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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 5 pp. 1147ñ1153, 2016 ISSN 0001-6837 Polish Pharmaceutical Society DRUG SYNTHESIS DESIGN, SYNTHESIS AND ANTICANCER ACTIVITY OF SOME NOVEL 1,2,4-TRIAZOLES CARRYING BIOLOGICALLY ACTIVE SULFONAMIDE MOIETIES MOSTAFA M. GHORAB1,2*, MANSOUR S. ALSAID1 and MOHAMMED S. AL-DOSARI1 Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 2 Department of Drug Radiation Research, National Center for Radiation Research and Technology, Nasr City, Cairo 113701, Egypt 1 Abstract: Thirteen novel 1, 2, 4-triazoles incorporating a biologically active sulfonamide moieties 1-13 were designed and synthesized. The structures of the prepared compounds were elucidated on the basis of elemental analyses, IR, 1H-NMR, 13C-NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. The corresponding triazole carrying a biologically active free sulfonamide with unsubstituted phenyl ring 1 and triazole bearing sulfonamide with dimethylpyrimidine 11 were the most potent in this study which showed higher activity than the reference drug 2í,7í-dichlorofluorescein (DCF). Cytotoxic screening of the tested compounds could offer an encouraging framework in the field that may lead to the discovery of potent anticancer activity. Keywords: Synthesis, triazoles, benzenesulfonamides, anticancer activity From the literature survey it was found that 1,2,4-triazoles and their derivatives have great importance in medicinal chemistry and can be used for the synthesis of numerous heterocyclic compounds with different biological activities such as antiviral, antibacterial, antifungal, antituberculosis, anticonvulsant, antidepressant, anti-inflammatory and anticancer activities (1). They have been reported to be inhibitors of glycogen synthase kinase-3 (2), antagonists of GABA receptors (3, 4), agonists of muscarine receptors (5), be neuroleptic (6), and these compounds also show anti-HIV-1 (7), cytotoxic (8), antihistaminic (9), and antiproliferative (10) activities. The advent of high-throughput screening systems has allowed us to evaluate a large number of small molecules in parallel and automated fashions. In response to this screening innovation, one of the greatest concerns in recent drug discovery programs has been directed toward how to design and prepare compound libraries for getting ìhitsî in various biological assays (11). In this regard, historical reviews of drug discovery often give us practical lessons. One highly informative example is represented by the sequential development of sulfonamide therapeutics such as antibiotic sulfa drugs, insulin-releasing hypoglycemic agents, carbonic anhydrase inhibitory diuretics, high-ceiling diuretics, and antihypertensive drugs (12-14). These diverse pharmacological effects were serendipitously found through the serial derivatization of a single chemical structure of sulfanilamide, indicating that the sulfonamide moiety is a crucial functionality capable of interacting with multiple cellular targets. Therefore, we have seriously considered that novel anticancer chemotherapeutics might be discovered from the sulfonamide class. E7010 was shown to reversibly bind to the colchicine site of β-tubulin, thereby halting mitosis (15-19). The compound exhibited good in vivo efficacy against rodent tumors and human tumor xenografts (20). As a p.o.active antimitotic agent, E7010 demonstrated objective responses in 2 of 16 patients in the single-dose study of phase I trials; spinal cord metastasis was reduced by 74% in a patient with uterine sarcoma, and a minor response was observed in a pulmonary adenocarcinoma patient (21). In contrast to E7010, * Corresponding author: e-mail: [email protected]; [email protected], phone: +966-53-4292-860; fax: +966-01-4670-560. 