Bioorganic & Medicinal Chemistry Letters 25 (2015) 1500–1505
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of GY3-based derivatives for anti-type 2 diabetes activity Lingling Fan a, Jianta Wang a, Xiao Ma a, Wan Xiao a, Zhiyan Li a, Gang Zhong a, Lei Tang a,⇑, Haoshu Wu b,⇑ a b
College of Pharmacy, Guiyang Medical University, Guiyang 550004, China College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
a r t i c l e
i n f o
Article history: Received 5 October 2014 Revised 5 February 2015 Accepted 11 February 2015 Available online 18 February 2015
a b s t r a c t A series of indole carboxylic acid derivatives were designed and synthesized. Their anti-type 2 diabetes activity was evaluated in HepG2 cell and db/db mice. The results showed that compounds 8c, 17a, 17b, 15a and 15b could significantly increase glucose consumption in HepG2 cell. Furthermore, compound 8c was able to lower the blood glucose level and induce less weight gain in db/db mice. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Indole carboxylic acid derivatives Design Synthesis Anti-type 2 diabetes activity
The prevalence of diabetes mellitus is increasing at an alarming rate and has become a major health problem globally.1 Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, which accounts for about 90% of all diagnosed cases and is therefore one of the biggest challenges in global health in 21st century.2,3 T2DM is characterized by insulin resistance (IR), hyperglycemia and obesity, etc.4–6 Insulin resistance is a major risk factor for T2DM.7 Therefore improving insulin sensitivity can effectively control blood glucose at an appropriate level, and postpone or avoid the occurrence of undesired complications. For example, thiazolidinediones (TZDs) are used to improve insulin resistance, which can decrease hyperinsulinemia and avoid secondary complications such as diabetic dyslipidemia, hypertension, fibrinolysis and hypercoagulation.8 However, due to side effects such as liver toxicity, weight gain and fluid retention, thiazolidinedione insulin-sensitizer faces an awkward situation in the market.9 We are interested in developing non-TZD insulin-sensitizers without declared side effects of the known TZDs. In our previous study, we had synthesized a series of 3-indoleacetic acid derivates with insulin-sensitizing activity.10 Among them, compound GY3, 1-(4-chlorobenzoyl)-5-benzyloxy-2-methyl-3-indoleacetitic acid (Fig. 1), exerts a potent hypoglycemic effect in db/db mice through activating AMPK signaling pathway.11,12 However, GY3 is defective in metabolic stability due to the existence of 2, 3-double bond in indole, which might result in the hydrolysis of the amide bond in ⇑ Corresponding authors. Tel./fax: +86 851 690 8318. E-mail addresses: [email protected] (L. Tang), [email protected] (H. Wu). http://dx.doi.org/10.1016/j.bmcl.2015.02.021 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
vivo. To improve the pharmacokinetic properties of GY3, a series of 2,3-dihydro-GY3 derivatives were designed and synthesized in this manuscript. Furthermore, a number of derivatives with extended side chains at 3-position were also designed and synthesized on the basis of GY3. As shown in Scheme 1, when compound 1 was reduced with NaBH3CN in the presence of acetic acid, two isomers were obtained. As reported in the literature,13 the C-2 methyl group in cis-isomer of similar structure should have a high-field shift and larger coupling constant in 1H NMR spectrum, thus the minor isomer with a methyl doublet at 1.17 (J = 6.4 Hz) and the major isomer with a methyl doublet at 1.25 (J = 6.0 Hz) were determined as structure 2a and 2b, respectively. Compounds 2a and 2b were then reacted with 4-chlorobenzoyl chloride to give compounds 3a and 3b. Following that, the target compounds 6f and 6f0 were prepared by hydrolysis of 3a and 3b in a solution of LiOH in water. 6f was unambiguously determined as the trans-isomer by means of single-crystal X-ray diffraction (Fig. 2), which further confirmed the relative configuration of intermediate 2b.14 The activities of trans-isomer 6f and cis-isomer 6f0 on glucose consumption were evaluated in HepG2 cells (Table 1), and found that 6f induced an marked increase in glucose consumption by 20.0%, but there was only 0.6% increase after 6f0 treatment. It indicated that the glucose consumption activity of trans-isomer might be much better than that of cis-isomer, so more trans-derivatives 6a–e with group change at 5-oxygen atom were synthesized as in Scheme 1.
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L. Fan et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1500–1505
O 4
BnO
3
OH 2
5 6
O
CH 3
N1 7
CO2 H OH
CH 3 BnO
N
O
n
BnO
CH3
O
Cl
O
OH
R1 O
CH 3
N R2
N R3
Cl
GY3
Figure 1. The design of GY3 derivatives.
