Accepted Manuscript Transition Metal Complexes of Neocryptolepine Analogues Part I: Synthesis, Spectroscopic Characterization, and In Vitro Anticancer Activity of Copper(II) Complexes Sanaa Moustafa Emam, Ibrahim El Tantawy El Sayed, Nagla Nassar PII: DOI: Reference:

S1386-1425(14)00537-X http://dx.doi.org/10.1016/j.saa.2014.03.114 SAA 11947

To appear in:

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Received Date: Revised Date: Accepted Date:

21 December 2013 9 March 2014 29 March 2014

Please cite this article as: S.M. Emam, I.E.T. Sayed, N. Nassar, Transition Metal Complexes of Neocryptolepine Analogues Part I: Synthesis, Spectroscopic Characterization, and In Vitro Anticancer Activity of Copper(II) Complexes, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), doi: http://dx.doi.org/ 10.1016/j.saa.2014.03.114

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Transition Metal Complexes of Neocryptolepine Analogues Part I: Synthesis, Spectroscopic Characterization, and In Vitro Anticancer Activity of Copper(II) Complexes Sanaa Moustafa Emam, Ibrahim El Tantawy El Sayed*, Nagla Nassar El-Menoufia University, Faculty of Science, Chemistry Department, Shebin El koom, Egypt (This paper is dedicated to the spirit of Professor Ahmed Donia, who died on April 24, 2013) Abstract: New generation of copper(II) complexes with aminoalkylaminoneocryptolepine as bidentate ligands has been synthesized and It is characterized by elemental analyses, magnetic moment, spectra (IR, UV-Vis, 1H NMR and ESR) and thermal studies. The IR data suggest the coordination modes for ligands which behave as a bidentate with copper(II) ion. Based on the elemental analysis, magnetic studies, electronic and ESR data, binuclear square planar geometry was proposed for complexes 7a, 7b, square pyramidal for 9a, 9b and octahedral for 8a, 8b, 10a, 10b. The molar conductance in DMF solution indicates that all complexes are electrolyte except 7a and 7b. The ESR spectra of solid copper(II) complexes in powder form showed an axial symmetry with 2B1g as a ground state and hyperfine structure. The thermal stability and degradation of the ligands and their metal complexes were studied employing DTA and TG methods. The metal-free ligands and their copper(II) complexes were tested for their in vitro anticancer activity against human colon carcinoma (HT-29). The results showed that the synthesized copper(II) complexes exhibited higher anticancer activity than their free ligands. Of all the studied copper(II) complexes, the bromo-substituted complex 9b exhibited high anticancer activity at low micromolar inhibitory concentrations (IC50 = 0.58 µM), compared to the other complexes and the free ligands.

Keywords: Neocryptolepine, Copper(II) complexes, Synthesis, Spectroscopic characterization, Anticancer activity Introduction: In recent years, there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clinical effectiveness, reduce general toxicity and broaden the spectrum of activity [1]. Cisplatin is regarded as one of the most effective 1

anticancer drugs, even if severe toxicities and drug resistance phenomena limit its clinical use [2]. Among extensive researches aiming to characterize other anticancer-active inorganic complexes with improved pharmacological properties compared to cisplatin are the ones focusing on the use of biologically active complexes formed by essential ions such as copper [3]. Copper has a long history of medicinal application but its potential anticancer activity has been explored only in the last decades [4,5]. In this context, complexes with biologically active ligands are particularly attractive, as they combine qualities of classic non-targeted coordination compounds and organic ligands with selectivity for cellular targets [1-11]. The inclusion of biologically active ligands into organometallic complexes offers much scope for the design of novel drugs with enhanced, targeted activity. Studies on such complexes are expected to indicate that new mechanisms of action are possible through combining the bioactivity of the ligand with the properties inherent to the metal, leading to the possibility of overcoming current drug resistance pathways. As an extension to our previous work on neocryptolepine-based therapy [12], we were interested in studying the effect of incorporation of metal ions into biologically active ligand with natural origin such as neocryptolepine (5-methyl-5H-indolo[2,3b]quinoline), Figure 1. Insert Figure 1 and its caption here The pharmacological importance of neocryptolepine is demonstrated by the fact that it is a natural product alkaloid isolated from the roots of Cryptolepis sanguinolenta, an African plant used in traditional medicine [13]. The medicinal applicability of neocryptolepine as antimalarial, antischistosomal and anticancer active compounds has been confirmed [12-18]. However, metal complexes with neocryptolepine containing ligand have never been reported in the literature. With the aim of improving the biological activity and reducing the cyctotoxcity of the neocryptolepine core herein we report on the synthesis and in vitro anticancer activity of the first generation of copper(II) complexes with aminoalkylamino substituted neocryptolepine ligand. Experimental Materials and physical measurements All chemicals and solvents were of analytical grade and were used as received without further purification. The metal salts CuCl2.2H2O (BDH), CuBr2 (BDH), Cu(OAc)2.H2O (Sigma) and Cu(ClO4)2.6 H2O were used as supplied. Elemental microanalyses (C,H,N) were performed at the Micro Analytical unit, Cairo University Giza, Egypt. Copper(II) content in the complexes was determined via complexmetric method, while halide ions were determined by Mohr's method [19a,b]. IR 2

