Synthesis,Characterization, and Biological Study of 3-Trifluoromethylpyrazole Tethered Chalcone-Pyrrole and Pyrazoline-Pyrrole Derivatives

The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All compounds were further screened for in vitro cytostatic activities on full NCI 60 cancer cell lines at National Cancer Institute, USA. Compounds (2E)-3-(1H-pyrrol-2-yl)-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}prop-2-en-1-one ( 5a ) and (2E)-1-{3-methyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-(1H-pyrrol-2-yl)prop-2-en-1-one ( 5c ) displayed significant antiproliferative activity (Growth Percentage: −77.10 and −92.13, respectively at 10 μM concentration) against the UO-31 cell lines from renal cancer and were further selected for assay at 10-fold dilutions of five different concentrations (10⁻⁴ to 10⁻⁸ M). Both compounds 5a and 5c exhibited promising antiproliferative activity (GI₅₀: 1.36 to 0.27 μM) against leukemia cancer cell lines HL-60 and RPMI-8226, colon cancer cell lines KM-12; breast cancer cell lines BT-549. Moreover, both compounds 5a and 5c were found to be non-cytotoxic (LC₅₀>100) against HL-60, RPMI-8226, and KM-12 cell lines. Remarkably, GI₅₀ values of compounds 5a and 5c were identified as more promising than sunitinib against most cancer cell lines. In silico study of compounds 5a and 5c exemplified the desired ADME properties for drug-likeness as well as tighter interactions with VEGFR-2. Hence, compounds 5a and 5c would be good cytotoxic agents after further clinical study.     

Novel ceramide analogues display selective cytotoxicity in drug-resistant breast tumor cell lines compared to normal breast epithelial cells.

The sphingolipid ceramide is involved in diverse cell signaling pathways related to proliferation and differentiation. Elevated ceramide also triggers apoptosis. Synthetic ceramide derivatives have been shown to be cytotoxic to tumors, yet few studies have evaluated whether cytotoxicity of synthetic ceramides is selective for tumor cells. We have evaluated the cytotoxic potency of several novel ceramide analogues in the drug-resistant breast tumor cell lines, SKBr3 and MCF-7/Adr, and compared their cytotoxicity in normal breast epithelial cells. Cytotoxicity was assessed using release of lactate dehydrogenase into the culture medium. (2S, 3S)-3-(6'-Dodecylpyridin-2'-yl)-2-butanoylamidopropane-1,3-diol (pyridine-C4-ceramide) produced non-selective cytotoxicity across the three cell types (EC50= 12.8-16.7 microM, at 24 hr). However, 2S,5R-2-(octanoylamido-(3E))-octadecene-1,5-diol (5R-OH-3E-C8-ceramide), (2S,3R)-2-(N-adamantoyl)-(4E)-octadecen-1,3-diol (adamantyl-ceramide), and (2S,3R)-3-(3'-dodecylphenyl)-2-butanoylamidopropane-1,3-diol (benzene-C4-ceramide) exhibited increased cytotoxicity in the tumor cell lines compared to the normal breast epithelial cells. The EC50 values (microM) at 24 hr for these compounds in SKBr3 cells, MCF-7/Adr cells, and normal breast epithelial cells, respectively, were as follows: 5R-OH-3E-C8-ceramide, 18.3, 21.2 and 58.7; adamantyl-ceramide, 10.9, 24.9 and >100; benzene-C4-ceramide, 18.9, 45.5 and >100. At a concentration of 30 microM, the fold increase in cytotoxicity in breast tumor cell lines compared with normal breast epithelial cells was as follows: 5R-OH-3E-C8-ceramide, 23.7 and 19; adamantyl-ceramide, 11.2 and 10.3 and benzene-C4-ceramide, 79.3 and 77.2, for SKBr3 and MCF-7/Adr cells, respectively. Possible mechanisms accounting for selectivity are discussed. Ceramide analogues with relatively selective toxicity against tumor cells may have potential as therapeutic agents. Elucidating the mechanisms of selective cytotoxicity could identify novel targets that may lead to development of anti-neoplastic agents with a higher therapeutic index.     

