 163.87, 161.82, 158.10, 155.14, 143.62, 129.38, 122.27, 119.65, 119.53, 105.43, 96.67, 93.38, 57.13, 56.88; ESI-MS, Calcd. for C15H11ClNO8S+, [M + H]+, 400; Anal. Calcd for C15H10ClNO8S: C, 45.07; H, 2.52; N, 3.50; Found, C, 45.12; H, 2.42; N, 3.55. Compounds 12 and 13 were prepared using the same procedure as compound 11 described above.
1,3-Dimethoxy-6-methyl-9-oxo-9H-xanthene-4sulfonyl chloride (12) The starting material was 1,3-Dimethoxy-6-methyl-9H-xanthen-9-one (9). Yield: 80.0%. 1H NMR (600 MHz, CDCl3, TMS) d 8.18 (dd, J = 21.4, 8.1 Hz, 1H, Ar), 7.17 (d, J = 8.1 Hz, 1H, Ar), 6.52 (d, J = 1.8 Hz, 1H, Ar), 6.37 (d, J = 1.7 Hz, 1H, Ar), 4.01 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 2.51 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3, TMS) d 175.48, 167.29, 164.92, 159.94, 155.03, 144.60, 125.42, 121.16, 116.32, 113.46, 107.17, 95.21, 92.80, 56.89, 56.55, 21.54; ESI-MS, Calcd. for C16H14ClO6S+, 3
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[M + H]+, 369; Anal. Calcd for C16H13ClO6S: C, 52.11; H, 3.55; Found, C, 52.15; H, 3.76.
7-bromo-1,3-Dimethoxy-9-oxo-9H-xanthene-4sulfonyl chloride (13) The starting material was 7-bromo-1,3-Dimethoxy-9H-xanthen-9-one (10). Yield: 78.9%. 1H NMR (600 MHz, CDCl3, TMS) d 7.84 (dd, J = 8.8, 2.5 Hz, 1H, Ar), 7.65 (d, J = 2.5 Hz, 1H, Ar), 7.53 (d, J = 8.8 Hz, 1H, Ar), 7.05 (dd, J = 27.3, 8.8 Hz, 1H, Ar), 4.19 (s, 3H, OCH3), 4.17 (s, 3H, OCH3); 13C NMR (150 MHz, CDCl3, TMS) d 173.06, 167.15, 163.93, 156.92, 152.98, 137.82, 128.70, 120.17, 118.66, 113.74, 109.03, 106.80, 91.05, 57.20, 56.41; ESI-MS, Calcd. for C15H11BrClO6S+, [M + H]+, 435; Anal. Calcd for C15H10BrClO6S: C, 41.54; H, 2.32; Found, C, 41.42; H, 2.39.
General procedure for the preparation of target compounds 1a–1k To a solution of 1,3-Dimethoxy-7-nitro-9-oxo-9H-xanthene-4-sulfonyl chloride (0.2 g, 0.5 mmol) in dioxane, corresponding aryl piperazine (0.6 mmol) was added, and the reaction was stirred at room temperature for 12 h. Then the product was poured into ice water, and extracted with dichloromethane (4 9 50 mL). The combined organic layers were washed with brine (2 9 100 mL), dried over anhydrous sodium sulfate, and removed under vacuum to give the crude product, which was purified by chromatography on silica using a mixture of dichloromethane and methanol (v/v = 50:1) as eluent to give the target compounds. Compounds 2a–j were synthesized from 1,3-Dimethoxy-6methyl-9-oxo-9H-xanthene-4-sulfonyl chloride using the same procedure as above. Compounds 3a–k were synthesized from 1,3-Dimethoxy7-bromo-9-oxo-9H-xanthene-4-sulfonyl chloride using the same procedure as above. The title compounds were characterized as follows. 3-(4-((1,3-Dimethoxy-7-nitro-9-oxo-9H-xanthen-4-yl)sulfonyl)piperazin-1-yl)benzonitrile (1a) Light yellow solid. Yield: 70.2%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.73 (d, 1H, J = 2.7 Hz, Ar), 8.58–8.54 (m, 1H, Ar), 7.77 (d, J = 9.3 Hz, 1H, Ar), 7.38– 7.14 (m, 4H, Ar), 6.77 (1H, s, Ar), 4.06 (d, J = 5.4 Hz, 6H, OCH3), 3.65–3.54 (m, 4H, CH2), 3.28–3.13 (m, 4H, CH2); 13 C NMR (150 MHz, CDCl3, TMS) d 173.37, 165.56, 163.82, 157.13, 149.52, 146.13, 144.47, 130.55, 128.43, 126.64, 124.74, 122.80, 122.34, 121.43, 119.69, 118.42, 113.58, 108.62, 102.54, 91.91, 56.91, 56.30, 49.75, 46.06, 45.98, 44.78; ESI-MS, Calcd. for C26H23N4O8S+, [M + H]+, 551; Anal. Calcd for C26H22N4O8S: C, 56.72; H, 4.03; N, 10.18; Found, C, 56.88; H, 4.16; N, 10.04. 4
4-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy-7-nitro-9H-xanthen-9-one (1b) Light yellow powder. Yield: 72.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.72 (d, J = 2.7 Hz, 1H, Ar), 8.56–8.52 (m, 1H, Ar), 7.80 (d, J = 8.9 Hz, 1H, Ar), 7.40– 7.02 (m, 4H, Ar), 6.79 (s, 1H, Ar), 4.08 (d, J = 5.3 Hz, 6H, OCH3), 3.40 (s, 4H, CH2), 3.03 (s, 4H, CH2); ESI-MS, Calcd. for C25H23ClN3O8S+, [M + H]+, 560; Anal. Calcd for C25H22ClN3O8S: C, 53.62; H, 3.96; N, 7.50; Found, C, 53.66; H, 3.94; N, 7.41. 4-((4-(4-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy-7-nitro-9H-xanthen-9-one (1c) Light yellow powder. Yield: 76.8%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.79–8.43 (m, 3H, Ar), 7.76 (dd, J = 9.1, 6.6 Hz, 2H, Ar), 7.20 (d, J = 8.9 Hz, 1H, Ar), 6.91 (d, J = 9.0 Hz, 1H, Ar), 6.76 (s, 1H, Ar), 4.07 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 3.67–3.58 (m, 4H, CH2), 3.25–3.14 (m, 4H, CH2); 13C NMR (75 MHz, DMSO-d6, TMS) d 172.46, 165.08, 164.50, 157.45, 157.10, 149.51, 144.01, 129.95, 129.02, 128.80, 122.78, 122.57, 121.87, 120.15, 119.07, 117.98, 106.67, 105.98, 93.65, 66.93, 66.48, 57.82, 57.13, 45.83, 45.61; ESI-MS, Calcd. for C25H23ClN3O8S+, [M + H]+, 560; Anal. Calcd for C25H22ClN3O8S: C, 53.62; H, 3.96; N, 7.50; Found, C, 53.69; H, 3.91; N, 7.61. 4-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-7-nitro-9H-xanthen-9-one (1d) Light yellow powder. Yield: 74.6%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.73 (s, 1H, Ar), 8.57–8.53 (m, 1H, Ar), 7.78 (d, J = 9.3 Hz, 1H, Ar), 7.20–6.85 (m, 4H, Ar), 6.77 (s, 1H, Ar), 4.06 (d, J = 5.4 Hz, 6H, OCH3), 3.66–3.32 (m, 4H, CH2), 3.27–3.23 (m, 4H, CH2); ESI-MS, Calcd. for C25H23ClN3O8S+, [M + H]+, 560; Anal. Calcd for C25H22ClN3O8S: C, 53.62; H, 3.96; N, 7.50; Found, C, 53.49; H, 4.01; N, 7.45. 4-((4-(2,4-Dichlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-7-nitro-9H-xanthen-9-one (1e) Light green solid. Yield: 77.5%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (d, J = 2.7 Hz, 1H, Ar), 8.56–8.52 (m, 1H, Ar), 7.78 (d, J = 9.0 Hz, 1H, Ar), 7.32– 7.15 (m, 3H, Ar), 6.79 (s, 1H, Ar), 4.08 (d, J = 6.0 Hz, 6H, OCH3), 3.40 (s, 4H, CH2), 3.05 (s, 4H, CH2); ESI-MS, Calcd. for C25H22Cl2N3O8S+, [M + H]+, 594; Anal. Calcd for C25H21Cl2N3O8S: C, 50.51; H, 3.56; N, 7.07; Found, C, 50.56; H, 3.54; N, 7.01. 4-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy7-nitro-9H-xanthen-9-one (1f) Light yellow powder. Yield: 74.7%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (d, J = 2.7 Hz, 1H, Ar), Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors
8.57–8.53 (m, 1H, Ar), 7.78 (d, J = 9.3 Hz, 1H, Ar), 7.06– 6.90 (m, 4H, Ar), 6.77 (s, 1H, Ar), 4.07 (d, J = 6.2 Hz, 6H, OCH3), 3.55 (s, 4H, CH2), 3.20–3.11 (m, 4H, CH2); ESIMS, Calcd. for C25H23FN3O8S+, [M + H]+, 544; Anal. Calcd for C25H22FN3O8S: C, 55.24; H, 4.08; N, 7.73; Found, C, 55.21; H, 3.98; N, 7.81. 1,3-Dimethoxy-7-nitro-4-((4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)sulfonyl)-9H-xanthen-9-one (1g) Light yellow solid. Yield: 78.9%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.73 (d, J = 3.0 Hz, 1H, Ar), 8.57–8.53 (m, 1H, Ar), 7.77 (d, J = 8.4 Hz, 1H, Ar), 7.41– 7.05 (m, 4H, Ar), 6.76 (s, 1H, Ar), 4.07 (d, J = 6.6 Hz, 6H, OCH3), 3.40 (s, 4H, CH2), 3.34–3.21 (m, 4H, CH2); ESIMS, Calcd. for C26H23F3N3O8S+, [M + H]+, 594; Anal. Calcd for C26H22F3N3O8S: C, 52.61; H, 3.74; N, 7.08; Found, C, 52.66; H, 3.77; N, 7.11. 1,3-Dimethoxy-4-((4-(3-methoxyphenyl)piperazin-1-yl)sulfonyl)-7-nitro-9H-xanthen-9-one (1h) Light green solid. Yield: 79.1%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (d, J = 3.0 Hz, 1H, Ar), 8.58–8.54 (m, 1H, Ar), 7.78 (d, J = 8.4 Hz, 1H, Ar), 7.11–6.35 (m, 4H, Ar), 5.57 (s, 1H, Ar), 4.07 (d, J = 6.0 Hz, 6H, OCH3), 3.67 (s, 3H, OCH3), 3.48–3.40 (m, 4H, CH2), 3.24–3.15 (m, 4H, CH2); ESI-MS, Calcd. for C26H26N3O9S+, [M + H]+, 556; Anal. Calcd for C26H25N3O9S: C, 56.21; H, 4.54; N, 7.56; Found, C, 56.26; H, 4.52; N, 7.51. 