spectra have been recorded on Neneyeus Nicolidite–640MSAFT-IR, Thermo Electronic CO. using KBr pellets. The electronic spectra have been measured in nujol mull using 4802 UV-Vis spectrophotometer. The 1H NMR spectrum was recorded in DMSO-d6 on a Varian Gemini 200 NMR spectrometer at 300 MHz. The electron paramagnetic resonance (EPR) spectra were recorded on a Varian E-109c spectrometer equipped with a field modulation unit at 100 kHz. Measurements were effected in the X-band on a microcrystalline powder at room temperature; the microwave power was around 10 mW. The molar conductivity has been measured at room temperature with approximately 10-3 M in DMF solution using a CON6000 conductometer, Cyberscan, Eutech instruments. Magnetic susceptibility of metal complexes was measured using the modified Gouy method at room temperature on Magnetic susceptibility Johnson Matthey balance. Diamagnetic corrections were made using Pascal's constant [20]. The Thermal analysis (TG/DTA)were carried out by using a Shimadzu DAT/TG-50 thermal analyzer with a heating rate of 10oC/min under N2 atmosphere with a flowing rate of 20 mL/min in the temperature range 20-900oC using platinum crucibles. Melting points were measured by using Stuart melting point apparatus. Synthesis of ligands L1 and L2 : The starting material 11-chloro-6H-indolo[2,3-b]quinoline 5, was prepared as described previously [18]. The L1/L2 ligands were synthesized by refluxing a hot ethanolic solution of 5 (0.5g/1.8mmol) with excess of 1,2-diaminoethane and 1,3-diaminopropane, respectively for 3-5 h at 80 0C. The progress of reaction was monitored by TLC. The reaction mixture was poured into cold water, the product was extracted with chloroform dried over anhydrous Na2SO4, evaporate the organic layer to give yellow precipitate, the formed precipitate was collected by filtration, washed and dried in vacuum over anhydrous CaCl2. N-(2-Aminoethyl)-5-methyl-5H-indolo[2,3-b]quinolin-11-amine (L1): Yield (90%); yellow solid; m.p: 100 °C. FT-IR (KBr, cm-1): 3392, 3352 υ(NH2); 1613, 1549, 1240, 1161, 742 δ(NH2); 3247, 3160 υ(NH)sec; 1H NMR (DMSO-d6, δ ppm): 2.88 (br. s, 2H, -NH-CH2-CH2NH2), 3.78 (br. s, 2H, NH2), 3.87 (br. m, 2H, -NH-CH2-CH2-NH2), 4.16 (s, 3H, N-CH3), 5.37 (br. s, 1H, NH ), 6.88 (br. s, 1H, NH), 7.08 (d, 1H, Ar-H), 7.27-7.50 (m, 3H, Ar-H); 7.80-7.99 (m, 3H, Ar-H); 8.49 (d, 1H, Ar-H). N-(3-Aminopropyl)-5-methyl-5H-indolo[2,3-b]quinolin-11-amine (L2). Yield 95%; yellow solid; m.p: 95−98 °C. FT-IR (KBr, cm-1): 3322, 3260 υ(NH2); 1604, 1551, 1249, 1120, 738 δ(NH2); 3195, 3150 υ(NH)sec; 1H NMR (DMSO-d6, δ ppm): 1.74 (br. m, 2H, -NH-CH2-CH2CH2-NH2), 2.61 (br. s, 2H, -NH-CH2-CH2-CH2-NH2), 2.98 (br. s, 2H, NH2), 3.61 (br. s, 2H, NH-CH2-CH2-CH2-NH2), 4,14 (s, 3H, N-CH3), 6.85 (br. s, 1H, NH) 7.09 (t, 1H, Ar-H), 7.27 (t, 3

1H, Ar-H), 7.39 (t, 1H, Ar-H), 7.50 (d, 1H, Ar-H ), 7.81 (t, 1H, Ar-H), 7.93 (t, 1H, Ar-H), 8.49 (br. m., 1H, Ar-H ). General method for the preparation of copper(II) complexes, 7a-10a, 7b- 10b: All copper(II) complexes were prepared by adding a hot ethanolic solution of the appropriate copper(II) salts (1.0 mmol) to a stirred absolute ethanolic solution of ligands (1.0 mmol) L1/L2. The reaction mixture was further stirred for 4-6 h, the precipitated complexes were filtered off, washed several times with ethanol and finally dried under vacuum over anhydrous calcium chloride. Anticancer activity: The inhibition of cell growth by copper(II) complexes 7a,7b; 8a, 8b; 9a, 9b; 10a, 10b and the corresponding uncoordinated ligands L1 and L2 was evaluated using a 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cleavage assay with colorectal adenocarcinoma (HT-29) cells [21]. The cells were seeded at 1×10 4 cells/well in 96-well plates in RPMI medium supplemented with 10% FBS. After 20 h of culture, copper(II) complexes 7a,7b; 8a, 8b; 9a, 9b; 10a, 10b and the corresponding uncoordinated ligands L1 and L2 M at 10 µM concentration were added in triplicate, and the cells were further cultured for 72 h. The cells were then exposed to 5 mg/mL MTT in PBS at a final concentration of 1 mg/mL in culture for 5 h. Formazan crystals formed during the incubation period were dissolved overnight at 37 ◦C by adding 10% SDS containing 20 mM HCl. The absorbance was measured at 570 nm. Results and discussion Neocryptolepines with amino-substitution in position 11th were prepared from methyl 1H-indole-3-carboxylate, 1 and N-methylaniline 2 (Scheme 1). The intermediate methyl 2-(Nmethylphenylamino)-1H-indole-3-methylcarboxylate 3, obtained via chlorination with Nchlorosuccinimide in the presence of 1,4-dimethylpiperazine, followed by addition of Nmethylaniline as trichloroacetate, was cyclized in boiling diphenyl ether to 5,6-dihydro-11Hindolo[2,3-b]quinolin-11-one 4, which was dehydroxy chlorinated with POCl3 to afford the key structure 11-chloroneocryptolepine 5, which was aminated via SNAr reaction in ethanol with the appropriate amines at high temperature, yielding target ligands 6 (L1 and L2). This method is used for synthesis of neocryptolepines with substitutions on B rings (11-substitution) as depicted in Scheme 1. Insert Scheme 1 and its caption here

4

All spectroscopic data are consistent with the proposed structures for all compounds (cf. experimental section). Insert Scheme 2 and its caption here The reaction of L1 and L2 ligands with CuX2 salts (X= OAc, Cl, Br and ClO4) in the (1:1) molar ratio led to the formation of copper(II) complexes 7a-10a and 7b-10b, Scheme 2. The analytical Table (1); spectral data, Tables (2), (3) and (5) and thermal studies Table (4) are consistent with the formulation in Scheme 2. All copper(II) complexes derived from L1 and L2 ligands are separated with (1M:1L) molar ratio whereas, the binuclear metal complexes 7a and 7b are formed through the reaction containing 1 mole of ligand (L1 or L2 ) and 1 mole of copper(II) acetate. All the metal complexes are stable, nonhydroscopic, partially soluble in most organic solvents such as absolute ethanol, methanol, acetone, acetonitrile, chloroform, dichloromethane, and benzene. They are completely soluble in DMSO and DMF. The molar conductivity measurements for all metal complexes in (1x10-3 M) DMF solution at 25° C are found within the range of conducting feature except complexes 7a and 7b. The molar conductance

values,

73.1,

86,

61.2

and

62.5

Ω-1cm2mol-1

[Cu(L1)Cl(H2O)3].Cl.3H2O.0.5EtOH,

for

complexes

[Cu(L1)Br(H2O)2].Br.3.25H2O,

[Cu(L2)Cl(H2O)3].Cl.6H2O, and [Cu(L2)Br(H2O)2].Br.3H2O.0.5EtOH are found of the type 1:1 electrolytes 1

[22-24].