Antioxidant and anticancer activities of novel p-alkylaminophenols and p-acylaminophenols (aminophenol analogues)

Novel compounds were designed based on fenretinide, N-(4-hydroxyphenyl)retinamide (2), which is a synthetic amide of all-trans-retinoic acid (1) that is a potent antioxidant and anticancer agent. Our recent findings indicated that antioxidant and anticancer activities were due to p-methylaminophenol moiety (8) in 2, and that p-octylaminophenol (7), which has an elongated alkyl chain, was more potent than 8. This finding lets us to investigate whether compounds containing alkyl or acyl chains linked to an aminophenol residue as long as 2 and 1, would show activities greater than 2. For this purpose, we prepared p-dodecanoylaminophenol (3), p-decanoylaminophenol (4), p-dodecylaminophenol (5), and p-decylaminophenol (6). The p-alkylaminophenols, 5 and 6, exhibited superoxide scavenging activities, but not p-acylaminophenols, 3 and 4. Elongation of the alkyl chain length reduced superoxide trapping capability (8>7>6>5). In contrast, lipid peroxidation in rat liver microsomes was reduced by 5 and 6 in dose-dependent manner. Compounds 3 and 4 were poor lipid peroxidation inhibitors, being approximately 400- to 1300-fold lower than 5 and 6. In addition, all compounds inhibited cell growth of human leukemia cell lines, HL60 and HL60R, in dose-dependent manners (5>6>3=4). The HL60R cell line is resistant against 1. Growth of both cell lines was suppressed by 5 and 6 in a fashion dependent on the length of the aminophenol alkyl chain, but not by 3 and 4. These results indicate that 5, a potent anticancer agent greater than 2, may potentially have clinical utility, and that its anticancer activity is correlated with inhibitory potency against lipid peroxidation, but not with superoxide scavenging activity.     

Novel Pyrazoloquinolin-2-ones: Design,synthesis, docking studies,and biological evaluation as antiproliferative EGFR-TK inhibitors

Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC₅₀ = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC₅₀ = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds’ activity.     

Synthesis,cytotoxic evaluation,docking and in silico pharmacokinetic prediction of 4-arylideneamino/cycloalkylidineamino 1, 2-naphthoquinone thiosemicarbazones

In an attempt to develop potent anticancer agents, a series of 4-arylideneamino/cycloalkylidineamino-1, 2-naphthoquinone thiosemicarbazones were synthesized and characterized using FT-IR, ¹H NMR, ¹³C NMR spectroscopy and elemental analysis. The compounds were screened for antiproliferative activity against three human cancer cell lines (Hep-G2, MG-63 and MCF-7) using the MTT assay. Significant anticancer activity was observed for several members of the series. The compounds 4-(3, 4, 5-trimethoxybenzylidene amino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS10) and 4-(4-hydroxy-3-methoxy benzylideneamino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS13) were active cytotoxic agents in all three cancer cell lines, with IC₅₀ values in the range of 3.5–6.4 µM. Further evaluation of some of these potent cytotoxic compounds demonstrated their good safety profile in a normal cell line (MCF-12A). Docking experiments showed a good correlation between the predicted glide scores and the IC₅₀ values of these compounds. In silico ADME studies revealed that these compounds can be used for second generation development.     

Photochemical synthesis and anticancer activity of barbituric acid,thiobarbituric acid,thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives

2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines.     

Cytotoxic metabolites from Perenniporia tephropora, an endophytic fungus from Taxus chinensis var. mairei

Based on bioactivity-oriented isolation, the EtOAc extract of a culture broth of the endophytic fungus Perenniporia tephropora Z41 from Taxus chinensis var. mairei, with strong anti-Pyricularia oryzae activity, afforded a new sesquiterpenoid, perenniporin A (1), together with three known compounds, ergosterol (2), rel-(+)-(2aR,5R,5aR,8S,8aS,8bR)-decahydro-2,2,5,8-tetramethyl-2H-naphtho[1,8-bc]genfuran-5-ol (3), and albicanol (4). Their structures were elucidated by means of spectroscopic methods. All the isolated compounds and the EtOAc extract of P. tephropora Z41 (EPT) were evaluated for their cytotoxic activity against three human cancer cell lines (HeLa, SMMC-7721, and PANC-1). EPT demonstrated significant cytotoxicity with IC₅₀ values ranging from 2 to 15 μg/mL. Compound 2 was the most cytotoxic constituent against the tested cell lines with IC₅₀ values of 1.16, 11.63, and 11.80 μg/mL, respectively, while compounds 1, 3, and 4 exhibited moderate cytotoxicity with IC₅₀ values ranging from 6 to 58 μg/mL. We conclude that the endophytic fungus P. tephropora is a promising source of novel and cytotoxic metabolites.     

Synthesis and cytotoxic activity evaluation of indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones and 6-anilinoindoloquinoline derivatives

Certain indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones 4a,b, 6, 8, 16a-c and 6-anilinoindoloquinoline derivatives 10a,b, 11a,b, 12a,b have been synthesized and evaluated in vitro against a 3-cell lines panel consisting of MCF7 (Breast), NCI-H460 (Lung), and SF-268 (CNS). Those active compounds 4a,b, 6, 8, 10a,b, 11a,b, 12a,b were then evaluated in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results have shown that cytotoxicity decreases in the order of 6-anilinoindoloquinolines>indoloquinolin-2(1H)-ones>pyrroloquinolin-2(1H)-ones>benzofuroquinolin-2(1H)-ones. Among them, 1-[3-(11H-indolo[3,2-c]quinolin-6ylamino)phenyl]ethanone oxime hydrochloride (11a) and its 2-chloro derivative (11b) were most active, with mean GI(50) values of 1.70 and 1.35 microM, respectively. Both compounds 11a,b were also found to inhibit the growth of SNB-75 (CNS cancer cell) with a GI(50) value of less than 0.01 microM, and, therefore, were selected for further evaluation for in vivo antitumor activity.     