1147 1148 MOSTAFA M. GHORAB et al. E7070 was found to block cell cycle progression of P388 murine leukemia cells in the G1 phase, accompanied by a decrease in the S-phase fraction (16). Although its precise mode of action has not yet been determined, E7070 appears to be considerably different from conventional anticancer drugs in clinical use with respect to its cell cycle effect and its tumor type selectivity (18-22). Furthermore, preclinical animal tests established the promising efficacy of E7070 against human tumor xenografts (22). Thus, the compound has progressed to clinical evaluation in collaboration with the European Organization for Research and Treatment of Cancer (23). In the phase I setting, one patient with a uterine adenocarcinoma experienced a partial response with a > 50% shrinkage of measurable tumors after i.v. administration on the weekly schedule (24). Another partial response was reported in a patient with breast cancer on the daily ◊ 5 schedule (25). Phase II studies of E7070 are currently ongoing in Europe and the United States. On the basis of the significant observations described above, together with our interest in the synthesis of biologically active heterocyclic compounds (26-31) we decided to synthesize several novel sulfonamide carrying a biologically active 1,2,4-triazole analogs of E7010, E7070, ER-67865, and ER-68487 (Fig. 1) to evaluate their anticancer activity. Germany) were used for thin layer chromatography. A developing solvent system of chloroform/ methanol (8 : 2, v/v) was used and the spots were detected by ultraviolet light. IR spectra (KBr disc) were recorded using an FT-IR spectrophotometer (Perkin Elmer, USA). 1H-NMR spectra were scanned on a NMR spectrophotometer (Bruker AXS Inc., Switzerland), operating at 500 MHz for 1H- and 125.76 MHz for 13C spectra. Chemical shifts are expressed in ppm values relative to TMS as an internal standard, using DMSO-d6 as a solvent. Elemental analyses were done on a model 2400 CHNSO analyzer (Perkin Elmer, USA). All the values were within ± 0.4% of the theoretical values. All reagents used were of AR grade. The starting materials for sulfonamide derivatives were purchased from Sigma (USA) and were directly used for the preparation of target compounds. Synthesis of 1,2,4-triazole-sulfonamide derivatives (1-13). General procedure A mixture of benzoylhydrazine (1.22 g, 0.01 mol), dimethylformamide-dimethylacetal (1.91 g, 0.01 mol)) and sulfa-drugs (0.012 mol) in dry acetonitrile (15 mL) containing acetic acid (3 mL) was refluxed for 9 h., then left to cool. The solid product formed was collected by filtration and recrystallized from dioxane to give compounds 1-13, respectively. EXPERIMENTAL Chemistry Melting points (uncorrected) were determined in open capillary on a Gallenkamp melting point apparatus (Sanyo Gallenkamp, UK). Precoated silica gel plates (Kieselgel 60 F254, 0.25 mm, Merck, 4-(3-Phenyl-4H-1,2,4-triazol-4-yl) benzenesulfonamide (1) Yield 66%; m.p. 191.9OC. IR (KBr, cm-1): 3202, 3114 (SO2NH2), 3074 (CH arom.), 1615 (C=N), 1367, 1161 (SO2). 