Also,

the

molar

conductance

values

for

complexes

2

[Cu(L )(H2O)4](ClO4)2.2.75H2O and [Cu(L )(H2O)4](ClO4)2.7.5H2O.0.5EtOH are found to be 100 and 95 Ω-1 cm2 mol-1 indicating the 2:1 electrolytic nature of these complexes [22-24,25]. However, the low conductance value for [Cu2(L2)(OAc)4].3H2O (15.5 Ω-1cm2mol-1) indicates its non-electrolytic nature. The low molar conductivity of non-electrolyte of this complex is due to partial displacement of the anion by DMF molecules [22]. Insert Table 1 and its caption here Infrared spectral data of L1, L2 ligands and their Cu(II) complexes The important IR spectral bands with their assignment of L1, L2 and their metal complexes taken in the region 4000-400 cm-1 are given in Table (2). These spectra proved some information regarding the mode of coordination in copper(II) complexes and are compared carefully with that of the free ligands, possessed several donor sites as quinolone and indole nitrogens, NH2 group and secondary NH which have a great tendency to interact with copper(II) ion. L1 and L2 ligands have characteristic bands at around (3392, 3358), 1613 and (3322, 5

3260), 1604 cm-1 which are associated to the asymmetric, symmetric NH2 stretching vibrations and in plane –NH2 deformation vibrations, respectively [26-28]. These bands are splitted and lost their intensities for both L1 and L2 complexes. Also, they display a bathochromic shift by 36-117 cm-1 for L1 complexes and they are shifted to different frequencies for L2 complexes. Besides, the red (1582-1608) and the blue (1610-1619) cm-1 shifting of the in plane –NH2 vibrations for L1 and L2 complexes is due to the participation of the NH2 group in coordination. On the other hand, the bands observed at around 1549, 1240, 1161, 745 and 1551, 1249, 1120, 738 cm-1 are assigned to the amino scissoring [27,29], twisting, wagging and rocking modes for L1 and L2 ligands, respectively [28b,29]. The result, as Table (2) shows, is that these amino vibrational bands are strongly affected by complexation. Also, the ligands were characterized by the relevant peaks assignable to the secondary N-H stretching vibration in the range 31503247 cm-1 [30,31]. Upon complexation of L1 and L2 ligands to the copper(II) ion, the stretching vibration of this group is red and blue shifted for L1 and L2 complexes, respectively. All other bands characterized to quinoline and indole nitrogens remain unchanged in copper(II) complexes when compared with the free ligands, indicating that the ring nitrogens are not involved in the coordination. The above results proved that the side-chain nitrogens on the indoloquinoline core are involved in the coordination with the copper(II) ion. The IR spectra of the acetate complexes 7a and 7b exhibit two new bands at 1563-1597 and 1300-1339 cm-1, attributed to asymmetric and symmetric stretching vibrations of acetate ion, respectively. The coordination mode of acetate group has been proved from the difference value (∆υ) between υasym(COO- ) and υsym (COO-). This value is around 264 and 258 cm-1 in copper(II) complexes 7a and 7b, respectively, indicating that the acetate ions are coordinated to the metal ion in the monodentate fashion [32]. In addition, the acetate complexes display medium bands at 1563-1566 and 1403-1409 cm-1 corresponding to bridged bidentate acetate ion [33]. In copper(II) complexes 10a and 10b the presence of perchlorate ion is confirmed by the appearance of strong absorption bands in the region 1080-1089 and 930-934 cm-1 pointed to the asymmetric and symmetric stretching of ClO-4 ion, respectively, in addition to a relatively medium band in the range of 624-627 cm-1 due to bending mode for ClO-4 ion [34]. This indicates that the symmetry of perchlorate ion is maintained in complexes 10a and 10b. Therefore, these data are in agreement with the molar conductance values, Table (1), indicates that the perchlorate ions were found outside the coordination sphere of these complexes. The medium to strong absorption bands of the copper(II) complexes at 3210-3580 cm-1 were found to be ascribed to the overlap between the different NH2 vibrations, lattice/coordinated water 6

molecules or ethanol. Moreover, the spectra of all complexes except 7a and 7b display an additional band at 915-969 cm-1 assigned to coordinated water molecules [24,25]. The appearance of weak bands at 432-486 and 500-595 cm-1 regions in all metal complexes may be assigned to υ(M-N) [33b] and υ(M-O) vibrations, respectively [33a,35a]. Insert Table 2 and its caption here Electronic spectra and magnetic moments: Electronic spectral data of L1, L2, their copper(II) complexes and the room temperature magnetic moment values (µeff BM.) per metal ion are recorded in Table (3). The electronic spectra of L1 and L2 ligands displayed five electronic bands at 250, 285, 315, 345, 380 nm and 255, 283, 310, 340, 385 nm, respectively. The first and the second electronic bands correspond to π-π* transitions of the benzenoid system and heterocyclic rings of the compounds [36,37] which remain nearly unchanged in the spectra of their metal complexes. The third and the fourth bands correspond to n-π* due to the lone pairs of electrons on the nitrogen atom [36] and indole ring. The fifth band can be ascribed to the transition within the whole molecule, essentially an intramolecular charge transfer interaction. The CT bands seem to be originated from the aryl moiety. Copper(II) complexes (d9 system) have different structures due to their various coordination numbers. Six coordinated Cu(II) complexes possesses distorted octahedral structure. Also, four coordinated copper(II) complexes possess distorted tetrahedral or square planar geometry, whereas, five coordinated copper(II) complexes have distorted square pyramidal or triagonal bipyramidal geometry. The observed tetragonal distortion is due to splitting of the eg and t2g levels of the 2D free ion term into B1g, A1g, B2g and Eg levels, respectively. The energy level sequence that depends on the amount of distortion is attributed to the ligand field and Jahn-Teller effect [37]. The electronic spectra of copper(II) complexes 7a and 7b display broad bands at 730, 620, 533 and 720, 610, 520 nm assigned to 2B1g→2A1g(υ1), 2

B1g→2B2g(υ2) and 2B1g→2Eg (υ3) transitions, respectively indicating the square-planar structure

[38]. A moderately intense band observed at 400-430 nm is attributed to O→Cu charge transfer [39]. Also, the electronic spectra of Cu(II) complexes 8a, 8b, 10a and 10b exhibit three bands at 840-860, 600-760 and 480-530 nm corresponding to 2B1g→2A1g(υ1), 2B1g→2B2g(υ2) and 2

B1g→2Eg (υ3), respectively. The spectra are typical of copper(II) complexes with an elongated

tetragonal geometry [40]. This is due to the splitting of 2Eg and 2T2g states of the octahedral Cu(II) (d9) under the effect of the tetragonal distortion. The copper(II) complexes 9a and 9b show three absorption bands with variable intensities at 823-872, 640-711 and 514-580 nm, assigned to