Benzimidazole bearing oxadiazole and triazolo-thiadiazoles nucleus: Design and synthesis as anticancer agents

Two new series of benzimidazole bearing oxadiazole[1-(1H-benzo[d]imidazol-2-yl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)propan-1-ones (4a-l)] and triazolo-thiadiazoles[1-(1H-benzo[d]imidazol-2-yl)-3-(6-(substituted)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)propan-1-one (7a-e)] have been synthesized successfully from4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide (3) with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were screened at the National Cancer Institute (NCI), USA, according to their applied protocol against full NCI 60 human cell lines panel; results showed good to remarkable anticancer activity. Among them, compound (4j, NCS: 761980) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100μM) with GI(50) values ranging from 0.49 to 48.0μM and found superior for the non-small cell lung cancer cell lines like HOP-92 (GI(50) 0.49, TGI 19.9,LC(50) >100 and Log(10)GI(50) -6.30, Log(10)TGI -4.70, Log(10)LC(50) >-4.00).     

Modified norcantharidins; synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity

Fourteen modified norcantharidin analogues have been synthesised and screened for their ability to inhibit the serine/threonine protein phosphatases 1 and 2A. The most potent compounds found were 10 (PP1 IC(50)=13+/-5 microM; PP2A IC(50)=7+/-3 microM) and 16 (PP1 IC(50)=18+/-8 microM; PP2A IC(50)=3.2+/-0.4 microM). Overall, only analogues possessing at least one acidic residue at the former anhydride warhead displayed any PP1 or PP2A inhibitory action. The ability of these analogues to inhibit PP1 and PP2A correlates well with their observed anti-cancer activity against a panel of five cancer cell lines: A2780 (human ovarian carcinoma), G401 (human kidney carcinoma), HT29 (human colorectal carcinoma), H460 (human lung carcinoma) and L1210 (murine leukemia).     

Synthesis, spectroscopy (IR, multinuclear NMR, ESI-MS), diffraction, density functional study and in vitro antiproliferative activity of pyrazole-beta-diketone dihalotin(IV) compounds on 5 melanoma cell lines

Novel 4-acylpyrazolon-5-ato-dihalotin(IV) complexes, [Q2SnX2], (X = F, Cl, Br or I); HQ = HQ(CHPh2) (1,2-dihydro-3-methyl-1-phenyl-4-(2,2-diphenylacetyl)pyrazol-5-one), HQ(Bn) (1,2-dihydro-3-methyl-1-phenyl-4-(2-phenylacetyl)pyrazol-5-one) or HQ(CF3,py) (4-(2,2,2-trifluoroacetyl)-1,2-dihydro-3-methyl-1-(pyridin-2-yl)pyrazol-5-one) have been synthesized and characterized by spectroscopic (IR, 1H, 13C, 19F and 119Sn NMR, electrospray ionisation mass spectrometry (ESI-MS)), analytical and structural methods (X-ray and density functional theory). 119Sn chemical shifts depend on the nature of the halides bonded to tin. Isomer conversion, detected in solution by NMR spectroscopy, is related to the acyl moiety bulkiness while the cis(Cl)-cis(acyl)-trans(pyrazolonato) scheme is found in the solid state. The in vitro antiproliferative tests of three derivatives on three human melanoma cell lines (JR8, SK-MEL-5, MEL501) and two melanoma cell clones (2/21 and 2/60) show dose-dependent decrease of cell proliferation in all cell lines. The activity correlates with the nature of the substituent on position 1 of pyrazole, decreasing in the order pyridyl>Ph>methyl. The activity for (Q(CF3,py))2SnCl2 on the SK-MEL-5 cell line is IC50 = 50 microM.     

Synthesis, biological active molecular design, and molecular docking study of novel deazaflavin-cholestane hybrid compounds

Novel deazaflavin-cholestane hybrid compounds, 3',8'-disubstituted-5'-deazacholest-2,4-dieno[2,3-g]pteridine-2',4'(3'H,8'H)-diones, have been synthesized by condensation reaction between 6-(monosubstituted amino)-pyrimidin-2,4(1H,3H)-diones and 2-hydroxymethylenecholest-4-en-3-one in presence of p-toluenesulfonic acid monohydrate and diphenyl ether. The antitumor activities against human tumor cell lines (CCRF-HSB-2 and KB cells) have been investigated in vitro, and many of these compounds showed promising antitumor activities. Furthermore, molecular docking study using LigandFit within the software package Discovery Studio 1.7 was done for lead optimization of these compounds as potential PTK inhibitors. In general, all of the synthesized steroid-hybrid compounds showed good binding affinities into PTK (PDB code: 1t46).     