1H-NMR (DMSO-d6): 7.4-7.9 (m, 11H, Ar-H + SO2NH2), 9.7 (s, 1H, CH Figure 1. Drug discovery flow chart of a series of antitumor sulfonamides Design, synthesis and anticancer activity of some novel 1,2,4-triazoles... triazole). 13C-NMR (DMSO-d6): 127.4 (2), 127.9 (2), 128.7 (2), 128.9 (2), 131.5 (2), 133.7 (2), 158.1, 166.3. MS m/z (%): 300 (M+) (10.08), 74 (100). Analysis: calcd. for C14H12N4O2S (300): C, 55.99; H, 4.03; N, 18.65%; found: C, 55.68; H, 4.32; N, 18.34%. N-[4-(3-phenyl-4H-1,2,4-triazol-4-yl) phenylsulfonyl]acetamide (2) Yield 81%; m.p. 233.8OC. IR (KBr, cm-1): 3254 (NH), 3067 (CH arom.), 2913, 2836 (CH aliph.), 1703 (C=O), 1378, 1183 (SO2). 1H-NMR (DMSOd6): 2.8 (s, 3H, COCH3), 7.3-8.0 (m, 9H, Ar-H), 9.3 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSOd6): 19.0, 127.7 (2), 128.2 (2), 129.4 (2), 129.9, 132.9 (2), 133.1, 134.9, 137.3, 144.1, 154.2, 191.8. MS m/z (%): 342 (M+) (8.34), 121 (100). Analysis: calcd. for C16H14N4O3S (342): C, 56.13; H, 4.12; N, 16.36%; found: C, 56.41; H, 4.37; N, 16.11%. N-carbamimidoyl-4-(3-phenyl-4H-1,2,4-triazol-4yl) benzenesulfonamide (3) Yield 77%; m.p. 225.3OC. IR (KBr, cm-1): 3343, 3222, 3132 (NH, NH2), 3054 (CH arom.), 1373, 1152 (SO2). 1H-NMR (DMSO-d6): 7.5 (s, 3H, NH2 + NH imino, exchangeable with D2O), 7.6-7.9 (m, 9H, Ar-H), 10.5 (s, 2H, SO2NH + CH triazole), 13C-NMR (DMSO-d6):126.7 (2), 127.9 (2), 128.9 (3), 129.8 (2), 132.3 (2), 133.0, 142.8, 162.3, 166.3. MS m/z (%): 342 (M+) (3.94), 119 (100). Analysis: calcd. for C15H14N6O2S (342): C, 52.62; H, 4.12; N, 24.55%; found: C, 52.29; H, 4.46; N, 24.84%. N-(3-methylisoxazol-5-yl)-4-(3-phenyl-4H-1,2,4triazol-4-yl) benzenesulfonamide (4) Yield 69%; m.p. 133.8OC. IR (KBr, cm-1): 3254 (NH), 3071 (CH arom.), 2943, 2854 (CH aliph.), 1602 (C=N), 1366, 1145 (SO2). 1H-NMR (DMSOd6): 2.3 (s, 3H, CH3), 6.2 (s, 1H, CH isoxazole), 6.48.0 (m, 9H, Ar-H), 10.5 [s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 12.6, 97.5, 127.1 (2), 127.9 (2), 128.7 (2), 129.6, 129.9 (2), 132.2, 133.5, 137.0 (2), 154.4, 161.0, 170.9. MS m/z (%): 381 (M+) (7.97), 81 (100). Analysis: calcd. for C18H15N5O3S (381): C, 56.68; H, 3.96; N, 18.36%; found: C, 56.34; H, 3.59; N, 18.09%. N-(3,4-dimethylisoxazol-5-yl)-4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (5) Yield 71%; m.p. 254.2OC. IR (KBr, cm-1): 3332 (NH), 3088 (CH arom.), 2932, 2822 (CH aliph.), 1589 (C=N), 1367, 1166 (SO2). 1 H-NMR (DMSOd6): 2.1, 2.4 (2s, 6H, 2CH3), 6.7-8.3 (m, 9H, Ar-H), 1149 10.0 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 6.7, 10.3, 113.0, 127.9 (2), 128.1 (2), 128.9 (2), 129.0, 129.1 (2), 132.3 (2), 132.7 (2), 153.6, 160.4, 161.5. MS m/z (%): 395 (M+) (9.41), 174 (100). Analysis: calcd. for C19H17N5O3S (395): C, 57.71; H, 4.33; N, 17.71%; found: C, 57.42; H, 4.69; N, 17.98%. N-(1-phenyl-1H-pyrazol-5-yl)- 4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (6) Yield 76%; m.p. 317.6OC. IR (KBr, cm-1): 3197 (NH), 3049 (CH arom.), 1584 (C=N), 1372, 1165 (SO2). 