1,3-Dimethoxy-4-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)-7-nitro-9H-xanthen-9-one (1i) Light yellow solid, Yield: 72.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (s, 1H, Ar), 8.57–8.53 (m, 1H, Ar), 7.78 (d, J = 8.4 Hz, 1H, Ar), 6.88–6.78 (m, 4H, Ar), 5.70 (s, 1H, Ar), 4.07 (d, J = 4.5 Hz, 6H, OCH3), 3.65 (s, 3H, OCH3), 3.48–3.39 (m, 4H, CH2), 3.32–3.20 (m, 4H, CH2); ESI-MS, Calcd. for C26H26N3O9S+, [M + H]+, 556; Anal. Calcd for C26H25N3O9S: C, 56.21; H, 4.54; N, 7.56; Found, C, 56.18; H, 4.62; N, 7.61. 1,3-Dimethoxy-4-((4-(2-methoxyphenyl)piperazin-1-yl)sulfonyl)-7-nitro-9H-xanthen-9-one (1j) Light yellow solid, Yield: 75.2%; Mp: 248–250 °C; 1H NMR (300 MHz, CDCl3, TMS) d 9.08 (d, J = 2.7 Hz, 1H, Ar), 8.50 (m, 1H, Ar), 7.69 (d, J = 9.1 Hz, 1H, Ar), 7.27 (s, 1H, Ar), 7.05–6.81 (m, 3H, Ar), 6.46 (s, 1H, Ar), 4.12 (s, 6H, OCH3), 3.83 (s, 3H, OCH3), 3.63–3.46 (m, 4H), 3.17 (s, 4H); 13C NMR (75 MHz, CDCl3, TMS) d 172.91, 165.30, 164.30, 163.97, 157.70, 157.22, 152.25, 144.67, 129.03, 124.16, 123.12, 122.11, 121.17, 120.97, 119.70, 111.47, 108.40, 106.45, 91.91, 67.29, 67.29, 67.29, 56.46, 55.62, 50.78, 46.06; ESI-MS, Calcd. for C26H26N3O9S+, [M + H]+, 556; Anal. Calcd for C26H25N3O9S: C, 56.21; H, 4.54; N, 7.56; Found, C, 56.15; H, 4.59; N, 7.63. Chem Biol Drug Des 2014
4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-7-nitro-9H-xanthen-9-one (1k) Light yellow solid. Yield: 76.1%; Mp: 240–242 °C; 1H NMR (300 MHz, CDCl3, TMS) d 9.09 (s, 1H, Ar), 8.51 (s, 1H, Ar), 7.70 (s, 1H, Ar), 7.27 (s, 1H, Ar), 7.16–6.93 (m, 3H, Ar), 4.16 (s, 6H, OCH3), 3.78–3.58 (m, 4H, CH2), 3.16–3.07 (m, 4H, CH2), 2.26 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3, TMS) d 173.08, 165.53, 163.66, 158.93, 157.03, 144.45, 144.16, 138.49, 130.99, 129.10, 125.63, 123.10, 122.56, 119.38, 116.90, 108.41, 106.82, 101.19, 90.86, 57.88, 56.98, 52.61, 52.23, 47.29, 46.32, 20.66, 20.66; ESI-MS, Calcd. for C27H28N3O8S+, [M + H]+, 554; Anal. Calcd for C27H27N3O8S: C, 58.58; H, 4.92; N, 7.59; Found, C, 58.64; H, 4.97; N, 7.61. 4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-6-methyl-9H-xanthen-9-one (2a) Light yellow solid. Yield: 65.2%; Mp: 194.4 °C; 1H NMR (600 MHz, DMSO-d6, TMS) d 8.01–7.94 (m, 1H, Ar), 7.43– 7.38 (m, 1H, Ar), 7.33–7.27 (m, 1H, Ar), 7.09–7.01 (m, 1H, Ar), 6.94–6.86 (m, 2H, Ar), 6.75–6.70 (m, 1H, Ar), 4.08 (d, J = 16.7 Hz, 6H, OCH3), 3.59 (s, 8H, CH2), 2.48 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.10 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6, TMS) d 173.61, 165.48, 163.60, 157.22, 154.53, 151.28, 146.39, 137.96, 131.05, 130.00, 126.60, 126.33, 125.79, 125.14, 120.07, 117.83, 117.18, 106.73, 106.36, 93.19, 72.57, 57.71, 57.05, 52.15, 46.41, 29.03, 21.41, 20.54; ESI-MS, Calcd. for C28H31N2O6S+, [M + H]+, 523; Anal. Calcd for C28H30N2O6S: C, 64.35; H, 5.79; N, 5.36; Found, C, 64.236; H, 5.74; N, 5.41. 3-(4-((1,3-Dimethoxy-6-methyl-9-oxo-9H-xanthen-4-yl) sulfonyl)piperazin-1-yl)benzonitrile (2b) Light yellow solid. Yield: 53.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.31 (s, 1H, Ar), 7.94 (d, J = 7.8 Hz, 1H, Ar), 7.38–7.14 (m, 5H, Ar), 6.69 (s, 1H, Ar), 4.04 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 3.36–3.21 (m, 8H, CH2), 2.48 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6, TMS) d 174.89, 165.55, 163.37, 157.95, 154.48, 145.97, 141.45, 130.41, 129.94, 129.50, 126.47, 125.12, 121.89, 120.14, 119.10, 116.92, 113.60, 106.90, 100.87, 90.41, 67.14, 66.25, 57.13, 56.30, 49.97, 44.56, 21.97; ESI-MS, Calcd. for C27H26N3O6S+, [M + H]+, 520; Anal. Calcd for C27H25N3O6S: C, 62.41; H, 4.85; N, 8.09; Found, C, 62.52; H, 4.82; N, 8.11. 4-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-6-methyl-9H-xanthen-9-one (2c) Pale yellow solid; Yield: 77.8%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.31 (s, 1H, Ar), 7.93 (d, J = 8.1 Hz, 1H, Ar), 7.38–6.79 (m, 5H, Ar), 6.69 (s, 1H, Ar), 4.04 (s, 3H, OCH3), 4.02 (s, 3H, OCH 3), 3.34–3.25 (m, 8H, CH 2), 2.48 (s, 3H, CH 3); ESI-MS, Calcd. for C26H 26ClN 2O6S +, [M + H]+ , 529; Anal. Calcd for C26H 25ClN 2O6S: C, 59.03; H, 4.76; N, 5.30; Found, C, 59.07; H, 4.72; N, 5.19. 5
Li et al.
4-((4-(4-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dizmethoxy-6-methyl-9H-xanthen-9-one (2d) Light yellow solid; Yield: 74.6%; Mp: 217.2 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 7.93 (d, J = 7.8 Hz, 1H, Ar), 7.38–7.19 (m, 4H, Ar), 6.93–6.90 (m, 2H, Ar), 6.69 (s, 1H, Ar), 4.04 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 3.35–3.25 (m, 4H, CH2), 3.24–3.11 (m, 4H, CH2), 2.49 (3H, s, CH3); ESIMS, Calcd. for C26H26ClN2O6S+, [M + H]+, 529; Anal. Calcd for C26H25ClN2O6S: C, 59.03; H, 4.76; N, 5.30; Found, C, 59.11; H, 4.73; N, 5.25.
1,3-Dimethoxy-4-((4-(3-methoxyphenyl)piperazin-1-yl)sulfonyl)-6-methyl-9H-xanthen-9-one (2i)
4-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-6-methyl-9H-xanthen-9-one (2e) Light green solid. Yield: 72.1%; Mp: 237.2 °C; H NMR (300 MHz, DMSO-d6, TMS) d 7.93 (d, J = 7.8 Hz, 1H, Ar), 7.39–7.05 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 3.42–3.31 (m, 4H, CH2), 3.04–2.98 (m, 4H, CH2), 2.46 (s, 3H, CH3); ESI-MS, Calcd. for C26H26ClN2O6S+, [M + H]+, 529; Anal. Calcd for C26H25ClN2O6S: C, 59.03; H, 4.76; N, 5.30; Found, C, 59.12; H, 4.68; N, 5.24. 1
4-((4-(2,3-Dichlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dizmethoxy-6-methyl-9H-xanthen-9-one (2f) Light green solid. Yield: 66.5%; Mp: 213.5 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 7.93 (d, J = 8.1 Hz, 1H, Ar), 7.39–7.15 (m, 5H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 3.55 (s, 4H, CH2), 3.10–3.00 (m, 4H, CH2), 2.49 (s, 3H, CH3); ESI-MS, Calcd. for C26H25Cl2N2O6S+, [M + H]+, 563; Anal. Calcd for C26H24Cl2N2O6S: C, 55.42; H, 4.29; N, 4.97; Found, C, 55.47; H, 4.33; N, 4.91. 4-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy6-methyl-9H-xanthen-9-one (2g) Light green solid. Yield: 63.2%; Mp: 228–229 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.13 (d, J = 8.1 Hz, 1H, Ar), 7.33 (s, 1H, Ar), 7.19 (d, J = 8.1 Hz, 1H, Ar), 7.04 (d, J = 6.8 Hz, 2H, Ar), 6.40 (s, 1H, Ar), 4.10 (d, J = 5.9 Hz, 6H, OCH3), 3.72 (t, J = 16.2 Hz, 4H, CH2), 3.25–3.17 (m, 4H, CH2), 2.48 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3, TMS) d 174.86, 165.53, 163.26, 163.06, 157.33, 154.44, 146.00, 141.08, 126.02, 120.28, 119.54, 119.38, 117.41, 116.38, 116.01, 115.63, 107.42, 105.97, 90.71, 57.20, 57.20, 56.09, 56.09, 45.09, 45.09, 21.53; ESI-MS, Calcd. for C26H26FN2O6S+, [M + H]+, 513; Anal. Calcd for C26H25FN2O6S: C, 60.93; H, 4.92; N, 5.47; Found, C, 60.95; H, 4.93; N, 5.49. 1,3-Dimethoxy-6-methyl-4-((4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)sulfonyl)-9H-xanthen-9-one (2h) Light yellow solid. Yield: 78.6%; Mp: 247–248 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.13 (d, J = 8.1 Hz, 1H, Ar), 7.94 (s, 1H, Ar), 7.78 (s, 1H, Ar), 7.62 (d, J = 13.6 Hz, 2H, Ar), 7.30 (d, 6
J = 9.1 Hz, 1H, Ar), 7.19 (d, J = 8.1 Hz, 1H, Ar), 6.45 (d, J = 23.4 Hz, 1H, Ar), 4.17 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 4.00–3.92 (m, 4H, CH2), 3.60 (s, 4H, CH2), 2.48 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3, TMS) d 174.95, 165.15, 162.97, 157.64, 155.15, 154.55, 146.33, 132.87, 131.00, 126.02, 125.04, 124.12, 123.46, 121.56, 120.00, 117.52, 116.22, 108.41, 107.19, 90.26, 57.58, 56.99, 54.12, 54.12, 43.50, 43.50, 21.83; ESI-MS, Calcd. for C27H26F3N2O6S+, [M + H]+, 563; Anal. Calcd for C27H25F3N2O6S: C, 57.65; H, 4.48; N, 4.98; Found, C, 57.69; H, 4.55; N, 5.01.