2

B1g→2A1g(υ1),

2

B1g→2Eg(υ2) and

2

B1g→2B2g(υ3) transitions, respectively,

indicating the five-coordinated Cu(II) in square-pyramidal geometry [35,41]. In all copper(II) 7

complexes, a moderately intense peak observed at 345-480 nm is assigned to ligand-metal charge transfer transition [42,43]. The measured magnetic moment values for Cu(II) complexes except 7a and 7b are 1.98-2.2 BM. The value of magnetic moments is higher than the normal value (1.73 BM.) of the copper(II) complexes. This may be due to the spin-orbital coupling [36]. Complexes 7a and 7b show low magnetic moment of 1.4 and 1.3 BM. per copper ion, respectively. The subnormal magnetic moment indicates that the copper centers are antiferromagnetically coupled. Insert Table 3 and its caption here Thermal studies: DTA, (TG and DTG) curves and the data characterized the thermal decomposition behaviors of L1, L2 ligands and their copper(II) complexes 7a-10a, 7b-10b are presented in Table (4). Thermal degradation of ligands L1, L2 and their copper(II) complexes were studied within the temperature range of 20-900°C. DTA curves of L1 and L2 ligands depict two broad endothermic peaks and one asymmetric peak at Tmax=76, 122°C and Tmax =80 °C, respectively. The TG weight losses (12.25 %) and (15.08 %) in these temperature ranges confirm the loss of 2.25 and 3.0 moles of hydrated water. The lower temperature of dehydration Tmax=76 and 80 °C, as well as the weak nature of DTA peak indicating that, the water molecules do not participate in the lattice forces [44,46]. The dehydration process is followed by several endothermic/exothermic peaks located at Tmax = 269, 440, 588, and 148, 403, 428, 497, 675 °C assigned to decomposition of L1 and L2 ligands, respectively, Table (4). The TG curves of ligands ended with 1.0 C as a final product which is stable up to 800-900 °C. The observed differences in the thermal stability of L1 and L2 ligands may be related to the presence of the lattice water molecules that keep the structure of L1 ligand less flexible due to the inner and inter hydrogen bonding [45]. DTA and TG data of copper(II) complexes established that the complexes lose their solvent of crystallization in the temperature range 20-308°C. The desolvation/dehydration process has been characterized by endothermic behavior. The lower onset temperature of desolvation and/or dehydration process (20-26°C) together with its extended range of temperature pointed to the fact that the solvent of crystallizations are distributed in the crystal voids with a physical bonding [35a,46-48]. The desolvation peak is followed by successive endothermicl⁄exothermic peaks assignable to decomposition process. The thermal decomposition of all complexes ended with the formation of copper metal [44,48], copper metal mixed with some of carbon [49a,50a] or a mixture of copper(II) oxide and carbon [49b].

8

The thermal decomposition of acetate complexes 7a and 7b takes place mainly in three successive stages in the temperature range 26-129, 129-223, 223-600 and 20-170, 170-255, 255-450°C, respectively. The first decomposition stage corresponds to the loss 0.75 mole of EtOH+0.75 mole of hydrated H2O and 2.5 moles of hydrated H2O with mass losses of 6.85 % and 6.24 % for complexes 7a and 7b, respectively. The desolvation process is characterized by two successive endothermic DTA peaks at Tmax (53,113°C) and (54,142°C) for complexes 7a and 7b, respectively. The dehydration or desolvation process started at low temperature with weak and broad nature of endothermic peaks suggesting that the solvent has a different crystalline nature [51] as well as the uncoordinated nature of the solvent molecules [48,52-54]. The second stage accompanied by the removal of 2.0 moles of coordinated acetate and (3.0 moles of coordinated acetate+0.5 mole of lattice water) for complexes 7a and 7b, respectively. The DTA curves represented the second stage depicting three/two weak-medium endothermic peaks at Tmax (148, 182, 216) and (205,229°C) for complexes 7a and 7b, respectively. These peaks may be ascribed to the rupture of the coordinate and covalent bonds formed between metal ions and acetate ions [55a], confirming the coordination of acetate [55b]. The third stage assigned to mass loss of 1.46 and 0.46 mole of coordinated acetate associated with ligand decomposition, as indicative from TG mass loss for complexes 7a and 7b, respectively. The third decomposition stage is associated by one strong exothermic DTA peak at Tmax (281°C) and two distinct exothermic DTA peaks at Tmax (297, 368°C) for complex 7a and 7b, respectively. The observed higher percentages of the residue in 7a and 7b than the calculated ones for 2CuO may be due to contamination of the oxide with some of carbon or the formation of other compounds during thermal reaction [49b]. The contamination of the oxide with some of carbon expected to result from the anion breakdown process [50b,c]. The thermal decomposition of halogen complexes 8a, 9a, 8b and 9b proceeds mainly in three stages within temperature range 20-900 °C, Table (4). The first step within temperature range 20-308°C corresponds to loss of TG mass loss of 0.5EtOH, 2.75 H2O in complexes 8a and 9b, complete dehydration in complex 9a and partially dehydration for complex 8b, (loss of 4.75 moles of H2O molecules). This stage is characterized by endothermic peaks, Table (4). In the second decomposition stage within the temperature range 224-404, 308-452, 210-433 and 284-431°C, lattice and/or coordinated water molecules together with the partial decomposition of chlorine or bromine gas were eliminated for 8a, 9a, 8b and 9b chelates, respectively. This stage is associated with endothermic reaction, Table (4). In the third decomposition stage the elimination of 0.25 mole Cl2 gas along with one mole of L1; 0.95 mole of L1; 0.5 mole of Cl2 gas along with 0.85 mole of L2 and 0.6 mole of Br2 gas together 0.84 mole of L2 are 9