1H-NMR (DMSO-d6): 6.8-8.7 (m, 16H, ArH), 9.2 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 110.3, 121.6 (2), 124.8, 125.9 (2), 126.2 (2), 127.4 (2), 128.7 (2), 128.9, 130.4 (2), 133.6, 135.5, 135.8, 142.7, 143.9 (2), 147.6, 155.8. MS m/z (%): 442 (M+) (7.53), 92 (100). Analysis: calcd. for C23H18N6O2S (442): C, 62.43; H, 4.10; N, 18.99%; found: C, 62.10; H, 4.35; N, 18.64%. 4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-N-(thiazol-2yl) benzenesulfonamide (7) Yield 83%; m.p. 243.0OC. IR (KBr, cm-1): 3231 (NH), 3100 (CH arom.), 1601 (C=N), 1365, 1149 (SO2). 1H-NMR (DMSO-d6): 7.5-7.9 (m, 11H, ArH), 10.5 (s, 2H, SO2NH + CH triazole), 13C-NMR (DMSO-d6): 122.3, 127.9 (2), 128.7 (3), 128.9 (2), 132.3 (3), 133.0 (2), 166.3 (2). MS m/z (%): 383 (M+) (19.48), 76 (100). Analysis: calcd. for C17H13 N5O2S2 (383): C, 53.25; H, 3.42; N, 18.26%; found: C, 53.56; H, 3.11; N, 17.93%. 4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-N-(pyridin-2yl) benzenesulfonamide (8) Yield 88%; m.p. 197.2OC. IR (KBr, cm-1): 3363 (NH), 3082 (CH arom.), 1620 (C=N), 1393, 1159 (SO2). 1H-NMR (DMSO-d6): 6.6-8.1 (m, 13H, ArH), 11.0 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 112.6, 117.5, 126.1 (2), 126.2 (3), 129.2 (3), 129.3 (2), 139.2 (2), 139.4 (2), 146.7, 152.8, 153.2. MS m/z (%): 377 (M+) (4.32), 77 (100). Analysis: calcd. for C19H15N5O2S (377): C, 60.46; H, 4.01; N, 18.56%; found: C, 60.78; H, 3.83; N, 18.19%. 4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-N-(pyrimidin2-yl) benzenesulfonamide (9) Yield 73%; m.p. 268.8OC. IR (KBr, cm-1): 3194 (NH), 3077 (CH arom.), 1598 (C=N), 1375, 1191 (SO2). 1H-NMR (DMSO-d6): 6.0-8.4 (m, 12H, ArH), 11.2 (s, 2H, SO2NH + CH triazole),13C-NMR (DMSO-d6): 112.6, 125.2 (2), 125.3 (2), 129.0 (2), 129.1 (3), 130.1 (2), 130.3 (2), 153.5, 157.7 (2), 1150 MOSTAFA M. GHORAB et al. 158.7. MS m/z (%):378 (M+) (6.74), 58 (100). Analysis: calcd. for C18H14N6O2S (378): C, 57.13; H, 3.73; N, 22.21%; found: C, 57.48; H, 3.47; N, 21.88%. N-(4-methylpyrimidin-2-yl)-4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (10) Yield, 75%; m.p. 239.1OC. IR (KBr, cm-1): 3280 (NH), 3039 (CH arom.), 2941, 2855 (CH aliph.), 1618 (C=N), 1359, 1164 (SO2). 1H-NMR (DMSO-d6): 2.0 (s, 3H, CH3), 6.6-8.3 (m, 11H, ArH), 11.1 (s, 2H, SO2NH + CH triazole).13C-NMR (DMSO-d6): 23.8, 112.5, 125.5 (4), 130.5 (5), 136.7 (4), 153.4, 157.4, 158.0, 168.4. MS m/z (%): 392 (M+) (13.62), 92 (100). Analysis: calcd. for C19H16N6O2S (392): C, 58.15; H, 4.11; N, 21.42%; found: C, 57.82; H, 4.43; N, 21.11%. N-(4,6-dimethylpyrimidin-2-yl)-4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (11) Yield 78%; m.p. 248.3OC. IR (KBr, cm-1): 3312 (NH), 3063 (CH arom.), 2967, 2863 (CH aliph.), 1613 (C=N), 1356, 1181 (SO2). 1H-NMR (DMSOd6): 2.2 (s, 6H, 2CH3), 6.0 (s, 1H, CH pyrimidine), 7.5-7.9 (m, 9H, Ar-H), 10.9 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 23.8 (2), 112.6, 127.1 (4), 127.9 (3), 128.9 (2), 132.3 (2), 133.0 (2), 157.2, 166.3 (3). MS m/z (%): 406 (M+) (23.24), 79 (100). Analysis: calcd. for C20H18N6O2S (406): C, 59.10; H, 4.46; N, 20.68%; found: C, 58.84; H, 4.15; N, 20.32%. N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-phenyl4H-1,2,4-triazol-4-yl) benzenesulfonamide (12) Yield 68%; m.p. 153.6OC. IR (KBr, cm-1): 3228 (NH), 3059 (CH arom.), 2933, 2862 (CH aliph.), 1622 (C=N), 1368, 1181 (SO2), 1H-NMR (DMSOd6): 3.80, 3.89 (2s, 6H, 2OCH3), 6.2 (s, 1H, CH pyrimidine), 6.4-7.5 (m, 9H, Ar-H), 7.9 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 54.3, 54.8, 88.4, 113.1 (3), 122.6 (3), 124.9 (4), 129.6 (3), 154.2, 161.6, 164.3, 172.2. MS m/z (%): 438 (M+) (19.38), 142 (100). Analysis: calcd. for C20H18N6O4S (438): C, 54.79; H, 4. 