Light yellow solid. Yield: 73.4%; Mp: 205.5 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.13 (d, J = 8.1 Hz, 1H, Ar), 7.33 (s, 1H, Ar), 7.18 (t, J = 7.6 Hz, 2H, Ar), 6.50 (t, J = 10.9 Hz, 3H, Ar), 6.39 (s, 1H, Ar), 4.08 (d, J = 3.0 Hz, 6H, OCH3), 3.77 (s, 3H, OCH3), 3.48 (dd, J = 16.8, 9.7 Hz, 4H, CH2), 3.29 (s, 4H, CH2), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3, TMS) d 174.80, 165.15, 163.74, 160.18, 159.89, 157.34, 154.17, 145.57, 130.21, 126.02, 126.02, 119.93, 118.51, 117.05, 109.61, 107.79, 103.14, 98.97, 90.34, 67.90, 65.41, 57.27, 56.83, 55.77, 49.68, 45.77, 21.85; ESI-MS, Calcd. for C27H29N2O7S+, [M + H]+, 525; Anal. Calcd for C27H28N2O7S: C, 61.82; H, 5.38; N, 5.34; Found, C, 61.87; H, 5.44; N, 5.42. 1,3-Dimethoxy-4-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)-6-methyl-9H-xanthen-9-one (2j) Light yellow powder. Yield: 72.7%; Mp: 228.5 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.14 (d, J = 8.1 Hz, 1H, Ar), 7.36–6.84 (m, 6H, Ar), 6.40 (s, 1H, Ar), 4.10 (s, 6H, OCH3), 3.80 (s, 3H, OCH3), 3.53–3.30 (m, 4H, CH2), 3.19–3.16 (m, 4H, CH2), 2.49 (s, 3H, CH3); ESI-MS, Calcd. for C27H29N2O7S+, [M + H]+, 525; Anal. Calcd for C27H28N2O7S: C, 61.82; H, 5.38; N, 5.34; Found, C, 61.85; H, 5.36; N, 5.37. 7-bromo-4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)sulfonyl)1,3-Dimethoxy-9H-xanthen-9-one (3a) Light green solid. Yield: 75.6%; Mp: 182–182.6 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.11 (s, 1H, Ar), 6.95–6.73 (m, 5H, Ar), 6.56 (s, 1H, Ar), 4.08 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 3.41– 3.33 (m, 4H, CH2), 2.88–2.81 (m, 4H, CH2), 2.16 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3, TMS) d 173.08, 164.88, 163.08, 157.34, 152.37, 140.26, 137.39, 137.02, 134.46, 129.18, 127.38, 123.16, 119.26, 117.83, 114.20, 108.86, 107.43, 90.71, 89.96, 57.88, 56.46, 55.78, 55.40, 53.96, 43.66, 22.27, 20.45; ESI-MS, Calcd. for C27H28BrN2O6S+, [M + H]+, 589; Anal. Calcd for C27H27BrN2O6S: C, 55.20; H, 4.63; N, 4.77; Found, C, 55.24; H, 4.72; N, 4.78. 3-(4-((7-bromo-1,3-Dimethoxy-9-oxo-9H-xanthen-4-yl) sulfonyl)piperazin-1-yl)benzonitrile (3b) Light yellow powder. Yield: 77.8%; Mp: 218.5 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors
7.15 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.41–3.21 (m, 8H, CH2); ESI-MS, Calcd. for C26H23BrN3O6S+, [M + H]+, 586; Anal. Calcd for C26H22BrN3O6S: C, 53.43; H, 3.79; N, 4.72; Found, C, 53.41; H, 3.82; N, 4.78. 7-bromo-4-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3c) Light yellow powder. Yield: 76.6%; Mp: 244–245 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– 6.77 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.36 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.34–3.25 (m, 8H, CH2); ESI-MS, Calcd. for C25H23BrClN2O6S+, [M + H]+, 595; Anal. Calcd for C25H22BrClN2O6S: C, 50.56; H, 3.73; N, 4.72; Found, C, 50.55; H, 3.66; N, 4.76. 7-bromo-4-((4-(4-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3d) Light green powder. Yield: 72.8%; Mp: 203–204 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– 6.90 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.35 (s, 6H, OCH3), 3.64–3.56 (m, 4H, CH2), 3.15–3.08 (m, 4H, CH2); ESI-MS, Calcd. for C25H23BrClN2O6S+, [M + H]+; Anal. Calcd for C25H22BrClN2O6S: C, 50.56; H, 3.73; N, 4.72; Found, C, 50.71; H, 3.72; N, 4.79. 7-bromo-4-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3e) Light green powder. Yield: 74.6%; Mp: >250 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.36 (s, 1H, Ar), 7.77 (d, J = 7.4 Hz, 1H, Ar), 7.43 (dd, J = 35.8, 8.3 Hz, 3H, Ar), 7.22–6.91 (m, 2H, Ar), 6.43 (s, 1H, Ar), 4.11 (s, 6H, OCH3), 3.58 (s, 4H, CH2), 3.18 (s, 4H, CH2); 13C NMR d (75 MHz, CDCl3, TMS) d 173.36, 165.17, 163.44, 158.91, 156.95, 153.04, 137.38, 130.61, 129.17, 128.14, 124.88, 123.45, 120.59, 119.99, 119.24, 118.10, 107.79, 100.25, 91.02, 57.51, 56.46, 50.75, 50.75, 46.53, 46.53; ESI-MS, Calcd. for C25H23BrClN2O6S+, [M + H]+, 595; Anal. Calcd for C25H22BrClN2O6S: C, 50.56; H, 3.73; N, 4.72; Found, C, 50.48; H, 3.72; N, 4.79. 7-bromo-4-((4-(2,3-Dichlorophenyl)piperazin-1-yl)sulfonyl)1,3-Dimethoxy-9H-xanthen-9-one (3f) Light green powder. Yield: 75.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.95–7.15 (m, 5H, Ar), 6.73 (s, 1H, Ar), 4.06 (d, J = 6.0 Hz, 6H, OCH3), 3.44–3.38 (m, 4H, CH2), 3.12–3.01 (m, 4H, CH2); 13 C NMR (75 MHz, CDCl3, TMS) d 173.58, 165.33, 163.80, 161.41, 157.71, 153.34, 137.07, 133.85, 128.58, 127.74, 127.74, 125.34, 123.84, 119.91, 118.87, 118.19, 107.94, 106.66, 91.00, 56.68, 56.47, 51.04, 51.04, 460.5, 46.05; ESI-MS, Calcd. for C25H22BrCl2N2O6S+, [M + H]+, 629; Anal. Calcd for C25H21BrCl2N2O6S: C, 47.79; H, 3.37; N, 4.46; Found, C, 47.88; H, 3.36; N, 4.49. Chem Biol Drug Des 2014
7-bromo-4-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3g) Light yellow powder. Yield: 76.9%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.95–6.90 (m, 6H, Ar), 6.72 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.34–3.28 (m, 4H, CH2), 3.14–3.05 (m, 4H, CH2); ESI-MS, Calcd. for C25H23BrFN2O6S+, [M + H]+, 579; Anal. Calcd for C25H22BrFN2O6S: C, 52.00; H, 3.84; N, 4.85; Found, C, 52.06; H, 3.88; N, 4.89. 7-bromo-1,3-Dimethoxy-4-((4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)sulfonyl)-9H-xanthen-9-one (3h) Light green powder. Yield: 72.7%; Mp: 227–232 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.95–7.05 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.34–3.24 (m, 8H, CH2); ESIMS, Calcd. for C26H23BrF3N2O6S+, [M + H]+, 629; Anal. Calcd for C26H22BrF3N2O6S: C, 49.77; H, 3.53; N, 4.46; Found, C, 49.73; H, 3.58; N, 4.51. 7-bromo-1,3-Dimethoxy-4-((4-(3-methoxyphenyl)piperazin1-yl)sulfonyl)-9H-xanthen-9-one (3i) Light yellow powder. Yield: 74.3%; Mp: 243–244 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– 6.35 (m, 7H, Ar), 4.06 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.22–3.18 (m, 8H, CH2); ESI-MS, Calcd. for C26H26BrN2O7S+, [M + H]+, 591; Anal. Calcd for C26H25BrN2O7S: C, 52.98; H, 4.27; N, 4.75; Found, C, 52.91; H, 4.36; N, 4.76. 7-bromo-1,3-Dimethoxy-4-((4-(4-methoxyphenyl)piperazin1-yl)sulfonyl)-9H-xanthen-9-one (3j) Light green powder. Yield: 76.2%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96–6.72 (m, 7H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.34–3.28 (m, 4H, CH2), 3.12–3.04 (m, 4H, CH2); ESI-MS, Calcd. for C26H26BrN2O7S+, [M + H]+, 591; Anal. Calcd for C26H25BrN2O7S: C, 52.98; H, 4.27; N, 4.75; Found, C, 52.85; H, 4.15; N, 4.72. 7-bromo-1,3-Dimethoxy-4-((4-(2-methoxyphenyl)piperazin1-yl)sulfonyl)-9H-xanthen-9-one (3k) Light green powder. Yield: 72.3%; Mp: >250 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.33 (d, J = 2.4 Hz, 1H, Ar), 7.75 (dd, J = 8.8, 2.4 Hz, 1H, Ar), 7.44 (d, J = 8.8 Hz, 1H, Ar), 7.11 (s, 1H, Ar), 7.03–6.75 (m, 3H, Ar), 6.39 (d, J = 13.2 Hz, 1H, Ar), 4.10 (d, J = 5.5 Hz, 6H, OCH3), 3.88 (s, 3H, OCH3), 3.66 (s, 4H, CH2), 3.24 (s, 4H, CH2); 13 C NMR (75 MHz, CDCl3, TMS) d 173.06, 165.14, 163.42, 157.33, 153.04, 151.62, 140.38, 139.50, 137.01, 129.18, 123.47, 121.34, 119.53, 118.78, 117.81, 112.16, 107.81, 106.74, 91.05, 56.83, 56.48, 56.48, 55.03, 51.95, 51.13, 46.08; ESI-MS, Calcd. for C26H26BrN2O7S+, 7
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[M + H]+, 591; Anal. Calcd for C26H25BrN2O7S: C, 52.98; H, 4.27; N, 4.75; Found, C, 52.96; H, 4.37; N, 4.66.
Table 1: Structure and ACAT inhibition rate (Inh.) of 1a–1k, 2a– 2j, and 3a–3k at 10 µg/mL concentration Sample
Results and Discussion Evaluation of ACAT inhibitory activities The inhibitory activity of the newly synthesized compounds in vitro against ACAT was firstly studied at a concentration of 10 lg/mL. From the data summarized in Table 1, it was concluded that most of the title compounds showed certain inhibitory activities against ACAT, of which compounds 1b, 1c, 1e–1g, 1i, 2b, 2d, 2e, 3d–3f, and 3h–3j exhibited moderate inhibitory activities. Among them, compounds 1c, 1e, 1f, 1i, 2b, 2d, 2e, and 3d exhibited higher inhibitory activities than the positive control Sandoz 58-035 (inhibition rate = 55.00%) with the inhibition rate 66.53%, 91.52%, 79.47%, 60.09%, 82.43%, 84.53%, and 71.16%, respectively. Moreover, compounds 1c, 1e, 1f, 1i, 2d, 2e, and 3d exhibited higher inhibitory activity than that of the leading compound 14 (inhibitory rate = 64.80%). To further investigate the inhibitory activities of these new compounds, IC50 values of some selected compounds were measured, which was shown in Table 2. Results showed that the selected compounds 1c, 1e, 1f, 1g, 1i, 2b, 2d, 2e, 3d, and 3e exhibited strong inhibitory activities against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Moreover, compounds 1e, 1f, 2d, and 2e exhibited excellent inhibitory activities with the IC50 values 4.42, 8.78, 7.17, and 5.57 lM, respectively, which were more potent than the leading compound 14.
Structure–activity relationship Thus, a preliminary structure–activity relationship (SAR) can be summarized. In general, these three series of xanthone sulfonamides also exhibited the inhibitory activities against ACAT when compared with the leading compound 14, and some compounds showed higher inhibitory activities. There was no significant influence on inhibitory activity, whether the methyl group or the bromine atom was introduced to xanthone framework. But the compounds 1a–1k with nitro group introduced, a strong electron withdrawing group, exhibited more potent inhibitory activities than that with methyl group and bromine atom. When different groups were introduced to the side phenyl ring, compounds showed different levels of inhibitory activities. It can be summarized that compounds with a chlorine group on the phenyl ring showed strong inhibitory activity against ACAT usually. And among these, compounds with chlorine substituted at ortho and para positions of the phenyl ring exhibited more potent inhibitory effect than those with chlorine substituted at meta position. The results reminded us that to introduce a strong electron withdrawing group to the xanthone framework and the chlorine atom to the side phenyl ring was an effective way in improving the inhibitory activities of the compounds against ACAT. Further study was in progress. 8
Sandoz 58-035a 14 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 2a 2b 2c 2d
R
3-CN 3-Cl 4-Cl 2-Cl 2,4-di-Cl 4-F 3-CF3 3-OCH3 4-OCH3 2-OCH3 2,3-di-CH3 2,3-di-CH3 3-CN 3-Cl 4-Cl
% Inh.
Sample
R
% Inh.
55.00
2e
2-Cl
84.53
64.80 4.83 43.67 66.53 34.99 91.52 79.47 53.45 17.83 60.09 34.01 4.83 17.83 60.09 34.01 82.43
2f 2g 2h 2i 2j 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k
2,3-di-Cl 4-F 3-CF3 3-OCH3 4-OCH3 2,3-di-CH3 3-CN 3-Cl 4-Cl 2-Cl 2,3-di-Cl 4-F 3-CF3 3-OCH3 4-OCH3 2-OCH3
18.43 17.57 38.67 37.81 14.98 34.76 23.35 38.24 71.16 52.10 40.71 1.61 48.45 42.78 41.00 26.42
a
Sandoz 58-035, an inhibitor toward ACAT, as a positive control, at 10 µg/mL.
Docking To further understand the action mechanism between the synthesized compounds and the target enzyme, compound 14 (the purple stick) and 1e (the green stick) were docked into the active site of ACAT-2 (PDB code: 1WL4; Figure 3).The docking results revealed that both compound 14 and 1e could occupy the active site of ACAT-2, which might contribute to their potent inhibitory activities against ACAT. To sum up, both the xanthone core of compound 14 and 1e extended toward the back hydrophobic pocket, composed of Gln186, Arg223, Ser226, Asn227, Ala230, Ile349, and Ala350, and the two oxygen atoms of the xanthone core along with the sulfonamide formed two hydrogen bonds with Arg223. Compared with compound 14, however, the oxygen atom of the sulfonamide could form another hydrogen bond with Arg223, and the oxygen atom of seven-substituted nitro group also formed a hydrogen bond with Gln186. Thus, because of the second extra H-bond, the aryl piperazine moiety of 1e was better inserted into the hydrophobic pocket composed of Met231, Leu234, Lys235, Thr247, and Table 2: Structure and ACAT inhibition concentration (50% Inh.) of selected compounds Sample Sandoz 58-035 14 1c 1e 1f 1g
R
4-Cl 2,4-di-Cl 4-F 3-CF3
IC50 (lM)
Sample
R
IC50 (lM)
19.87
1i
4-OCH3
21.92
18.23 17.68 4.42 8.78 21.06
2b 2d 2e 3d 3e
3-CN 4-Cl 2-Cl 4-Cl 2-Cl
20.32 7.17 5.57 19.13 18.87
Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors A
B
C
Figure 3: Computed binding geometry of the xanthone sulfonamides 14 and 1e in the active site of ACAT-2 (compound 14: the purple stick, 1e: the green stick).