OCH3
BnO
O
O
O a
OCH 3
BnO
CH3
CH 3
OCH 3
BnO N H
N H
N H
2b
2a
1 O
OCH3
BnO
CH 3 O
N
c O
Cl
N
d
O
O
Cl
Cl
Cl 3a
CH 3
CH 3
N +
OCH 3
OCH 3 R1 O
HO
CH 3
N
O
O
O
OCH3
BnO
b
CH3
+
3b
4
5a-e
e
e
e O
O OH
BnO
O OH
R1 O OH
BnO
CH 3
CH 3 N
CH 3
N
N O
O O Cl
Cl
Cl
6f′
6f
6a-e
R 1: N N 6a
6b
6c
6d
6e
Scheme 1. Synthesis of compounds 6a–f and 6f0 . Reagents and conditions: (a) NaBH3CN, acetic acid, 20 °C, 4 h, 60%; (b) anhydrous dichloromethane, DIPEA, 4-chlorobenzoyl chloride, 18 °C to rt, 4 h, 88%; (c) ethyl acetate, Pd/C, H2, rt, 5 h, 100%; (d) diethyl ether anhydrous, diethyl azodicarboxylate, Ph3P, R1OH, rt, 3.5 h-overnight, 60–97%; (e) THF/ MeOH = 3:1, 1 N LiOH or 1 N NaOH, 18 °C to rt, overnight, 17–88%.
Further, more trans-derivatives 8a–j with substitution group change at 1-nitrogen atom were also designed and synthesized. As shown in Scheme 2, compounds 7a–i were gained when compound 2b reacted with aromatic acids or aliphatic acids in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCHCl) and N-methylmorpholine (NMM). And compound 7j was obtained when compound 2b reacted with 4chlorobenzenesulfonyl chloride. Finally compounds 8a–j were got from the hydrolysis of 7a–j with LiOH.
Derivatives 15a–b and 17a–b with extended side chains at 3position were synthesized as outlined in Scheme 3. Starting from compounds 9a–b and 10, intermediates 11a–b were synthesized via classical Fisher reaction. Then products 15a–b and 17a–b were prepared from intermediates 11a–b in two routes. 11a–b reacted with 4-chlorobenzenesulfonyl chloride and sodium hydride (NaH) yielded 16a–b, hydrolysis of 16a–b with LiOH provided corresponding compounds 17a–b. Compounds 15a–b could be obtained from 11a–b via ester hydrolysis, allyl bromide protection,
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L. Fan et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1500–1505
Figure 2. X-ray crystal structure of 6f.
amidation and then de-protection. The structures of the target compounds were well characterized by 1H NMR, 13C NMR and ESI-MS. The activities of all above synthetic compounds on glucose consumption were investigated in HepG2 cells as previously described.15 As shown in Table 1, Compared to the control group (DMSO), 103 M of metformin (MET), 105 M of rosiglitazone (ROS) and 105 M of GY3 induced an increase of glucose consumption in HepG2 cells by 51.0% (P
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of GY3-based derivatives for anti-type 2 diabetes activity Lingling Fan a, Jianta Wang a, Xiao Ma a, Wan Xiao a, Zhiyan Li a, Gang Zhong a, Lei Tang a,⇑, Haoshu Wu b,⇑ a b
College of Pharmacy, Guiyang Medical University, Guiyang 550004, China College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
a r t i c l e
i n f o
Article history: Received 5 October 2014 Revised 5 February 2015 Accepted 11 February 2015 Available online 18 February 2015
a b s t r a c t A series of indole carboxylic acid derivatives were designed and synthesized. Their anti-type 2 diabetes activity was evaluated in HepG2 cell and db/db mice. The results showed that compounds 8c, 17a, 17b, 15a and 15b could significantly increase glucose consumption in HepG2 cell. Furthermore, compound 8c was able to lower the blood glucose level and induce less weight gain in db/db mice. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Indole carboxylic acid derivatives Design Synthesis Anti-type 2 diabetes activity
The prevalence of diabetes mellitus is increasing at an alarming rate and has become a major health problem globally.1 Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, which accounts for about 90% of all diagnosed cases and is therefore one of the biggest challenges in global health in 21st century.2,3 T2DM is characterized by insulin resistance (IR), hyperglycemia and obesity, etc.4–6 Insulin resistance is a major risk factor for T2DM.7 Therefore improving insulin sensitivity can effectively control blood glucose at an appropriate level, and postpone or avoid the occurrence of undesired complications. For example, thiazolidinediones (TZDs) are used to improve insulin resistance, which can decrease hyperinsulinemia and avoid secondary complications such as diabetic dyslipidemia, hypertension, fibrinolysis and hypercoagulation.8 However, due to side effects such as liver toxicity, weight gain and fluid retention, thiazolidinedione insulin-sensitizer faces an awkward situation in the market.9 We are interested in developing non-TZD insulin-sensitizers without declared side effects of the known TZDs. In our previous study, we had synthesized a series of 3-indoleacetic acid derivates with insulin-sensitizing activity.10 Among them, compound GY3, 1-(4-chlorobenzoyl)-5-benzyloxy-2-methyl-3-indoleacetitic acid (Fig. 1), exerts a potent hypoglycemic effect in db/db mice through activating AMPK signaling pathway.11,12 However, GY3 is defective in metabolic stability due to the existence of 2, 3-double bond in indole, which might result in the hydrolysis of the amide bond in ⇑ Corresponding authors. Tel./fax: +86 851 690 8318. E-mail addresses: [email protected] (L. Tang), [email protected] (H. Wu). http://dx.doi.org/10.1016/j.bmcl.2015.02.021 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