14; N, 19.17%; found: C, 54.46; H, 4.43; N, 19.50%. N-(5,6-dimethoxypyrimidin-4-yl)-4-(3-phenyl4H-1,2,4-triazol-4-yl) benzenesulfonamide (13). Yield 72%; m.p. 198.1OC. IR (KBr, cm-1): 3310 (NH), 3073 (CH arom.), 2974, 2832 (CH aliph.), 1611 (C=N), 1366, 1154 (SO2). 1H-NMR (DMSOd6): 3.6, 3.8 (2s, 6H, 2OCH3), 6.0-8.1 (m, 10H, ArH), 10.6 (s, 2H, SO2NH + CH triazole).13C-NMR (DMSO-d6): 54.3, 60.6, 112.6 (2), 125.6 (3), 127.2 (3), 130.2 (4), 151.0 (3), 151.2, 153.9, 161.5. MS m/z (%): 438 (M+) (2.27), 152 (100). Analysis: calcd. for C20H18N6O4S (438): C, 54.79; H, 4.14; N, 19.17%; found: C, 54.40; H, 4.45; N, 19.45%. In vitro anticancer evaluation Cell culture Human cancer cell lines HeLa (cervical), A549 (lungs) and Lovo (colorectal) were grown in DMEM Table 1. In vitro anticancer screening of the synthesized compounds against four cell lines. Compd. No. A549 (lungs) HeLa (cervical) Lovo (colorectal) MDA-231 (breast) IC50(µg/mL)a 1 37.01 68.96 NA 67.24 2 NA NA NA NA 3 NA NA NA NA 4 NA NA NA NA 6 NA NA NA NA 7 NA NA NA NA 8 NA NA NA NA 9 NA NA NA NA 10 NA NA NA NA 11 NA 55.71 NA 73.77 12 NA NA NA NA 13 NA NA NA NA DCF 124.87 54.07 114.12 113.94 All experiments were performed in triplicate, and the mean is used to calculate the IC50. NA = No activity, DCF = 2',7'-dichlorofluorescein. a Design, synthesis and anticancer activity of some novel 1,2,4-triazoles... 1151 Scheme 1. Synthetic pathways for compounds 1-13 + GlutaMax (Invitrogen), and MDA MB321 (breast) were grown in DMEM-F12 + GlutaMax) medium (Invitrogen), supplemented with 10% heat-inactivated bovine serum (Gibco) and 1◊ penicillin-streptomycin (Gibco) at 37OC in a humified chamber with 5% CO2 supply. The source of the used cancer cell lines is ATCC, Virginia, USA, and all experiments were performed in triplicate, and the mean is used to calculate the IC50. Cytotoxicity assay The in vitro anticancer screening was done at Pharmacognosy Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Cells were seeded (105 cells/well) in 96-well flat-bottom plates (Becton-Dickinson Labware) a day before treatment and grown overnight. Compounds were dissolved in dimethyl sulfoxide (DMSO; Sigma) and finally prepared as 1.0 mg/mL stocks, respectively, in the culture media. The final concentration of DMSO never exceeded 0.1% in the treatment doses. Four different doses of compounds (50, 25, 12.5 and 6.25 µg/mL) were further prepared by diluting the stocks in culture media, and cells were treated (in triplicate/dose). 2í,7í-dichlorofluorescein (DCF) was included as standard reference drug (positive control) and untreated culture was considered as negative control. The treated cultures were further incubated for 48 h. At 48 h post-treatment, cell viability test was performed using TACS MTT Cell Proliferation and Viability Assay Kit (TACS) acc. to manufacturerís instructions. The optical density (OD) was recorded at 570 nm in a microplate reader (BioTek, ELx800) and cell survival fraction was determined. The cell survival fraction was calculated