characterized by mass losses of 55.42%; 45.26 %; 49.06% and 54.97% for complexes 8a, 9a, 8b and 9b, respectively. The decomposition of L1 and L2 ligands as gases appeared in the DTA graph as broad exothermic peaks at Tmax (719, 810, 719 and 760°C) for these complexes. The thermal decomposition of halogen complexes ended with copper [44] or copper mixed with some of carbon as a final product [49a,50a]. This is attributed to the reducing properties of halide ions towards the copper(II) ions, in addition to the reducing properties of the ligands [44]. Complex 10b is behaving in a manner different from complexes 7a-9a and 7b-9b because during further heating, this complex undergoes delegation reaction in one stage accompanied with the loss of lattice/coordinated water molecules and ionic perchlorate at low temperature but some of the other Cu(II) complexes undergo delegation reaction in more than one stage at higher temperature. This is evident from their plateaus observed in TG curves. The degradation of complex 10b comprises three stages in the temperature range 20-218, 218-229 and 229-400°C. The first one starts with release of 0.5 mole of ethanol and 2.5 moles of hydrated water molecules with a weight loss of 8.54%, whereas, the second decomposition stage within the temperature range 218-229°C corresponds to the loss of five moles of lattice water together with 1.5 moles of ionic perchlorate with a weight loss of 30.02%. Finally, the third decomposition stage exhibits a weight loss of 53.47 % attributed to elimination of four moles of coordinated water, half mole of ionic perchlorate along with one mole of L2 ligand. The TG data, Table (4) indicated that complex 10b starts its decomposition at 218°C to give copper metal as an ultimate pyrolysis product [50,55a]. The mass loss of the final residue of copper(II) complexes 8a, 9a and 8b, 9b has confirmed the chemical formulae agrees with the Cu% which is determined by complexmetric titration. The above discussion and Table (4) showed that all copper(II) complexes of L2 ligand are thermally more stable than those of L1. This may be due to the difference in the size of the chelate ring formed between ligand and copper(II) ion. Insert Table 4 and its caption here Electron spins resonance (ESR) spectral studies The ESR spectral data for copper(II) complexes are listed in Table (5). The ESR spectra of powdered complexes are measured at room temperature and are all axial symmetry with g // › g ⊥ › 2.0023, Table (5). Also, the observed data pointed to the fact that the unpaired electron lies predominantly in the dx2-y2 orbital [37], resulting in a 2B1g ground state [24,56]. In these

10

complexes the g ⊥ > 2.03 where all the principal axes aligned parallel indicating the

tetragonal distorted structure for Cu(II) complexes. The geometric parameter G, which is a measure of the exchange interaction between Cu(II) ions has been calculated using this relation

G = g // − 2.0023 g ⊥ − 2.0023 . In this case the axial symmetry parameter G, lies in the range 4.10-4.35 for all complexes except complexes 7a and 7b, indicating to the absence of the exchange interaction, while, the G values for complexes 7a and 7b are found to be 3.71 and 3.24, respectively, indicating the existence of some exchange interactions between Cu(II) centers. In addition, the g // values < 2.3 indicating a considerable covalence character in copper-ligand bonding in the bonding between copper(II) ion and the ligand [35a,57]. The complexes showed hyperfine spectral lines at the lower field, in addition to an intense unresolved peak in the higher field region as in complex 8b. The high field parts of the spectra are slightly splitted in most of copper(II) complexes. The complexes showed hyperfine splitting and their g // , g ⊥ , A// , A⊥ values have been estimated in Table (5). In case of complex 9a, no detectable hyperfine structure was observed in the solid state, indicating the presence of one species. The spectrum of this complex is anisotropic with g // =2.22 and g ⊥ =2.056 components. The g // region does not exhibit hyperfine coupling. This may be attributed to dipolar interactions between the copper(II) ions in the unit cell [58]. The ESR parameters g // , g ⊥ , A// , A⊥ and the energies of d-d transitions were used to calculate the bonding parameters α2, β2 and γ2 which may measure the covalence of the in-plane σ bonds, inplane π bonds and out-of-plane π bonds, respectively [35a]. The values of the bonding parameters α2, β2 , γ2 and the orbital reduction factors were calculated using the equations reported elsewhere [59]. The observed α 2 values (0.60-0.72) for complexes 7a-9a and 7b-9b, indicate that these complexes have some covalent character for σ-bond between Cu(II) ion and ligands. Meanwhile, the α 2 values are found to be 0.58 and 0.50 for complexes 10a and 10b, indicating complete covalent bonding between copper(II) ion and the ligands [24]. According to Hathaway [59], the K // and K ⊥ values for the complexes under investigation are in agreement with the relation K // < K ⊥ which indicates the presence of significant in-plane π bonding. This is further supported by the bonding parameters α2 and β2 which are less than one, indicating significant in-plane σ-bonding and in-plane π-bonding. Moreover, γ2 values of all complexes except (8a, 7b and 8b) are found to be less than 1.0 indicating the covalent character of the bonds whereas, γ2 values for complexes 8a, 7b and 8b are found to be greater than 1.0 indicate to some ionic character for out-of-plane π bonding. The empirical factor ƒ = g // A// , can be considered as diagnostic of the stereochemistry. The range reported for square planar 11

complexes may vary from 105 to 135 cm, for small to extreme distortion and 150 to 250 cm for tetragonal distorted complexes. The calculated ƒ values for complexes 7a and 7b are in 134.7138.1 cm indicating the distorted square planar structure. Meanwhile, the large ƒ values 161.0214.15 cm, indicate the moderate distortion from planarity. Anticancer Activity: All copper(II) complexes 7a,7b; 8a,8b; 9a,9b; and 10a,10b and the corresponding uncoordinated ligands L 1 and L2 were examined in vitro for their anticancer activity against human colon carcinoma (HT-29) cell line. Screening for

anticancer activity included

measurement of % of the in vitro cell inhibition by using MTT colorimetric assay at 10 µM concentration [21]. The results shown in Table (6) indicated that these complexes exhibited much higher anticancer activity when compared to the corresponding ligands which indicate that the coordination of the chelate ligand around the copper(II) enhances the anticancer activity. Insert Table 6 and its caption here

Furthermore, this result confirmed that the participation of the chloro, bromo, acetate and perchlorate substituent groups in the complex anticancer activities has slight effect. IC50 values were estimated for the most active complexes 7b, 8a and 9b at around 8.77 µM for 7b, 2.21 µM for 8a and 0.58 µM for 9b where complex 9b showed the best anticancer activity as depicted in Figure 2. Insert Figure 2 and its caption here Conclusion In

summary,

new

copper(II)

complexes

coordinated

with

aminoalkylaminoneocryptolepine ligands have been synthesized. The analytical and the spectral data supported the structure and the geometry of complexes. The evaluation of anticancer activity against human colon carcinoma (HT-29) cell line proved that both ligands and their copper(II) complexes are promising anticancer active agents. Of all the studied copper(II) complexes, compound 9b exhibited higher anticancer activity with an IC50 of 0.58 µM. The results also proved that the complexes are more biologically active than that of their ligands. Further variation in transition metal type to obtain more biologically active complexes is currently underway in our laboratory.

Acknowledgements

12

The authors would like to thank Professor Masaharu Seno research team, Division of Biochemistry, Graduate School of Natural Science and Technology, Okayama University for their help with the in vitro anticancer activity.