vivo. To improve the pharmacokinetic properties of GY3, a series of 2,3-dihydro-GY3 derivatives were designed and synthesized in this manuscript. Furthermore, a number of derivatives with extended side chains at 3-position were also designed and synthesized on the basis of GY3. As shown in Scheme 1, when compound 1 was reduced with NaBH3CN in the presence of acetic acid, two isomers were obtained. As reported in the literature,13 the C-2 methyl group in cis-isomer of similar structure should have a high-field shift and larger coupling constant in 1H NMR spectrum, thus the minor isomer with a methyl doublet at 1.17 (J = 6.4 Hz) and the major isomer with a methyl doublet at 1.25 (J = 6.0 Hz) were determined as structure 2a and 2b, respectively. Compounds 2a and 2b were then reacted with 4-chlorobenzoyl chloride to give compounds 3a and 3b. Following that, the target compounds 6f and 6f0 were prepared by hydrolysis of 3a and 3b in a solution of LiOH in water. 6f was unambiguously determined as the trans-isomer by means of single-crystal X-ray diffraction (Fig. 2), which further confirmed the relative configuration of intermediate 2b.14 The activities of trans-isomer 6f and cis-isomer 6f0 on glucose consumption were evaluated in HepG2 cells (Table 1), and found that 6f induced an marked increase in glucose consumption by 20.0%, but there was only 0.6% increase after 6f0 treatment. It indicated that the glucose consumption activity of trans-isomer might be much better than that of cis-isomer, so more trans-derivatives 6a–e with group change at 5-oxygen atom were synthesized as in Scheme 1.
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L. Fan et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1500–1505
O 4
BnO
3
OH 2
5 6
O
CH 3
N1 7
CO2 H OH
CH 3 BnO
N
O
n
BnO
CH3
O
Cl
O
OH
R1 O
CH 3
N R2
N R3
Cl
GY3
Figure 1. The design of GY3 derivatives.
OCH3
BnO
O
O
O a
OCH 3
BnO
CH3
CH 3
OCH 3
BnO N H
N H
N H
2b
2a
1 O
OCH3
BnO
CH 3 O
N
c O
Cl
N
d
O
O
Cl
Cl
Cl 3a
CH 3
CH 3
N +
OCH 3
OCH 3 R1 O
HO
CH 3
N
O
O
O
OCH3
BnO
b
CH3
+
3b
4
5a-e
e
e
e O
O OH
BnO
O OH
R1 O OH
BnO
CH 3
CH 3 N
CH 3
N
N O
O O Cl
Cl
Cl
6f′
6f
6a-e
R 1: N N 6a
6b
6c
6d
6e
Scheme 1. Synthesis of compounds 6a–f and 6f0 . Reagents and conditions: (a) NaBH3CN, acetic acid, 20 °C, 4 h, 60%; (b) anhydrous dichloromethane, DIPEA, 4-chlorobenzoyl chloride, 18 °C to rt, 4 h, 88%; (c) ethyl acetate, Pd/C, H2, rt, 5 h, 100%; (d) diethyl ether anhydrous, diethyl azodicarboxylate, Ph3P, R1OH, rt, 3.5 h-overnight, 60–97%; (e) THF/ MeOH = 3:1, 1 N LiOH or 1 N NaOH, 18 °C to rt, overnight, 17–88%.
Further, more trans-derivatives 8a–j with substitution group change at 1-nitrogen atom were also designed and synthesized. As shown in Scheme 2, compounds 7a–i were gained when compound 2b reacted with aromatic acids or aliphatic acids in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCHCl) and N-methylmorpholine (NMM). And compound 7j was obtained when compound 2b reacted with 4chlorobenzenesulfonyl chloride. Finally compounds 8a–j were got from the hydrolysis of 7a–j with LiOH.
Derivatives 15a–b and 17a–b with extended side chains at 3position were synthesized as outlined in Scheme 3. Starting from compounds 9a–b and 10, intermediates 11a–b were synthesized via classical Fisher reaction. Then products 15a–b and 17a–b were prepared from intermediates 11a–b in two routes. 11a–b reacted with 4-chlorobenzenesulfonyl chloride and sodium hydride (NaH) yielded 16a–b, hydrolysis of 16a–b with LiOH provided corresponding compounds 17a–b. Compounds 15a–b could be obtained from 11a–b via ester hydrolysis, allyl bromide protection,
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L. Fan et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1500–1505
Figure 2. X-ray crystal structure of 6f.
amidation and then de-protection. The structures of the target compounds were well characterized by 1H NMR, 13C NMR and ESI-MS. The activities of all above synthetic compounds on glucose consumption were investigated in HepG2 cells as previously described.15 As shown in Table 1, Compared to the control group (DMSO), 103 M of metformin (MET), 105 M of rosiglitazone (ROS) and 105 M of GY3 induced an increase of glucose consumption in HepG2 cells by 51.0% (P