Pro248. Therefore, the nitro group might be the key group in the interaction between the compound 1e and the receptor, which was consistent with former SAR. The results above demonstrated that these novel xanthone sulfonamides had stronger interactions with ACAT-2 compared with compound 14, which contributed to their strong inhibitory activities against ACAT, and further study was in progress.
Conclusion In conclusion, three series of 1,3-Dimethoxyxanthone-4-sulfonamide derivatives were designed and synthesized in high yields. Preliminary pharmacological evaluation showed that most title compounds had good inhibitory activity against ACAT. Interestingly, the synthetic xanthone sulfonamides 1a–1k with nitro group showed higher ACAT inhibitory activities than two other series, and in one separate series, the inhibitory activities of the compounds were greatly dependent on the various substituents on the phenyl. Compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more potent than the positive control Sandoz 58-035. Computational docking experiments indicated that the hydrophilic H-bond interaction, the hydrophobic interaction, and the narrow
Chem Biol Drug Des 2014
hydrophobic cleft might contribute to the potent inhibitory activities against ACAT.
Acknowledgments This work was supported by grants from Science & Technology Commission of Shanghai Municipality (Nos 054319909 and 08JC1405500) and Shanghai Leading Academic Discipline Project (No. B906).
Conflict of interest There is no conflict of interests among the authors.
References 1. Brown W.V. (1990) Review of clinical trials: proving the lipid hypothesis. Eur Heart J;11(Suppl H):15–20. 2. Tremblay A.J., Lamarche B., Guay V., Charest A., Lemelin V., Couture P. (2013) Short-term, high-fat diet increases the expression of key intestinal genes
9
Li et al.
involved in lipoprotein metabolism in healthy men. Am J Clin Nutr;98:32–41. 3. Brown M.S., Dana S.E., Goldstein J.L. (1975) Cholesterol ester formation in cultured human fibroblasts. Stimulation by oxygenated sterols. J Biol Chem;250:4025–4027. 4. Grundy S.M. (1978) Cholesterol metabolism in man. West J Med;128:13–25. 5. Grundy S.M., Balady G.J., Criqui M.H., Fletcher G., Greenland P., Hiratzka L.F., Houston-Miller N., Kris-Etherton P., Krumholz H.M., LaRosa J., Ockene I.S., Pearson T.A., Reed J., Washington R., Smith S.C. Jr (1998) Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction. American Heart Association. Circulation;97:1876–1887. 6. Papacleovoulou G., Abu-Hayyeh S., Nikolopoulou E., Briz O., Owen B.M., Nikolova V., Ovadia C. et al. (2013) Maternal cholestasis during pregnancy programs metabolic disease in offspring. J Clin Invest;123:3172– 3181. 7. Lee O., Chang C.C., Lee W., Chang T.Y. (1998) Immunodepletion experiments suggest that acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines. J Lipid Res;39:1722–1727. 8. Zamorano-Leon J.J., Fernandez-Sanchez R., Lopez Farre A.J., Lapuente-Tiana L., Alonso-Orgaz S., Sacristan D., Junquera D., Delhon A., Conesa A., MateosCaceres P.J., Macaya C. (2006) Direct effect of F12511, a systemic inhibitor of Acyl-CoA cholesterol acyltransferase on bovine aortic endothelial cells. J Cardiovasc Pharmacol;48:128–134. 9. An S., Park Y.D., Paik Y.K., Jeong T.S., Lee W.S. (2007) Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon. Bioorg Med Chem Lett;17:1112–1116. 10. Pal P., Gandhi H., Giridhar R., Yadav M.R. (2013) ACAT inhibitors: the search for novel cholesterol lowering agents. Mini Rev Med Chem;13:1195–1219. 11. Puglielli L., Konopka G., Pack-Chung E., Ingano L.A., Berezovska O., Hyman B.T., Chang T.Y., Tanzi R.E., Kovacs D.M. (2001) Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol;3:905–912. 12. Alger H.M., Brown J.M., Sawyer J.K., Kelley K.L., Shah R., Wilson M.D., Willingham M.C., Rudel L.L. (2010) Inhibition of acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization. J Biol Chem;285:14267–14274. 13. Meuwese M.C., Franssen R., Stroes E.S., Kastelein J.J. (2006) And then there were acyl coenzyme A:
10
cholesterol acyl transferase inhibitors. Curr Opin Lipidol;17:426–430. 14. Li H.Y., DeLucca I., Boswell G.A., Billheimer J.T., Drummond S., Gillies P.J., Robinson C. (1997) Design, synthesis and structure-activity relationship studies of novel 4,4-bis(trifluoromethyl)imidazolines as acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors and antihypercholesterolemic agents. Bioorg Med Chem;5: 1345–1361. 15. Terasaka N., Miyazaki A., Kasanuki N., Ito K., Ubukata N., Koieyama T., Kitayama K., Tanimoto T., Maeda N., Inaba T. (2007) ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice. Atherosclerosis;190: 239–247. 16. Lee M.K., Moon S.S., Lee S.E., Bok S.H., Jeong T.S., Park Y.B., Choi M.S. (2003) Naringenin 7-sO-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats. Bioorg Med Chem;11:393–398. 17. Lada A.T., Davis M., Kent C., Chapman J., Tomoda H., Omura S., Rudel L.L. (2004) Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. J Lipid Res;45:378–386. 18. Lee K., Cho S.H., Lee J.H., Goo J., Lee S.Y., Boovanahalli S.K., Yeo S.K., Lee S.J., Kim Y.K., Kim D.H., Choi Y., Song G.Y. (2013) Synthesis of a novel series of 2-alkylthio substituted naphthoquinones as potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors. Eur J Med Chem;62:515–525. 19. Harris N.V., Smith C., Ashton M.J., Bridge A.W., Bush R.C., Coffee E.C., Dron D.I. et al. (1992) Acyl-CoA: cholesterol O-acyl transferase (ACAT) inhibitors. 1. 2(Alkylthio)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. J Med Chem;35:4384–4392. 20. O’Brien P.M., Sliskovic D.R., Picard J.A., Lee H.T., Purchase C.F., Roth B.D., White A.D. et al. (1996) Inhibitors of acyl-CoA: cholesterol O-acyltransferase. Synthesis and pharmacological activity of (+/ )-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide and structurally related tetrazole amide derivatives. J Med Chem;39:2354–2366. 21. Hu H., Liao H., Zhang J., Wu W., Yan J., Yan Y., Zhao Q., Zou Y., Chai X., Yu S., Wu Q. (2010) First identification of xanthone sulfonamides as potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors. Bioorg Med Chem Lett;20:3094–3097. 22. Grover P.K., Shah G.D., Shah R.C. (1955) Xanthones. Part IV. A new synthesis of hydroxyxanthones and hydroxybenzophenones. J Chem Soc;3982–3985.
Chem Biol Drug Des 2014
Synthesis, Biological Evaluation, and Molecular Docking Studies of Xanthone Sulfonamides as ACAT Inhibitors Xiang Li, Yan Zou, Qingjie Zhao, Yan Yang, Maocheng Wu, Ting Huang, Honggang Hu* and Qiuye Wu* Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China *Corresponding authors: Honggang Hu, [email protected]; Qiuye Wu, [email protected] Xiang Li and Yan Zou contributed equally to this work. Three series of xanthone sulfonamides were synthesized, and their inhibitory activities against acyl-CoA: cholesterol acyltransferase (ACAT) were evaluated. Results showed that most of the title compounds exhibited strong inhibitory activity against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Computational docking experiments indicated that the interaction between inhibitors and ACAT contained the H-bond interaction, the hydrophobic interaction, and the narrow hydrophobic cleft. Key words: ACAT, docking, Structure–activity relationship, sulfonamide, xanthone Received 6 May 2014, revised 24 July 2014 and accepted for publication 13 August 2014
Arteriosclerosis, as the most common sclerosis, has become the underlying cause of most myocardial infractions. Arteriosclerosis is usually caused by an excess accumulation of cholesteryl esters in macrophages and smooth muscle cells in the arterial wall (1–3). Thus, hypercholesterolemia has been identified as an independent risk factor for coronary heart disease. Recent studies have demonstrated that controlling the level of serum cholesterol is an effective way in the treatment of atherosclerosis (4–6). As Acyl-CoA: cholesterol acyltransferase (EC 2.3.1.26, ACAT), which plays a key role in the absorption and metabolism of cholesterol, is principally responsible for the intracellular esterification of cholesterol. The inhibition of ACAT is expected to reduce plasma lipid levels by inhibiting ª 2014 John Wiley & Sons A/S. doi: 10.1111/cbdd.12419
intestinal cholesterol absorption and thus to prevent progression of atherosclerotic lesions (7–9). Therefore, ACAT has become an important target enzyme in the treatment of the arteriosclerosis (10–12). In this area, considerable efforts have been made directly to the development of potent ACAT inhibitors in recent years (13–20). Our group has always focused on the study of the xanthone compounds, including synthesizing novel xanthone compounds and evaluating the inhibitory activities against ACAT. In our previous study, a series of 1,3,6,7tetramethoxyxanthone-4-sulfonamide derivatives were successfully synthesized as potent ACAT inhibitors for the first time, of which compound 14, shown in Figure 1, was proved to be more potent than the positive control Sandoz 58-035 (21) (an ACAT inhibitor, from Sigma). In an effort to develop new xanthone derivatives with potent ACAT inhibitory effect, further optimization and modification have been conducted. Based on the previous study, the present work had focused on introducing different groups to the xanthone sulfonamide framework to further study the structure and activity relationships. As shown in Figure 2, three series of 1,3-Dimethoxyxanthone4-sulfonamide derivatives were designed, synthesized, and evaluated for their ACAT inhibitory activities. In addition, a docking study of these compounds was performed in an attempt to understand their mechanism of action on the ACAT-2, an expected target enzyme of hypercholesterolemia and atherosclerosis.
Experimental Chemistry The synthetic route designed for the novel xanthone sulfonamides was shown in Scheme 1. Three key intermediates 8–10 were prepared from the substituted salicylic acid. Herein, Eaton’s reagent (phosphorus pentoxide in methanesulfonic acid) was successfully used to promote the cyclization in high yield under mild conditions. This method was inexpensive and Eaton’s reagent could be destroyed conveniently with water, thus avoiding the usage of PPA (Polyphosphoric acid) in the traditional Grover, Shah and Shah reaction (22). Compounds 11–13 were obtained by the sulfonylation of 8–10 using chlorosulfonic acid in high yield. Finally, nucleophilic substitutions of 11–13 with 1
Li et al.
Figure 1: The structure of xanthone sulfonamide 14 in our previous study.
the corresponding substituted aryl piperazines furnished the target compounds 1a–1k, 2a–2j, and 3a–3k. All new compounds were characterized by NMR and MS.
Fluorescent ACAT assay HepG2 cells were cultured in low-glucose DMEM supplement with 100 U/mL streptomycin and penicillin. Twenty thousand cells were plated per well on 96-well culture plates and grew overnight at 37 °C. Cells were incubated in medium containing either different samples, Sandoz 58-035 (positive control) or without sample (negative control and blank control) for 1 h. Then, NBD-cholesterol with final concentration of 2 lg/mL was added into the medium except for blank control and incubated overnight. NBDcholesterol was added from a 1 mg/mL stock in ethanol, and ethanol concentrations did not exceed 0.1%. After incubation, medium was removed, and the cells were washed three times with 20 lL PBS buffer. Plates were read fluorescence from the bottom using WALLAC Victor 2 plate reader (PerkinElmer, Waltham, MA, USA) equipped with 485-nm excitation and 535-nm emission filters. The inhibition rate was calculated based on fluorescence as the FSamfollowing equation: Inhibition % = (FNegative FBlank) 9 100%. ple FBlank)/(FNegative
Molecular docking All the molecular modeling calculations were performed using SYBYL 6.9 version (Tripos International, St. Louis, MO, USA). And the structures of the compounds were €ckle partial atomic charges. assigned with Gasteiger–Hu Energy minimization was performed using the Tripos force field, Powell optimization method, and MAXIMIN2 minimizer with a convergence criterion 0.001 Kcal/mol A. Simulated annealing was then performed. The system was heated to 1000 K for 1.0 ps and then annealed to 250 K for 1.5 ps. The annealing function was exponential; 50 such cycles of annealing were run and the resulting 50 conformers were optimized using methods described above. The lowest energy conformation was selected. All the other parameters were default value.