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20

11

A

B N 5 Me

4

8

D

2 3

9

10

1

C N

7 6

Figure 1. Structure of neocryptolepine.

Figure 2. Dose-survival curves for complexes 7b, 8a and 9b.

Relative cell number (%)

120 100 80 7b

60

9b

40

8a

20 0 0.0001 0.001

0.01

0.1

1

Log concentration (µM)

21

10

Scheme1: Synthesis of the amino neocryptolepine analogues containing N-substituted side-chains at C11. Reagents and conditions: (i) a. N-chlorosuccinimide, 1,4-dimethylpiperazine, CH2Cl2, 0 °C, 2-16 h. b. trichloroacetic acid, N-methylaniline 2, room temperature, 2 h. (ii) diphenyl ether, reflux, 3 h. (iii) POCl3, toluene, reflux, 6-12 h. (iv) appropriate amine, Ethanol, 80 °C, 3-5 h.

22

Compound no.

n

m

q

Compound no.

n

m

q

7a

2

0.75

0.75

9a

1

3.25

-

7b

3

3

-

9b

2

3

0.5

8a

1

3

0.5

10a

1

2.75

-

8b

2

6

-

10b

2

7.5

0.5

Scheme 2: Synthesis of copper(II) complexes of L1 and L2 ligands

23

Table 1: Analytical and physical data of L1, L2 ligands and their copper(II) complexes Empirical Formula No

Compound

Colour

Elemental analysis Found (calcd.) % Yield%

Formula weight L1.2.25 H2O

Brown

C18 H 22.5 N4O2.25

90

M.P. ( o C)

100

330.91 7a

[Cu2(L1)(OAc)4].0.75H2O. 0.75EtOH

Green

C27.5H36N4O9.5Cu2

30

115

701.62 8a

[Cu(L1)Cl(H2O)3].Cl.3H2O.0.5EtOH

Green

C19H33N4 O6.5CuCl2

60

601

556.001 9a

1

[Cu(L )Br(H2O)2].Br.3.25H2O

Green

C18H28.5 N4O5.25CuBr2

90.5

140

608.45 10a

1

[Cu(L )(H2O)4](ClO4)2. 2.75H2O

Beige

C18H31.5N4 O14.75CuCl2

45

230

674.474 L2. 3 H2O

Yellow

C18 H 25.5 N4O2.75

95

95

358.45 7b

[Cu2(L2)(OAc)4].3H2O

Green

C27H38N4 O11Cu2

44

145

721.63 8b

[Cu(L2)Cl(H2O)3].Cl.6H2O

Green

C19H38N4O9CuCl2

54

165

601.41 9b

2

[Cu(L )Br(H2O)2].Br.3H2O.0.5EtOH

Beige

C19H31N4 O5.5Cu Br2

67

162

641.01 10b

2

[Cu(L )(H2O)4](ClO4)2.7.5H2O. 0.5EtOH

Green

C20H46 N4O20CuCl2 797.12

a

: Ω-1 cm 2 mol -1,

X: anion (Cl, Br, ClO4, OAc)

41

265

a

Λ

C

H

N

M

X

65.70

6.03

15.60

-

-

(65.33)

(6.85)

(16.93)

-

-

47.19

5.22

9.01

18.4

-

Insoluble

(47.10)

(5.17)

(8.00)

(18.1)

41.00

6.09

10. 7

11.10

12.75

73.1

(41.04)

(5.98)

(10.1)

(11.42)

(12.77)

35.5

4.41

9.02

10.50

26.50

(35.53)

(4.72)

(9.21)

(10.44)

(26.30)

32.14

43.88

7.73

9.60

-

100

(32.05)

(4.67)

(8.31)

(9.41)

63.89

6.16

14.01

-

-

-

(63.67)

(7.31)

(15.63)

44.85

5.08

8.11

17.6

-

15.3

(44.94)

(5.30)

(7.76)

(17.0)

37.99

5.32

9.21

10.50

11.80

61.2

(37.97)

(6.37)

(9.32)

(10.57)

(11.81)

37.76

5.15

8.69

10.0

25.30

(37.48)

(5.19)

(8.74)

(9.91)

(24.96)

30.37

3.86

6.97

8.21

-

(30.15)

(5.82)

(7.03)

(7.97)

-

86.0

62.5

95.0

Table 2: IR Spectral bands (cm-1) and their assignments for L1, L2 and their copper(II) complexes Compound

υ(O-H)a

υas,υs (NH 2)

υsec (NH )

δ(NH 2)b

δscis (NH2 )

δr(NH2 )d

δt(NH2 )

δw (NH2 )

L1.2.25 H2O

3581w 3473w

3392s 3358s

3247w 3160w

1613 v.s

1549v.s

742 s

1240 m

1161 w

-

-

7a

3480w 3400w

3347s 3268w

3214w 3154w

1608 w

1563(br.s)c

745 s

1254 m

1157 w

474 w

600w

8a

3439(w) 3360(w) 932*

3306br 3241w

3200w 3147w

1582 s

1540w

746 s

1253 m 1234 w

1146 w

456w

520w

-

9a

3477w 3406w 951*

3311-3300m 3270w

3189m

1593 w

1540w

747 s

1253 m

1142 m 1104 w

480m

514w

-

10a

3541sh 3505s 969*

3404s 3350w 3322w

3237m 3178w

1582 sh

1521w 1511m

752 s

1262 m

1141 w

445w

500w

(1089s,934, 622m)f

L2 .3 H2O

3579sh 3434w 3373sh

3322s 3260w

3195w 3150w

7b

3560sh 3466s

3411s

8b

3454sh 3407sh 9430*

9b

3430w 951*

10b

3362sh 3500s 3408s 915*

υ(M-N)

υ(M-O)

υ(Anion) -

(1564,1300)e (1403)e

1604v.s

1551v.s

738 s

1249 w 1214 w

1120 m

-

-

-

3200w

1617 m

1566 (br.s)c

753 w 719 w

1257m 1219m

1140 w 1116 w

432 w

564 w

(1597,1339 )e (1409)e

3368sh 3320w 3210w

3180w 3114w

1615 s

1581sh 1502w

750 s

1255 m

1181 w 1150 w

439 m

595 w

-

3350s, 3277w 3215w 3295w 3261w

3171m

1610 s

1560sh

731 s

1243 m

1186 w 1132 m

479 w

548 w

-

3200w 3180w

1619 s

1589sh 1508m

747 s

1264 m

1154 m

486 w

527w

(1080s,930 624m)f

Abbreviations: br. broad ; m.medium ; s.strong ; v.very ; sh.shoulder; a :overlapping bands with (OH)of EtOH; b overlapped with pyridine and indole rings; c :overlapping with (COO - ); d overlapping with bands with wagging of secondary(NH); e :acetate anions f :perchlorate anions * :coordinated water

Table 3: Electronic spectra and magnetic moment values for copper(II) complexes: No

Compound

Electronic spectral bands (nm)

Assignments

μeff per metal (BM.)