as [(A-B)/A], where A and B are the optical densities (OD) of untreated and of treated cells, respectively. The IC50 values of the tested compound were estimated using the best fit regression curve method in Excel. Microscopy A direct visual investigation was made under an inverted microscope (Optica, 40◊ and 100◊) to 1152 MOSTAFA M. GHORAB et al. observe any morphological changes in the cells cultured with different treatment doses at 24 and 48 h. Chemistry The aim of this work was to design and synthesize a new series of 1,2,4-triazoles having a biologically active benzenesulfonamide moieties to evaluate their anticancer activity. There are many reported methods to synthesize substituted-1,2,4-triazole derivatives. An efficient one-pot, three components synthesis of substituted-1,2,4-triazoles has been developed by Michael (32), utilizing a wide range of substituted primary amines, acyl hydrazines, and dimethoxy-N,N-dimethylmethanamine. In this paper, the corresponding 1,2,4-triazole-sulfonamides 1-13 were synthesized by the Michael method: dimethoxy-N,N-dimethylmethanamine and benzoylhydrazine were reacted in acetonitrile containing acetic acid as catalyst for 9 h, and then sulfonamide derivatives were added to the mixture to obtain the corresponding 1,2,4-triazolesulfonamides 1-13, respectively (Scheme 1). The structures of the obtained products were established on the basis of microanalysis, IR, 1H-NMR, 13CNMR and mass spectral data. In vitro anticancer evaluation The synthesized compounds were evaluated for their in vitro anticancer activity against human lung cancer cell line (AS49-Raw), cervical (Hela) cancer cell line, colorectal cell line (Lovo) and breast cancer cell line (MDA-MB231) using 2í,7ídichlorofluorescein (DCF) as reference drug in this study. The relationship between surviving fraction and drug concentration was plotted to obtain the survival curve of cancer cell lines. From the results (Table 1) it was found that 1,2,4-triazole 1 having free sulfonamide SO2NH2 with unsubstituted phenyl ring exhibited higher activity against lung and breast cancer cell lines with IC50 values (37.01, 67.24 µg/mL) than the positive control DCF with IC50 values (124.87 and 113.94 µg/mL). Also, it was found that compound 1 exhibited a remarkable activity against Hela cell line with IC50 value (68.96 µg/mL). In addition, compound 1 revealed no activity against Lovo (colorectal) cell line. On the other hand, 1,2,4triazole 11 containing sulfonamide with dimethylpyrimidine showed higher activity with IC50 value (73.77 µg/mL) against breast cancer cell line compared with DCF with IC50 value (113.94 µg/mL). Compound 11 with IC50 value (55.71 µg/mL) is nearly as active as DCF with IC50 value (54.07 µg/mL) as positive control against HeLa cell line. CONCLUSION In this work, a novel 1,2,4-triazoles-sulfonamides hybrids were synthesized and their in vitro anticancer activity was evaluated on four human tumor cancer cell lines. Among the tested compounds, two candidates 1 and 11 were the most potent in this study, which showed higher activity than the reference drug 2í,7í-dichlorofluorescein (DCF). The active compounds could be considered as useful templates for further development to obtain more potent anticancer agent(s). 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