Chemistry: general procedures Melting points were measured on a Yamato MP-21 melting point apparatus and were uncorrected. NMR spectra were recorded in CDCl3 or DMSO-d6 unless otherwise indicated with a Bruker spectrometer (Bruker Biospin Inc., Zurich, Switzerland), using TMS as internal standard. ESI mass spectra were performed on an API-3000 LC-MS spectrometer (Applied Biosystems Inc., Foster City, CA, USA). Elemental analysis was undertaken with an Italian MOD 1106 analyzer (CarloErba., Italian, Milan, Italy) at the Analysis Center of Shanghai Institute of Pharmaceutical Industry. Column chromatography was carried out on silica gel (200–300 mesh). The solvents and reagents were used as received or dried prior to use as needed. All reactions were monitored using thin-layer chromatography (TLC) on silica gel plates. Detection was effected by examination under UV light.
1,3-Dimethoxy-7-nitro-9H-xanthen-9-one (8) 2-Hydroxy-5-nitrobenzoic acid (9.1 g, 0.050 mol) and 1,3,5-trimethoxybenzene (8.5 g, 0.055 mol) were added in a three-necked flask (500 mL) and then dropped the fresh
Figure 2: The structures of all the compounds we designed and synthesized.
2
Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors
Scheme 1: Reagents and conditions: (a) P2O5/CH3SO3H, 110 °C, 2.5 h, 78.2–83.74%; (b) HSO3Cl, 0 °C, 4 h, 78.9–82.1%; and (c) 1,4-dioxane, K2CO3, piperazine, r.t., overnight, 53.3–78.9%.
Eaton’s reagent (100 mL) slowly by a constant pressure dropping funnel. The reaction mixture was kept at 110 °C for 2.5 h. When it was cooled, the mixture was quenched by adding ice water mixture, and then the mixture was stirred for 2 h to give a precipitate which was filtered, washed with water until it was deemed neutral. At last, the precipitate was recrystallized from methanol to give a yellow solid with yield of 78.2%. 1H NMR (300 MHz, DMSO-d6, TMS) d 9.14 (d, J = 2.4 Hz, 1H, Ar), 8.47 (dd, J = 9.6, 3.0 Hz, 1H, Ar), 7.50 (d, J = 6.6 Hz, 1H, Ar), 6.55 (d, J = 1.8 Hz, 1H, Ar), 6.42 (d, J = 1.8 Hz, 1H, Ar), 4.01 (s, 3H, OCH3), 3.95 (s, 3H, OCH3); ESI-MS, Calcd. for C15H12NO6+, [M + H]+, 302; Anal. Calcd for C15H11NO6: C, 59.80; H, 3.68; N, 4.65; Found, C, 59.72; H, 3.58; N, 4.77. Compounds 9 and 10 were prepared using the same procedure as compound 8 described above.
1,3-Dimethoxy-6-methyl-9H-xanthen-9-one (9) The starting material was 2-hydroxy-4-methylbenzoic acid. Yield: 81.7%. 1H NMR (300 MHz, DMSO-d6, TMS) d 8.17 (d, J = 7.8 Hz, 1H, Ar), 7.16–7.13 (m, 2H, Ar), 6.48 (d, J = 2.4 Hz, 1H, Ar), 6.34 (d, 1H, J = 2.4 Hz, Ar), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 2.48 (s, 3H, CH3); ESI-MS, Calcd. for C16H15O4+, [M + H]+, 271; Anal. Calcd for C16H14O4: C, 71.10; H, 5.22; Found, C, 71.22; H, 5.25.
7-bromo-1,3-Dimethoxy-9H-xanthen-9-one (10) The starting material was 5-bromo-2-hydroxybenzoic acid. Yield: 83.4%. 1H NMR (300 MHz, DMSO-d6, TMS) d 8.38 (d, J = 1.8 Hz, 1H, Ar), 7.70 (dd, J = 8.7, 2.4 Hz, 1H, Ar), 7.25 (t, J = 3.6 Hz, 1H, Ar), 6.49 (d, J = 2.4 Hz, 1H, Ar), 6.35 (d, J = 2.4 Hz, 1H, Ar), 4.12 (s, 3H, OCH3), 3.96 (s, 3H, OCH3); ESI-MS, Calcd. for C15H12BrO4+, [M + H]+, 335; Anal. Calcd for C15H11BrO4: C, 53.76; H, 3.31; Found, C, 53.88; H, 3.19. Chem Biol Drug Des 2014
1,3-Dimethoxy-7-nitro-9-oxo-9H-xanthene-4sulfonyl chloride (11) To a stirred solution of 1,3-Dimethoxy-7-nitro-9H-xanthen9-one (8) (3.1 g, 0.011 mol) dissolved in dichloromethane (20 mL), chlorosulfonic acid (20 mL) was dropped slowly. The temperature was kept at 25 °C about 2.5 h, and the reaction was deemed completely by TLC analysis. Then the product was poured into the ice water slowly and extracted with ethyl acetate (4 9 100 mL). The combined organic layers were washed with brine (2 9 100 mL), dried over anhydrous sodium sulfate, and removed under vacuum to give the crude product, which was recrystallized from ethyl acetate to give the pure product with yield of 82.1%. The obtained product was used in next reaction immediately. 1H NMR (300 MHz, DMSO-d6, TMS) d 8.72 (d, J = 2.7 Hz, 1H, Ar), 8.53 (dd, J = 9.1, 2.9 Hz, 1H, Ar), 7.67 (dd, J = 33.3, 9.1 Hz, 1H, Ar), 6.92–6.45 (m, 1H, Ar), 3.93 (dd, J = 15.5, 7.4 Hz, 6H, OCH3); 13C NMR (75 MHz, DMSO-d6, TMS) d 174.53, 163.87, 161.82, 158.10, 155.14, 143.62, 129.38, 122.27, 119.65, 119.53, 105.43, 96.67, 93.38, 57.13, 56.88; ESI-MS, Calcd. for C15H11ClNO8S+, [M + H]+, 400; Anal. Calcd for C15H10ClNO8S: C, 45.07; H, 2.52; N, 3.50; Found, C, 45.12; H, 2.42; N, 3.55. Compounds 12 and 13 were prepared using the same procedure as compound 11 described above.
1,3-Dimethoxy-6-methyl-9-oxo-9H-xanthene-4sulfonyl chloride (12) The starting material was 1,3-Dimethoxy-6-methyl-9H-xanthen-9-one (9). Yield: 80.0%. 1H NMR (600 MHz, CDCl3, TMS) d 8.18 (dd, J = 21.4, 8.1 Hz, 1H, Ar), 7.17 (d, J = 8.1 Hz, 1H, Ar), 6.52 (d, J = 1.8 Hz, 1H, Ar), 6.37 (d, J = 1.7 Hz, 1H, Ar), 4.01 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 2.51 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3, TMS) d 175.48, 167.29, 164.92, 159.94, 155.03, 144.60, 125.42, 121.16, 116.32, 113.46, 107.17, 95.21, 92.80, 56.89, 56.55, 21.54; ESI-MS, Calcd. for C16H14ClO6S+, 3
Li et al.
[M + H]+, 369; Anal. Calcd for C16H13ClO6S: C, 52.11; H, 3.55; Found, C, 52.15; H, 3.76.
7-bromo-1,3-Dimethoxy-9-oxo-9H-xanthene-4sulfonyl chloride (13) The starting material was 7-bromo-1,3-Dimethoxy-9H-xanthen-9-one (10). Yield: 78.9%. 1H NMR (600 MHz, CDCl3, TMS) d 7.84 (dd, J = 8.8, 2.5 Hz, 1H, Ar), 7.65 (d, J = 2.5 Hz, 1H, Ar), 7.53 (d, J = 8.8 Hz, 1H, Ar), 7.05 (dd, J = 27.3, 8.8 Hz, 1H, Ar), 4.19 (s, 3H, OCH3), 4.17 (s, 3H, OCH3); 13C NMR (150 MHz, CDCl3, TMS) d 173.06, 167.15, 163.93, 156.92, 152.98, 137.82, 128.70, 120.17, 118.66, 113.74, 109.03, 106.80, 91.05, 57.20, 56.41; ESI-MS, Calcd. for C15H11BrClO6S+, [M + H]+, 435; Anal. Calcd for C15H10BrClO6S: C, 41.54; H, 2.32; Found, C, 41.42; H, 2.39.
General procedure for the preparation of target compounds 1a–1k To a solution of 1,3-Dimethoxy-7-nitro-9-oxo-9H-xanthene-4-sulfonyl chloride (0.2 g, 0.5 mmol) in dioxane, corresponding aryl piperazine (0.6 mmol) was added, and the reaction was stirred at room temperature for 12 h. Then the product was poured into ice water, and extracted with dichloromethane (4 9 50 mL). The combined organic layers were washed with brine (2 9 100 mL), dried over anhydrous sodium sulfate, and removed under vacuum to give the crude product, which was purified by chromatography on silica using a mixture of dichloromethane and methanol (v/v = 50:1) as eluent to give the target compounds. Compounds 2a–j were synthesized from 1,3-Dimethoxy-6methyl-9-oxo-9H-xanthene-4-sulfonyl chloride using the same procedure as above. Compounds 3a–k were synthesized from 1,3-Dimethoxy7-bromo-9-oxo-9H-xanthene-4-sulfonyl chloride using the same procedure as above. The title compounds were characterized as follows. 3-(4-((1,3-Dimethoxy-7-nitro-9-oxo-9H-xanthen-4-yl)sulfonyl)piperazin-1-yl)benzonitrile (1a) Light yellow solid. Yield: 70.2%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.73 (d, 1H, J = 2.7 Hz, Ar), 8.58–8.54 (m, 1H, Ar), 7.77 (d, J = 9.3 Hz, 1H, Ar), 7.38– 7.14 (m, 4H, Ar), 6.77 (1H, s, Ar), 4.06 (d, J = 5.4 Hz, 6H, OCH3), 3.65–3.54 (m, 4H, CH2), 3.28–3.13 (m, 4H, CH2); 13 C NMR (150 MHz, CDCl3, TMS) d 173.37, 165.56, 163.82, 157.13, 149.52, 146.13, 144.47, 130.55, 128.43, 126.64, 124.74, 122.80, 122.34, 121.43, 119.69, 118.42, 113.58, 108.62, 102.54, 91.91, 56.91, 56.30, 49.75, 46.06, 45.98, 44.78; ESI-MS, Calcd. for C26H23N4O8S+, [M + H]+, 551; Anal. Calcd for C26H22N4O8S: C, 56.72; H, 4.03; N, 10.18; Found, C, 56.88; H, 4.16; N, 10.04. 4