L1.2.25H2O

380, 345 (s.splitted) 315(s), 285 (s),250(s) 730(br) 620(sh) 533(sh) 430(s) 345(m) 285(s) 840(br) 670(sh) 520(sh) 440(s) 285(s) 872(br) 640(sh) 580(sh) 440(m)

n-π* π-π* 2 B1g→2A1g 2 B1g→2B2g 2 B1g→2E g O → Cu LM charge transfer Intraligand transition 2 B1g→2A1g 2 B1g→2B2g 2 B1g→2E g LM charge transfer Intraligand transition 2 B1g→2A1g 2 B1g→2E g 2 B1g→2B2g LM charge transfer

-

7a

[Cu2(L1)(OAc)4].0.75H 2O.0.75EtOH

8a

[Cu(L1)Cl(H2O)3].Cl.3H2O.0.5EtOH

9a

[Cu(L1)Br(H2O)2].Br.3.25H 2O

10a

[Cu(L1)(H2O)4](ClO 4)2.2.75H2O

L2.3H2O

7b

[Cu2(L2)(OAc)4].3H2O

8b

[Cu(L2)Cl(H2O)3].Cl.6H2O

9b

[Cu(L2)Br(H2O)2].Br.3H2O.0.5EtOH

10b

[Cu(L2)(H2O)4](ClO 4)2.7.5H2O.0.5 EtOH

br: broad, m: medium, s: strong, sh: shoulder

760(br) 510(sh) 420(sh) 347(s), 275(s) 385, 340 (s.splitted) 310(s), 283(s),255(s) 720 (br) 610(sh) 520(sh) 400(s) 360(m) 250(s) 860(br) 660(sh) 530(sh) 440(s) 340(m), 285(s) 823(br) 711(sh) 514(sh) 420(w.sh) 340(s), 280, 240 750(br) 538(sh) 480(m) 425(sh) 350(s), 280(s)

2

B1g→2B2g B1g→2E g LM charge transfer Intraligand transition n-π* π-π* 2 B1g→2A1g 2 B1g→2B2g 2 B1g→2E g O → Cu LM charge transfer Intraligand transition 2 B1g→2A1g 2 B1g→2B2g 2 B1g→2E g LM charge transfer Intraligand transition

1.40

2.1

1.8

2.2

2

2

B1g→2A1g B1g→2E g 2 B1g→2B2g LM charge transfer Intraligand transition 2 B1g→2A1g 2 B1g→2B2g 2 B1g→2E g LM charge transfer Intraligand transition 2

1.30

2.09

1.90

2.2

Table 4: Thermal analysis of Cu(II) complexes of L 1 and L 2 ligands : No

Compound L1.2.25 H2O

7a

8a

a

[Cu2(L1)(OAc)4].0.75H2O. 0.75EtOH

[Cu(L1)Cl(H2O)3].Cl.3H2O. 0.5EtOH

Ts (0C )

DTA range (°C)

DTA Peak (°C)

TG range (°C)

Mass Loss % Calcd. Found

21-115w 115-142w 196-386br 415-496

76(+) 122(+) 269(+) 440(+)

21-196

12.30

12.25

Loss of 2.25 moles of hydrated water a

196-400 400-500

46.70 10.66

47.20 10.9

Loss of C10H8N2 (= 0.54 mole of L1)c Loss of two moles of NH3 and one of H2 (= 0.12 mole of L1)c

528-656

588(-)

500-750

26.56

26.02

Loss of 7C and one mole of H2 (= 0.30 mole of L1)c

750

3.80

3.63

1.0 C (=0.04 mole of L1)f

26-129

6.79

6.85

129-223

16.82

16.83

Loss of 0.75 mole of ethanol molecule and 0.75 mole of hydrated water a Loss of two moles of coordinated acetate c

223-600

26.90

26.76

600

49.51

49.56

20-224

13.00

13.05

Loss of 0.5 mole of ethanol molecule and 2.75 moles of hydrated water a

224-404

19.80

20.11

404-900

55.45

55.42

Loss of 0.25 mole of lattice water, 3 moles of coordinated water and 0.75 mole of chlorine gas c Loss of 0.25 mole of chlorine gas and 2NH3, N2, 2C6H6 , 6C (= one mole of L1)c

900

11.12

11.42

26-80w 88-127m 129-167w 167-207s 207-223w 239-364vs 364-600br 20-122br 143-162s 162-191 280-346br 346-404br 365-434w 446-521s 601-787br 810-845w 845-900w

53(+) 113(+) 148(+) 182(+) 216(+) 281(-) 470(+) 70(+) 152(+) Sh. 324(+) 365(+) 404 (+) 484(+) 719(-) 826(+) 858(+)

Assignment

129

Loss of C4H6O 2 (=1.46 moles of coordinated acetate) and 4NH3, C2H2, 0.5C (=0.35 mole of L1)c 2CuO and ligand residue (0.65 mole of L1) f 224

Cuf

: Dehydration, b: Desolvation, c: Decomposition, f: Final residue, w: weak, s: strong, m: medium, br: broad, sh.: shoulder, endothermic peak, (-): exothermic peak

-1-

196

v.s: very strong, (+):

Table 4: Continued No

9a

Compound [Cu(L1)Br(H2O)2].Br.3.25H2O

L2.3 H2O

7b

[Cu2(L2)(OAc)4].3H2O

Ts (0C )

DTA range (°C)

DTA Peak (°C)

TG range (°C)

Mass Loss % Found Clacd.