4-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy-7-nitro-9H-xanthen-9-one (1b) Light yellow powder. Yield: 72.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.72 (d, J = 2.7 Hz, 1H, Ar), 8.56–8.52 (m, 1H, Ar), 7.80 (d, J = 8.9 Hz, 1H, Ar), 7.40– 7.02 (m, 4H, Ar), 6.79 (s, 1H, Ar), 4.08 (d, J = 5.3 Hz, 6H, OCH3), 3.40 (s, 4H, CH2), 3.03 (s, 4H, CH2); ESI-MS, Calcd. for C25H23ClN3O8S+, [M + H]+, 560; Anal. Calcd for C25H22ClN3O8S: C, 53.62; H, 3.96; N, 7.50; Found, C, 53.66; H, 3.94; N, 7.41. 4-((4-(4-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy-7-nitro-9H-xanthen-9-one (1c) Light yellow powder. Yield: 76.8%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.79–8.43 (m, 3H, Ar), 7.76 (dd, J = 9.1, 6.6 Hz, 2H, Ar), 7.20 (d, J = 8.9 Hz, 1H, Ar), 6.91 (d, J = 9.0 Hz, 1H, Ar), 6.76 (s, 1H, Ar), 4.07 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 3.67–3.58 (m, 4H, CH2), 3.25–3.14 (m, 4H, CH2); 13C NMR (75 MHz, DMSO-d6, TMS) d 172.46, 165.08, 164.50, 157.45, 157.10, 149.51, 144.01, 129.95, 129.02, 128.80, 122.78, 122.57, 121.87, 120.15, 119.07, 117.98, 106.67, 105.98, 93.65, 66.93, 66.48, 57.82, 57.13, 45.83, 45.61; ESI-MS, Calcd. for C25H23ClN3O8S+, [M + H]+, 560; Anal. Calcd for C25H22ClN3O8S: C, 53.62; H, 3.96; N, 7.50; Found, C, 53.69; H, 3.91; N, 7.61. 4-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-7-nitro-9H-xanthen-9-one (1d) Light yellow powder. Yield: 74.6%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.73 (s, 1H, Ar), 8.57–8.53 (m, 1H, Ar), 7.78 (d, J = 9.3 Hz, 1H, Ar), 7.20–6.85 (m, 4H, Ar), 6.77 (s, 1H, Ar), 4.06 (d, J = 5.4 Hz, 6H, OCH3), 3.66–3.32 (m, 4H, CH2), 3.27–3.23 (m, 4H, CH2); ESI-MS, Calcd. for C25H23ClN3O8S+, [M + H]+, 560; Anal. Calcd for C25H22ClN3O8S: C, 53.62; H, 3.96; N, 7.50; Found, C, 53.49; H, 4.01; N, 7.45. 4-((4-(2,4-Dichlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-7-nitro-9H-xanthen-9-one (1e) Light green solid. Yield: 77.5%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (d, J = 2.7 Hz, 1H, Ar), 8.56–8.52 (m, 1H, Ar), 7.78 (d, J = 9.0 Hz, 1H, Ar), 7.32– 7.15 (m, 3H, Ar), 6.79 (s, 1H, Ar), 4.08 (d, J = 6.0 Hz, 6H, OCH3), 3.40 (s, 4H, CH2), 3.05 (s, 4H, CH2); ESI-MS, Calcd. for C25H22Cl2N3O8S+, [M + H]+, 594; Anal. Calcd for C25H21Cl2N3O8S: C, 50.51; H, 3.56; N, 7.07; Found, C, 50.56; H, 3.54; N, 7.01. 4-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy7-nitro-9H-xanthen-9-one (1f) Light yellow powder. Yield: 74.7%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (d, J = 2.7 Hz, 1H, Ar), Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors
8.57–8.53 (m, 1H, Ar), 7.78 (d, J = 9.3 Hz, 1H, Ar), 7.06– 6.90 (m, 4H, Ar), 6.77 (s, 1H, Ar), 4.07 (d, J = 6.2 Hz, 6H, OCH3), 3.55 (s, 4H, CH2), 3.20–3.11 (m, 4H, CH2); ESIMS, Calcd. for C25H23FN3O8S+, [M + H]+, 544; Anal. Calcd for C25H22FN3O8S: C, 55.24; H, 4.08; N, 7.73; Found, C, 55.21; H, 3.98; N, 7.81. 1,3-Dimethoxy-7-nitro-4-((4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)sulfonyl)-9H-xanthen-9-one (1g) Light yellow solid. Yield: 78.9%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.73 (d, J = 3.0 Hz, 1H, Ar), 8.57–8.53 (m, 1H, Ar), 7.77 (d, J = 8.4 Hz, 1H, Ar), 7.41– 7.05 (m, 4H, Ar), 6.76 (s, 1H, Ar), 4.07 (d, J = 6.6 Hz, 6H, OCH3), 3.40 (s, 4H, CH2), 3.34–3.21 (m, 4H, CH2); ESIMS, Calcd. for C26H23F3N3O8S+, [M + H]+, 594; Anal. Calcd for C26H22F3N3O8S: C, 52.61; H, 3.74; N, 7.08; Found, C, 52.66; H, 3.77; N, 7.11. 1,3-Dimethoxy-4-((4-(3-methoxyphenyl)piperazin-1-yl)sulfonyl)-7-nitro-9H-xanthen-9-one (1h) Light green solid. Yield: 79.1%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (d, J = 3.0 Hz, 1H, Ar), 8.58–8.54 (m, 1H, Ar), 7.78 (d, J = 8.4 Hz, 1H, Ar), 7.11–6.35 (m, 4H, Ar), 5.57 (s, 1H, Ar), 4.07 (d, J = 6.0 Hz, 6H, OCH3), 3.67 (s, 3H, OCH3), 3.48–3.40 (m, 4H, CH2), 3.24–3.15 (m, 4H, CH2); ESI-MS, Calcd. for C26H26N3O9S+, [M + H]+, 556; Anal. Calcd for C26H25N3O9S: C, 56.21; H, 4.54; N, 7.56; Found, C, 56.26; H, 4.52; N, 7.51. 1,3-Dimethoxy-4-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)-7-nitro-9H-xanthen-9-one (1i) Light yellow solid, Yield: 72.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.74 (s, 1H, Ar), 8.57–8.53 (m, 1H, Ar), 7.78 (d, J = 8.4 Hz, 1H, Ar), 6.88–6.78 (m, 4H, Ar), 5.70 (s, 1H, Ar), 4.07 (d, J = 4.5 Hz, 6H, OCH3), 3.65 (s, 3H, OCH3), 3.48–3.39 (m, 4H, CH2), 3.32–3.20 (m, 4H, CH2); ESI-MS, Calcd. for C26H26N3O9S+, [M + H]+, 556; Anal. Calcd for C26H25N3O9S: C, 56.21; H, 4.54; N, 7.56; Found, C, 56.18; H, 4.62; N, 7.61. 1,3-Dimethoxy-4-((4-(2-methoxyphenyl)piperazin-1-yl)sulfonyl)-7-nitro-9H-xanthen-9-one (1j) Light yellow solid, Yield: 75.2%; Mp: 248–250 °C; 1H NMR (300 MHz, CDCl3, TMS) d 9.08 (d, J = 2.7 Hz, 1H, Ar), 8.50 (m, 1H, Ar), 7.69 (d, J = 9.1 Hz, 1H, Ar), 7.27 (s, 1H, Ar), 7.05–6.81 (m, 3H, Ar), 6.46 (s, 1H, Ar), 4.12 (s, 6H, OCH3), 3.83 (s, 3H, OCH3), 3.63–3.46 (m, 4H), 3.17 (s, 4H); 13C NMR (75 MHz, CDCl3, TMS) d 172.91, 165.30, 164.30, 163.97, 157.70, 157.22, 152.25, 144.67, 129.03, 124.16, 123.12, 122.11, 121.17, 120.97, 119.70, 111.47, 108.40, 106.45, 91.91, 67.29, 67.29, 67.29, 56.46, 55.62, 50.78, 46.06; ESI-MS, Calcd. for C26H26N3O9S+, [M + H]+, 556; Anal. Calcd for C26H25N3O9S: C, 56.21; H, 4.54; N, 7.56; Found, C, 56.15; H, 4.59; N, 7.63. Chem Biol Drug Des 2014
4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-7-nitro-9H-xanthen-9-one (1k) Light yellow solid. Yield: 76.1%; Mp: 240–242 °C; 1H NMR (300 MHz, CDCl3, TMS) d 9.09 (s, 1H, Ar), 8.51 (s, 1H, Ar), 7.70 (s, 1H, Ar), 7.27 (s, 1H, Ar), 7.16–6.93 (m, 3H, Ar), 4.16 (s, 6H, OCH3), 3.78–3.58 (m, 4H, CH2), 3.16–3.07 (m, 4H, CH2), 2.26 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3, TMS) d 173.08, 165.53, 163.66, 158.93, 157.03, 144.45, 144.16, 138.49, 130.99, 129.10, 125.63, 123.10, 122.56, 119.38, 116.90, 108.41, 106.82, 101.19, 90.86, 57.88, 56.98, 52.61, 52.23, 47.29, 46.32, 20.66, 20.66; ESI-MS, Calcd. for C27H28N3O8S+, [M + H]+, 554; Anal. Calcd for C27H27N3O8S: C, 58.58; H, 4.92; N, 7.59; Found, C, 58.64; H, 4.97; N, 7.61. 4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-6-methyl-9H-xanthen-9-one (2a) Light yellow solid. Yield: 65.2%; Mp: 194.4 °C; 1H NMR (600 MHz, DMSO-d6, TMS) d 8.01–7.94 (m, 1H, Ar), 7.43– 7.38 (m, 1H, Ar), 7.33–7.27 (m, 1H, Ar), 7.09–7.01 (m, 1H, Ar), 6.94–6.86 (m, 2H, Ar), 6.75–6.70 (m, 1H, Ar), 4.08 (d, J = 16.7 Hz, 6H, OCH3), 3.59 (s, 8H, CH2), 2.48 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.10 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6, TMS) d 173.61, 165.48, 163.60, 157.22, 154.53, 151.28, 146.39, 137.96, 131.05, 130.00, 126.60, 126.33, 125.79, 125.14, 120.07, 117.83, 117.18, 106.73, 106.36, 93.19, 72.57, 57.71, 57.05, 52.15, 46.41, 29.03, 21.41, 20.54; ESI-MS, Calcd. for C28H31N2O6S+, [M + H]+, 523; Anal. Calcd for C28H30N2O6S: C, 64.35; H, 5.79; N, 5.36; Found, C, 64.236; H, 5.74; N, 5.41. 3-(4-((1,3-Dimethoxy-6-methyl-9-oxo-9H-xanthen-4-yl) sulfonyl)piperazin-1-yl)benzonitrile (2b) Light yellow solid. Yield: 53.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.31 (s, 1H, Ar), 7.94 (d, J = 7.8 Hz, 1H, Ar), 7.38–7.14 (m, 5H, Ar), 6.69 (s, 1H, Ar), 4.04 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 3.36–3.21 (m, 8H, CH2), 2.48 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6, TMS) d 174.89, 165.55, 163.37, 157.95, 154.48, 145.97, 141.45, 130.41, 129.94, 129.50, 126.47, 125.12, 121.89, 120.14, 119.10, 116.92, 113.60, 106.90, 100.87, 90.41, 67.14, 66.25, 57.13, 56.30, 49.97, 44.56, 21.97; ESI-MS, Calcd. for C27H26N3O6S+, [M + H]+, 520; Anal. Calcd for C27H25N3O6S: C, 62.41; H, 4.85; N, 8.09; Found, C, 62.52; H, 4.82; N, 8.11. 4-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-6-methyl-9H-xanthen-9-one (2c) Pale yellow solid; Yield: 77.8%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.31 (s, 1H, Ar), 7.93 (d, J = 8.1 Hz, 1H, Ar), 7.38–6.79 (m, 5H, Ar), 6.69 (s, 1H, Ar), 4.04 (s, 3H, OCH3), 4.02 (s, 3H, OCH 3), 3.34–3.25 (m, 8H, CH 2), 2.48 (s, 3H, CH 3); ESI-MS, Calcd. for C26H 26ClN 2O6S +, [M + H]+ , 529; Anal. Calcd for C26H 25ClN 2O6S: C, 59.03; H, 4.76; N, 5.30; Found, C, 59.07; H, 4.72; N, 5.19. 5
Li et al.
4-((4-(4-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dizmethoxy-6-methyl-9H-xanthen-9-one (2d) Light yellow solid; Yield: 74.6%; Mp: 217.2 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 7.93 (d, J = 7.8 Hz, 1H, Ar), 7.38–7.19 (m, 4H, Ar), 6.93–6.90 (m, 2H, Ar), 6.69 (s, 1H, Ar), 4.04 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 3.35–3.25 (m, 4H, CH2), 3.24–3.11 (m, 4H, CH2), 2.49 (3H, s, CH3); ESIMS, Calcd. for C26H26ClN2O6S+, [M + H]+, 529; Anal. Calcd for C26H25ClN2O6S: C, 59.03; H, 4.76; N, 5.30; Found, C, 59.11; H, 4.73; N, 5.25.
1,3-Dimethoxy-4-((4-(3-methoxyphenyl)piperazin-1-yl)sulfonyl)-6-methyl-9H-xanthen-9-one (2i)
4-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-6-methyl-9H-xanthen-9-one (2e) Light green solid. Yield: 72.1%; Mp: 237.2 °C; H NMR (300 MHz, DMSO-d6, TMS) d 7.93 (d, J = 7.8 Hz, 1H, Ar), 7.39–7.05 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 3.42–3.31 (m, 4H, CH2), 3.04–2.98 (m, 4H, CH2), 2.46 (s, 3H, CH3); ESI-MS, Calcd. for C26H26ClN2O6S+, [M + H]+, 529; Anal. Calcd for C26H25ClN2O6S: C, 59.03; H, 4.76; N, 5.30; Found, C, 59.12; H, 4.68; N, 5.24. 1
4-((4-(2,3-Dichlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dizmethoxy-6-methyl-9H-xanthen-9-one (2f) Light green solid. Yield: 66.5%; Mp: 213.5 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 7.93 (d, J = 8.1 Hz, 1H, Ar), 7.39–7.15 (m, 5H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 3.55 (s, 4H, CH2), 3.10–3.00 (m, 4H, CH2), 2.49 (s, 3H, CH3); ESI-MS, Calcd. for C26H25Cl2N2O6S+, [M + H]+, 563; Anal. Calcd for C26H24Cl2N2O6S: C, 55.42; H, 4.29; N, 4.97; Found, C, 55.47; H, 4.33; N, 4.91. 4-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-1,3-Dimethoxy6-methyl-9H-xanthen-9-one (2g) Light green solid. Yield: 63.2%; Mp: 228–229 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.13 (d, J = 8.1 Hz, 1H, Ar), 7.33 (s, 1H, Ar), 7.19 (d, J = 8.1 Hz, 1H, Ar), 7.04 (d, J = 6.8 Hz, 2H, Ar), 6.40 (s, 1H, Ar), 4.10 (d, J = 5.9 Hz, 6H, OCH3), 3.72 (t, J = 16.2 Hz, 4H, CH2), 3.25–3.17 (m, 4H, CH2), 2.48 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3, TMS) d 174.86, 165.53, 163.26, 163.06, 157.33, 154.44, 146.00, 141.08, 126.02, 120.28, 119.54, 119.38, 117.41, 116.38, 116.01, 115.63, 107.42, 105.97, 90.71, 57.20, 57.20, 56.09, 56.09, 45.09, 45.09, 21.53; ESI-MS, Calcd. for C26H26FN2O6S+, [M + H]+, 513; Anal. Calcd for C26H25FN2O6S: C, 60.93; H, 4.92; N, 5.47; Found, C, 60.95; H, 4.93; N, 5.49. 1,3-Dimethoxy-6-methyl-4-((4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)sulfonyl)-9H-xanthen-9-one (2h) Light yellow solid. Yield: 78.6%; Mp: 247–248 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.13 (d, J = 8.1 Hz, 1H, Ar), 7.94 (s, 1H, Ar), 7.78 (s, 1H, Ar), 7.62 (d, J = 13.6 Hz, 2H, Ar), 7.30 (d, 6
J = 9.1 Hz, 1H, Ar), 7.19 (d, J = 8.1 Hz, 1H, Ar), 6.45 (d, J = 23.4 Hz, 1H, Ar), 4.17 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 4.00–3.92 (m, 4H, CH2), 3.60 (s, 4H, CH2), 2.48 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3, TMS) d 174.95, 165.15, 162.97, 157.64, 155.15, 154.55, 146.33, 132.87, 131.00, 126.02, 125.04, 124.12, 123.46, 121.56, 120.00, 117.52, 116.22, 108.41, 107.19, 90.26, 57.58, 56.99, 54.12, 54.12, 43.50, 43.50, 21.83; ESI-MS, Calcd. for C27H26F3N2O6S+, [M + H]+, 563; Anal. Calcd for C27H25F3N2O6S: C, 57.65; H, 4.48; N, 4.98; Found, C, 57.69; H, 4.55; N, 5.01.
Light yellow solid. Yield: 73.4%; Mp: 205.5 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.13 (d, J = 8.1 Hz, 1H, Ar), 7.33 (s, 1H, Ar), 7.18 (t, J = 7.6 Hz, 2H, Ar), 6.50 (t, J = 10.9 Hz, 3H, Ar), 6.39 (s, 1H, Ar), 4.08 (d, J = 3.0 Hz, 6H, OCH3), 3.77 (s, 3H, OCH3), 3.48 (dd, J = 16.8, 9.7 Hz, 4H, CH2), 3.29 (s, 4H, CH2), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3, TMS) d 174.80, 165.15, 163.74, 160.18, 159.89, 157.34, 154.17, 145.57, 130.21, 126.02, 126.02, 119.93, 118.51, 117.05, 109.61, 107.79, 103.14, 98.97, 90.34, 67.90, 65.41, 57.27, 56.83, 55.77, 49.68, 45.77, 21.85; ESI-MS, Calcd. for C27H29N2O7S+, [M + H]+, 525; Anal. Calcd for C27H28N2O7S: C, 61.82; H, 5.38; N, 5.34; Found, C, 61.87; H, 5.44; N, 5.42. 1,3-Dimethoxy-4-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)-6-methyl-9H-xanthen-9-one (2j) Light yellow powder. Yield: 72.7%; Mp: 228.5 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.14 (d, J = 8.1 Hz, 1H, Ar), 7.36–6.84 (m, 6H, Ar), 6.40 (s, 1H, Ar), 4.10 (s, 6H, OCH3), 3.80 (s, 3H, OCH3), 3.53–3.30 (m, 4H, CH2), 3.19–3.16 (m, 4H, CH2), 2.49 (s, 3H, CH3); ESI-MS, Calcd. for C27H29N2O7S+, [M + H]+, 525; Anal. Calcd for C27H28N2O7S: C, 61.82; H, 5.38; N, 5.34; Found, C, 61.85; H, 5.36; N, 5.37. 7-bromo-4-((4-(2,3-Dimethylphenyl)piperazin-1-yl)sulfonyl)1,3-Dimethoxy-9H-xanthen-9-one (3a) Light green solid. Yield: 75.6%; Mp: 182–182.6 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.11 (s, 1H, Ar), 6.95–6.73 (m, 5H, Ar), 6.56 (s, 1H, Ar), 4.08 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 3.41– 3.33 (m, 4H, CH2), 2.88–2.81 (m, 4H, CH2), 2.16 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3, TMS) d 173.08, 164.88, 163.08, 157.34, 152.37, 140.26, 137.39, 137.02, 134.46, 129.18, 127.38, 123.16, 119.26, 117.83, 114.20, 108.86, 107.43, 90.71, 89.96, 57.88, 56.46, 55.78, 55.40, 53.96, 43.66, 22.27, 20.45; ESI-MS, Calcd. for C27H28BrN2O6S+, [M + H]+, 589; Anal. Calcd for C27H27BrN2O6S: C, 55.20; H, 4.63; N, 4.77; Found, C, 55.24; H, 4.72; N, 4.78. 3-(4-((7-bromo-1,3-Dimethoxy-9-oxo-9H-xanthen-4-yl) sulfonyl)piperazin-1-yl)benzonitrile (3b) Light yellow powder. Yield: 77.8%; Mp: 218.5 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors
7.15 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.41–3.21 (m, 8H, CH2); ESI-MS, Calcd. for C26H23BrN3O6S+, [M + H]+, 586; Anal. Calcd for C26H22BrN3O6S: C, 53.43; H, 3.79; N, 4.72; Found, C, 53.41; H, 3.82; N, 4.78. 7-bromo-4-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3c) Light yellow powder. Yield: 76.6%; Mp: 244–245 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– 6.77 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.36 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.34–3.25 (m, 8H, CH2); ESI-MS, Calcd. for C25H23BrClN2O6S+, [M + H]+, 595; Anal. Calcd for C25H22BrClN2O6S: C, 50.56; H, 3.73; N, 4.72; Found, C, 50.55; H, 3.66; N, 4.76. 7-bromo-4-((4-(4-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3d) Light green powder. Yield: 72.8%; Mp: 203–204 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– 6.90 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.35 (s, 6H, OCH3), 3.64–3.56 (m, 4H, CH2), 3.15–3.08 (m, 4H, CH2); ESI-MS, Calcd. for C25H23BrClN2O6S+, [M + H]+; Anal. Calcd for C25H22BrClN2O6S: C, 50.56; H, 3.73; N, 4.72; Found, C, 50.71; H, 3.72; N, 4.79. 7-bromo-4-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3e) Light green powder. Yield: 74.6%; Mp: >250 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.36 (s, 1H, Ar), 7.77 (d, J = 7.4 Hz, 1H, Ar), 7.43 (dd, J = 35.8, 8.3 Hz, 3H, Ar), 7.22–6.91 (m, 2H, Ar), 6.43 (s, 1H, Ar), 4.11 (s, 6H, OCH3), 3.58 (s, 4H, CH2), 3.18 (s, 4H, CH2); 13C NMR d (75 MHz, CDCl3, TMS) d 173.36, 165.17, 163.44, 158.91, 156.95, 153.04, 137.38, 130.61, 129.17, 128.14, 124.88, 123.45, 120.59, 119.99, 119.24, 118.10, 107.79, 100.25, 91.02, 57.51, 56.46, 50.75, 50.75, 46.53, 46.53; ESI-MS, Calcd. for C25H23BrClN2O6S+, [M + H]+, 595; Anal. Calcd for C25H22BrClN2O6S: C, 50.56; H, 3.73; N, 4.72; Found, C, 50.48; H, 3.72; N, 4.79. 7-bromo-4-((4-(2,3-Dichlorophenyl)piperazin-1-yl)sulfonyl)1,3-Dimethoxy-9H-xanthen-9-one (3f) Light green powder. Yield: 75.3%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.95–7.15 (m, 5H, Ar), 6.73 (s, 1H, Ar), 4.06 (d, J = 6.0 Hz, 6H, OCH3), 3.44–3.38 (m, 4H, CH2), 3.12–3.01 (m, 4H, CH2); 13 C NMR (75 MHz, CDCl3, TMS) d 173.58, 165.33, 163.80, 161.41, 157.71, 153.34, 137.07, 133.85, 128.58, 127.74, 127.74, 125.34, 123.84, 119.91, 118.87, 118.19, 107.94, 106.66, 91.00, 56.68, 56.47, 51.04, 51.04, 460.5, 46.05; ESI-MS, Calcd. for C25H22BrCl2N2O6S+, [M + H]+, 629; Anal. Calcd for C25H21BrCl2N2O6S: C, 47.79; H, 3.37; N, 4.46; Found, C, 47.88; H, 3.36; N, 4.49. Chem Biol Drug Des 2014
7-bromo-4-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-1,3Dimethoxy-9H-xanthen-9-one (3g) Light yellow powder. Yield: 76.9%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.95–6.90 (m, 6H, Ar), 6.72 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.34–3.28 (m, 4H, CH2), 3.14–3.05 (m, 4H, CH2); ESI-MS, Calcd. for C25H23BrFN2O6S+, [M + H]+, 579; Anal. Calcd for C25H22BrFN2O6S: C, 52.00; H, 3.84; N, 4.85; Found, C, 52.06; H, 3.88; N, 4.89. 7-bromo-1,3-Dimethoxy-4-((4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)sulfonyl)-9H-xanthen-9-one (3h) Light green powder. Yield: 72.7%; Mp: 227–232 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.95–7.05 (m, 6H, Ar), 6.71 (s, 1H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.34–3.24 (m, 8H, CH2); ESIMS, Calcd. for C26H23BrF3N2O6S+, [M + H]+, 629; Anal. Calcd for C26H22BrF3N2O6S: C, 49.77; H, 3.53; N, 4.46; Found, C, 49.73; H, 3.58; N, 4.51. 7-bromo-1,3-Dimethoxy-4-((4-(3-methoxyphenyl)piperazin1-yl)sulfonyl)-9H-xanthen-9-one (3i) Light yellow powder. Yield: 74.3%; Mp: 243–244 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96– 6.35 (m, 7H, Ar), 4.06 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.22–3.18 (m, 8H, CH2); ESI-MS, Calcd. for C26H26BrN2O7S+, [M + H]+, 591; Anal. Calcd for C26H25BrN2O7S: C, 52.98; H, 4.27; N, 4.75; Found, C, 52.91; H, 4.36; N, 4.76. 7-bromo-1,3-Dimethoxy-4-((4-(4-methoxyphenyl)piperazin1-yl)sulfonyl)-9H-xanthen-9-one (3j) Light green powder. Yield: 76.2%; Mp: >250 °C; 1H NMR (300 MHz, DMSO-d6, TMS) d 8.10 (s, 1H, Ar), 7.96–6.72 (m, 7H, Ar), 4.06 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.34–3.28 (m, 4H, CH2), 3.12–3.04 (m, 4H, CH2); ESI-MS, Calcd. for C26H26BrN2O7S+, [M + H]+, 591; Anal. Calcd for C26H25BrN2O7S: C, 52.98; H, 4.27; N, 4.75; Found, C, 52.85; H, 4.15; N, 4.72. 7-bromo-1,3-Dimethoxy-4-((4-(2-methoxyphenyl)piperazin1-yl)sulfonyl)-9H-xanthen-9-one (3k) Light green powder. Yield: 72.3%; Mp: >250 °C; 1H NMR (300 MHz, CDCl3, TMS) d 8.33 (d, J = 2.4 Hz, 1H, Ar), 7.75 (dd, J = 8.8, 2.4 Hz, 1H, Ar), 7.44 (d, J = 8.8 Hz, 1H, Ar), 7.11 (s, 1H, Ar), 7.03–6.75 (m, 3H, Ar), 6.39 (d, J = 13.2 Hz, 1H, Ar), 4.10 (d, J = 5.5 Hz, 6H, OCH3), 3.88 (s, 3H, OCH3), 3.66 (s, 4H, CH2), 3.24 (s, 4H, CH2); 13 C NMR (75 MHz, CDCl3, TMS) d 173.06, 165.14, 163.42, 157.33, 153.04, 151.62, 140.38, 139.50, 137.01, 129.18, 123.47, 121.34, 119.53, 118.78, 117.81, 112.16, 107.81, 106.74, 91.05, 56.83, 56.48, 56.48, 55.03, 51.95, 51.13, 46.08; ESI-MS, Calcd. for C26H26BrN2O7S+, 7
Li et al.