Assignment

26-90w 90-184 184-235w 235-308 308-388 388-452w 452-692s 692-753w 783-831br

49(+) Sh. 213(+) Sh. Sh. 448(+) 527(+) 700(+) 810(-)

26-308

9.53

9.62

Loss of 3.25 moles of hydrated watera

308-452

32.50

32.22

452-900

45.05

45.26

Loss of two moles of coordinated water and one mole of bromine gasc Loss of 2NH3, N2, 2C6H6, 4.75C (=0.95 L1)c

900

12.99

12.9

Cu and 1.25C (=0.05L1)f Loss of 3.0 moles of hydrated water a Loss of two moles of NH3 gas and one mole of H2 gas (=0.12 mole of L2)c Loss of C11H9N2 (=0.56 mole of L2)c Loss of 1.5 moles of H2 gas and 6.75 moles of C (=0.28 mole of L2)c

308

21-111 129-164

80 (+) 148(+)

21-111 111-174

15.34 10.22

15.08 10.07

339-417 417-471 471-542 650-715

403(+) 428(+), 497(+) 675(-)

174-417 417-715

47.10 23.43

47.20 23.46

715

3.94

4.19

1.25C (=0.05mole of L2) f

20-170

6.40

6.24

Loss of 2.5 moles of hydrated water a

170-255

25.74

25.80

255-450

27.51

27.62

Loss of 0.5 mole of lattice water and 3 moles of coordinated acetate c Loss of 0.46 mole of coordinated acetate and 4NH3, C6H6, C2H2 (=0.57mole of L2)c

450

40.41

40.34

20-90br 100-170w 172-217s 217-255w 255-324s 324-477 434-600br

54 (+) 142(+) 205(+) 229(+) 297(-) 368(-) 477(+)

a

170

2CuO + ligand residue (=0.43mole of L2)f

: Dehydration, b: Desolvation, c: Decomposition, f: Final residue, w: weak, s: strong, m: medium, br: broad, sh.: shoulder, endothermic peak, (-): exothermic peak

-2-

111

v.s: very strong, (+):

Table 4 : Continued No

8b

9b

10b

Compound [Cu(L2)Cl(H2O)3].Cl.6H2O

[Cu(L2)Br(H2O)2].Br.3H2O. 0.5EtOH

[Cu(L2)(H2O)4](ClO4)2.7.5H2O. 0.5EtOH

DTA range (°C) 21-110br 141-171s 171-210 252-355s 355-433br 433-523br 601-787br

21-101br 127-151w 151-184br 200-284 284-319w 319-404br 404-431br 453-491w 491-526br 557622w 683-795br -

DTA Peak (°C) 62(+) 156(+) Sh.(+) 325(+) 377(+) 487(+) 719(-)

65(+) 141(+) 164(+) Sh. 304(+) 389(+) 416(+) 477(+) 509(+) 586(+) 760(-) -

TG range (°C) 21-210

Mass Loss % Foun Clacd. d 14.29 14.23

210-433

18.68

18.65

433-800

48.97

49.06

800

18.14

18.06

21-284

11.34

11.32

Loss of 0.5 mole of ethanol molecule and 2.75 moles of hydrated water a, b

284-431

16.15

16.31

Loss of 0.25 mole of lattice water , two moles of coordinated water and 0.4 mole of bromine gasc

431-850

55.12

54.97

Loss of 0.6 mole of bromine gas and 2NH3, N2, H2, 2C6H6, 3C (=0.84 mole of L2)c

850

17.03

17.4

Cu+4 C (=0.16 mole of L2) f

20-218

8.53

8.54

Loss of half mole of ethanol and 2.5 moles of hydrated water a,b

218-229

30.10

30.02

229-400

53.54

53.47

400

7.86

7.97

Loss of five moles of lattice water and 1.5 moles of ionic perchlorate c Loss of four moles of coordinated water, half mole of ionic perchlorate and one mole of L2)c Cuf

a

Assignment

Ts (0 C )

Loss of 4.75 moles of hydrated water a

210

Loss of 1.25 moles of lattice water, 3 moles of coordinated water and 0.5 mole of chlorine gas c Loss of 0.5 mole of chlorine gas and 2NH3, N2, H2 C6H6, 3.25C (=0.85 mole of L2)c Cu+3.75C(=0.15 mole of L2) f

: Dehydration, b: Desolvation, c: Decomposition, f: Final residue, w: weak, s: strong, m: medium, br: broad, sh.: shoulder, endothermic peak, (-): exothermic peak

-3-

284

218

v.s: very strong, (+):

Table 5: ESR spectral parameters of copper(II) complexes of L1 and L2 ligands: Parameter

7a

8a

9a

10a

7b

8b

9b

10b

g//

2.191

2.233

2.220

2.204

2.212

2.244

2.210

2.093

g⊥

2.053

2.058

2.056

2.051

2.068

2.062

2.050

2.031

a

gav

2.099

2.116

2.111

2.102

2.116

2.123

2.103

2.047

G

3.710

4.150

4.100

4.140

3.240

4.300

4.350

4.200

A//

162.0

104.27

-

114.35

160.1

104.79

136.0

129.99

A⊥

31.60

19.280

32.24

39.9

40.60

-

48.00

-

Aav

75.30

47.130

-

64.76

80.43

-

78.00

-

*ƒ

134.7

214.15

-

192.70

138.1

214.14

163.0

161.0

α2

0.700

0.600

-

0.580

0.720

0.604

0.650

0.510

β2

0.650

0.896

-

0.691

0.718

0.920

0.680

0.460

γ2

0.820

1.115

-

0.994

1.060

1.140

0.850

0.530

K//

0.670

0.720

-

0.633

0.719

0.741

0.660

0.480

K⊥

0.760

0.804

-

0.759

0.874

0.825

0.750

0.520

d

Kav

0.730

0.776

-

0.717

0.822

0.798

0.720

0.510

e

Δ2

16129

14925

-

13157

16393

15151

14065

16667

e

Δ3

18762

19231

-

19607

19231

18868

19455

20833

b

b

c

a

gav=2g⊥+g///3, d Kav=2K⊥+K///3,

b

A values in 10-4 cm-1, e d-d transition in cm-1,

c

Aav=2A⊥+A///3 * ƒ (in cm) = g///A//

Table 6: The percentages of cell inhibition induced by ligands and their corresponding copper(II) complexes in the human colon carcinoma cell line. Compound

% of cell inhibition after 72 h

Compound

% of cell inhibition after 72 h

L1

80

L2

83.7

7a

81

7b

95.4

8a

90.4

8b

89.1

9a

87.30

9b

92

10a

88.6

10b

90.1

*Inhibition rate (%) was calculated at 0.01 mM concentration using MTT assay, DMSO was used as solvent which is widely used in cell-culture studies.

Transition Metal Complexes of Neocryptolepine Analogues Part I: Synthesis, Spectroscopic Characterization, and In Vitro Anticancer Activity of Copper(II) Complexes S. M. Emam, I. El-T. El Sayed, N. M. Nassar

Highlights ► New series of copper(II) complexes bearing aminoalkylaminoneocryptolepine ligands were synthesized. ► Spectroscopic characterization of ligands and complexes. ► The ligands and complexes showed potent anticancer activity against HT-29. ► The complexation led to a remarkable increase in anticancer activity.