[M + H]+, 591; Anal. Calcd for C26H25BrN2O7S: C, 52.98; H, 4.27; N, 4.75; Found, C, 52.96; H, 4.37; N, 4.66.
Table 1: Structure and ACAT inhibition rate (Inh.) of 1a–1k, 2a– 2j, and 3a–3k at 10 µg/mL concentration Sample
Results and Discussion Evaluation of ACAT inhibitory activities The inhibitory activity of the newly synthesized compounds in vitro against ACAT was firstly studied at a concentration of 10 lg/mL. From the data summarized in Table 1, it was concluded that most of the title compounds showed certain inhibitory activities against ACAT, of which compounds 1b, 1c, 1e–1g, 1i, 2b, 2d, 2e, 3d–3f, and 3h–3j exhibited moderate inhibitory activities. Among them, compounds 1c, 1e, 1f, 1i, 2b, 2d, 2e, and 3d exhibited higher inhibitory activities than the positive control Sandoz 58-035 (inhibition rate = 55.00%) with the inhibition rate 66.53%, 91.52%, 79.47%, 60.09%, 82.43%, 84.53%, and 71.16%, respectively. Moreover, compounds 1c, 1e, 1f, 1i, 2d, 2e, and 3d exhibited higher inhibitory activity than that of the leading compound 14 (inhibitory rate = 64.80%). To further investigate the inhibitory activities of these new compounds, IC50 values of some selected compounds were measured, which was shown in Table 2. Results showed that the selected compounds 1c, 1e, 1f, 1g, 1i, 2b, 2d, 2e, 3d, and 3e exhibited strong inhibitory activities against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Moreover, compounds 1e, 1f, 2d, and 2e exhibited excellent inhibitory activities with the IC50 values 4.42, 8.78, 7.17, and 5.57 lM, respectively, which were more potent than the leading compound 14.
Structure–activity relationship Thus, a preliminary structure–activity relationship (SAR) can be summarized. In general, these three series of xanthone sulfonamides also exhibited the inhibitory activities against ACAT when compared with the leading compound 14, and some compounds showed higher inhibitory activities. There was no significant influence on inhibitory activity, whether the methyl group or the bromine atom was introduced to xanthone framework. But the compounds 1a–1k with nitro group introduced, a strong electron withdrawing group, exhibited more potent inhibitory activities than that with methyl group and bromine atom. When different groups were introduced to the side phenyl ring, compounds showed different levels of inhibitory activities. It can be summarized that compounds with a chlorine group on the phenyl ring showed strong inhibitory activity against ACAT usually. And among these, compounds with chlorine substituted at ortho and para positions of the phenyl ring exhibited more potent inhibitory effect than those with chlorine substituted at meta position. The results reminded us that to introduce a strong electron withdrawing group to the xanthone framework and the chlorine atom to the side phenyl ring was an effective way in improving the inhibitory activities of the compounds against ACAT. Further study was in progress. 8
Sandoz 58-035a 14 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 2a 2b 2c 2d
R
3-CN 3-Cl 4-Cl 2-Cl 2,4-di-Cl 4-F 3-CF3 3-OCH3 4-OCH3 2-OCH3 2,3-di-CH3 2,3-di-CH3 3-CN 3-Cl 4-Cl
% Inh.
Sample
R
% Inh.
55.00
2e
2-Cl
84.53
64.80 4.83 43.67 66.53 34.99 91.52 79.47 53.45 17.83 60.09 34.01 4.83 17.83 60.09 34.01 82.43
2f 2g 2h 2i 2j 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k
2,3-di-Cl 4-F 3-CF3 3-OCH3 4-OCH3 2,3-di-CH3 3-CN 3-Cl 4-Cl 2-Cl 2,3-di-Cl 4-F 3-CF3 3-OCH3 4-OCH3 2-OCH3
18.43 17.57 38.67 37.81 14.98 34.76 23.35 38.24 71.16 52.10 40.71 1.61 48.45 42.78 41.00 26.42
a
Sandoz 58-035, an inhibitor toward ACAT, as a positive control, at 10 µg/mL.
Docking To further understand the action mechanism between the synthesized compounds and the target enzyme, compound 14 (the purple stick) and 1e (the green stick) were docked into the active site of ACAT-2 (PDB code: 1WL4; Figure 3).The docking results revealed that both compound 14 and 1e could occupy the active site of ACAT-2, which might contribute to their potent inhibitory activities against ACAT. To sum up, both the xanthone core of compound 14 and 1e extended toward the back hydrophobic pocket, composed of Gln186, Arg223, Ser226, Asn227, Ala230, Ile349, and Ala350, and the two oxygen atoms of the xanthone core along with the sulfonamide formed two hydrogen bonds with Arg223. Compared with compound 14, however, the oxygen atom of the sulfonamide could form another hydrogen bond with Arg223, and the oxygen atom of seven-substituted nitro group also formed a hydrogen bond with Gln186. Thus, because of the second extra H-bond, the aryl piperazine moiety of 1e was better inserted into the hydrophobic pocket composed of Met231, Leu234, Lys235, Thr247, and Table 2: Structure and ACAT inhibition concentration (50% Inh.) of selected compounds Sample Sandoz 58-035 14 1c 1e 1f 1g
R
4-Cl 2,4-di-Cl 4-F 3-CF3
IC50 (lM)
Sample
R
IC50 (lM)
19.87
1i
4-OCH3
21.92
18.23 17.68 4.42 8.78 21.06
2b 2d 2e 3d 3e
3-CN 4-Cl 2-Cl 4-Cl 2-Cl
20.32 7.17 5.57 19.13 18.87
Chem Biol Drug Des 2014
Novel Xanthone Sulfonamides as ACAT Inhibitors A
B
C
Figure 3: Computed binding geometry of the xanthone sulfonamides 14 and 1e in the active site of ACAT-2 (compound 14: the purple stick, 1e: the green stick).
Pro248. Therefore, the nitro group might be the key group in the interaction between the compound 1e and the receptor, which was consistent with former SAR. The results above demonstrated that these novel xanthone sulfonamides had stronger interactions with ACAT-2 compared with compound 14, which contributed to their strong inhibitory activities against ACAT, and further study was in progress.
Conclusion In conclusion, three series of 1,3-Dimethoxyxanthone-4-sulfonamide derivatives were designed and synthesized in high yields. Preliminary pharmacological evaluation showed that most title compounds had good inhibitory activity against ACAT. Interestingly, the synthetic xanthone sulfonamides 1a–1k with nitro group showed higher ACAT inhibitory activities than two other series, and in one separate series, the inhibitory activities of the compounds were greatly dependent on the various substituents on the phenyl. Compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more potent than the positive control Sandoz 58-035. Computational docking experiments indicated that the hydrophilic H-bond interaction, the hydrophobic interaction, and the narrow
Chem Biol Drug Des 2014
hydrophobic cleft might contribute to the potent inhibitory activities against ACAT.
Acknowledgments This work was supported by grants from Science & Technology Commission of Shanghai Municipality (Nos 054319909 and 08JC1405500) and Shanghai Leading Academic Discipline Project (No. B906).
Conflict of interest There is no conflict of interests among the authors.
References 1. Brown W.V. (1990) Review of clinical trials: proving the lipid hypothesis. Eur Heart J;11(Suppl H):15–20. 2. Tremblay A.J., Lamarche B., Guay V., Charest A., Lemelin V., Couture P. (2013) Short-term, high-fat diet increases the expression of key intestinal genes
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involved in lipoprotein metabolism in healthy men. Am J Clin Nutr;98:32–41. 3. Brown M.S., Dana S.E., Goldstein J.L. (1975) Cholesterol ester formation in cultured human fibroblasts. Stimulation by oxygenated sterols. J Biol Chem;250:4025–4027. 4. Grundy S.M. (1978) Cholesterol metabolism in man. West J Med;128:13–25. 5. Grundy S.M., Balady G.J., Criqui M.H., Fletcher G., Greenland P., Hiratzka L.F., Houston-Miller N., Kris-Etherton P., Krumholz H.M., LaRosa J., Ockene I.S., Pearson T.A., Reed J., Washington R., Smith S.C. Jr (1998) Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction. American Heart Association. Circulation;97:1876–1887. 6. Papacleovoulou G., Abu-Hayyeh S., Nikolopoulou E., Briz O., Owen B.M., Nikolova V., Ovadia C. et al. (2013) Maternal cholestasis during pregnancy programs metabolic disease in offspring. J Clin Invest;123:3172– 3181. 7. Lee O., Chang C.C., Lee W., Chang T.Y. (1998) Immunodepletion experiments suggest that acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines. J Lipid Res;39:1722–1727. 8. Zamorano-Leon J.J., Fernandez-Sanchez R., Lopez Farre A.J., Lapuente-Tiana L., Alonso-Orgaz S., Sacristan D., Junquera D., Delhon A., Conesa A., MateosCaceres P.J., Macaya C. (2006) Direct effect of F12511, a systemic inhibitor of Acyl-CoA cholesterol acyltransferase on bovine aortic endothelial cells. J Cardiovasc Pharmacol;48:128–134. 9. An S., Park Y.D., Paik Y.K., Jeong T.S., Lee W.S. (2007) Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon. Bioorg Med Chem Lett;17:1112–1116. 10. Pal P., Gandhi H., Giridhar R., Yadav M.R. (2013) ACAT inhibitors: the search for novel cholesterol lowering agents. Mini Rev Med Chem;13:1195–1219. 11. Puglielli L., Konopka G., Pack-Chung E., Ingano L.A., Berezovska O., Hyman B.T., Chang T.Y., Tanzi R.E., Kovacs D.M. (2001) Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol;3:905–912. 12. Alger H.M., Brown J.M., Sawyer J.K., Kelley K.L., Shah R., Wilson M.D., Willingham M.C., Rudel L.L. (2010) Inhibition of acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization. J Biol Chem;285:14267–14274. 13. Meuwese M.C., Franssen R., Stroes E.S., Kastelein J.J. (2006) And then there were acyl coenzyme A:
10
cholesterol acyl transferase inhibitors. Curr Opin Lipidol;17:426–430. 14. Li H.Y., DeLucca I., Boswell G.A., Billheimer J.T., Drummond S., Gillies P.J., Robinson C. (1997) Design, synthesis and structure-activity relationship studies of novel 4,4-bis(trifluoromethyl)imidazolines as acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors and antihypercholesterolemic agents. Bioorg Med Chem;5: 1345–1361. 15. Terasaka N., Miyazaki A., Kasanuki N., Ito K., Ubukata N., Koieyama T., Kitayama K., Tanimoto T., Maeda N., Inaba T. (2007) ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice. Atherosclerosis;190: 239–247. 16. Lee M.K., Moon S.S., Lee S.E., Bok S.H., Jeong T.S., Park Y.B., Choi M.S. (2003) Naringenin 7-sO-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats. Bioorg Med Chem;11:393–398. 17. Lada A.T., Davis M., Kent C., Chapman J., Tomoda H., Omura S., Rudel L.L. (2004) Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. J Lipid Res;45:378–386. 18. Lee K., Cho S.H., Lee J.H., Goo J., Lee S.Y., Boovanahalli S.K., Yeo S.K., Lee S.J., Kim Y.K., Kim D.H., Choi Y., Song G.Y. (2013) Synthesis of a novel series of 2-alkylthio substituted naphthoquinones as potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors. Eur J Med Chem;62:515–525. 19. Harris N.V., Smith C., Ashton M.J., Bridge A.W., Bush R.C., Coffee E.C., Dron D.I. et al. (1992) Acyl-CoA: cholesterol O-acyl transferase (ACAT) inhibitors. 1. 2(Alkylthio)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. J Med Chem;35:4384–4392. 20. O’Brien P.M., Sliskovic D.R., Picard J.A., Lee H.T., Purchase C.F., Roth B.D., White A.D. et al. (1996) Inhibitors of acyl-CoA: cholesterol O-acyltransferase. Synthesis and pharmacological activity of (+/ )-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide and structurally related tetrazole amide derivatives. J Med Chem;39:2354–2366. 21. Hu H., Liao H., Zhang J., Wu W., Yan J., Yan Y., Zhao Q., Zou Y., Chai X., Yu S., Wu Q. (2010) First identification of xanthone sulfonamides as potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors. Bioorg Med Chem Lett;20:3094–3097. 22. Grover P.K., Shah G.D., Shah R.C. (1955) Xanthones. Part IV. A new synthesis of hydroxyxanthones and hydroxybenzophenones. J Chem Soc;3982–3985.
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