Cytotoxicity and topoisomerase I/II inhibition of glycosylated 2-phenyl-indoles, 2-phenyl-benzo[b]thiophenes and 2-phenyl-benzo[b]furans

A panel of glycosylated DNA binding agents (1-12) designed as functional anthracycline mimics was screened against three solid-tumor cell lines (MCF-7, HT 29 and HepG2/C3A) and three non-tumor cell lines by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell viability assay. Several compounds showed better in vitro cytotoxicity and selectivity against MCF-7 cells than daunomycin and doxorubicin, two known DNA binding agents that are clinically-used anti-cancer agents. Although the selectivity for HT 29 and HepG2/C3A cells is generally lower, the IC₅₀ values of some analogs against these two cancer cell lines were of the same magnitude as doxorubicin. Because there was no correlation between DNA binding affinity and cytotoxicity, and because topoisomerase (Topo) inhibition is another biological mechanism of action of most anthracycline drugs, Topo I/II inhibition assays with 1-12 were performed. Some of the compounds showed strong inhibition against these enzymes at 100 ??M, but there was no clear correlation between cytotoxicity and Topo I/II inhibition ability. Topo I/II inhibition mode assays were also performed, which verified that these compounds are topoisomerase suppressors, not poisons. Based on these results, we conclude that although DNA binding and/or topoisomerase inhibition may contribute to the observed cytotoxicity of 1-12, other mechanisms of action are also likely to be important.     

The novel C-5 aryl, alkenyl, and alkynyl substituted uracil derivatives of L-ascorbic acid: synthesis, cytostatic, and antiviral activity evaluations

The novel C-5 substituted uracil derivatives of l-ascorbic acid were synthesized by coupling of 5-iodouracil-4,5-didehydro-5,6-dideoxy-l-ascorbic acid with unsaturated stannanes under Stille reaction conditions. The new compounds were evaluated for their antitumoral and antiviral activities. Among all compounds evaluated the 5-propynyl substituted uracil derivative of l-ascorbic acid (7) exhibited the most pronounced cytostatic activities against all examined tumor cell lines (IC(50): 0.2-0.78 microM). However, this compound was also cytotoxic to human normal fibroblasts WI 38. The 5-(phenylethynyl)uracil-2,3-di-O-benzylated l-ascorbic acid derivative (4) exhibited an albeit slight (IC(50): 55-108 microM), but selective inhibitory effect toward all tumor cell lines except for cervical carcinoma (HeLa), pancreatic carcinoma (MiaPaCa-2), laryngeal carcinoma (Hep-2), and colon carcinoma (SW 620), and no cytotoxicity to normal human fibroblast (WI 38). Compound 7 showed some, not highly specific, inhibitory potential against vesicular stomatitis virus, Coxsackie B4 virus, and Sindbis viruses (EC(50): 1.6 microM).     

Synthesis and anticancer evaluation of thiazolyl-chalcones

Thirty-seven (E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones were synthesized via Claisen-Schmidt condensation of 1-(4-methyl-2-(arylamino)thiazol-5-yl)ethanone with the corresponding arylaldehydes. All these thiazolyl-chalcones were characterized and evaluated by MTT assay on human cancer cell lines BGC-823, PC-3, NCI-H460, BEL-7402 in vitro. Compounds 5, 8, 26, 37 and 41 are effective against cancer cell lines with IC(50)s below 10 μM. The antitumor activity in ICR mice bearing sarcoma 180 tumors indicates compounds 10 and 41 have moderate in vivo activity with 22-25% tumor-weight inhibition.     

Selective Induction of DNA Damage and Cell Cycle Arrest Mediated by Chromone-Triazole Dyads Derivatives: Effects on Breast and Prostate Cancer Cells

Chromones and triazoles are groups of heterocyclic compounds widely known to exhibit a broad spectrum of biological activities. The combination of these two pharmacophores could result in multiple mechanisms of action to increase the potency of anticancer drugs and reduce their side effects. The in vitro antitumor effect of eight chromone-based compounds was evaluated in breast (T-47D and MDA-MB-231) and prostate (PC3) cancer cell lines, and in non-cancerous human mammary epithelial cells (HuMEC) using a resazurin-based method. Flow cytometry was used to evaluate the cell cycle and cell death, and ɣ-H2AX detection to identify DNA damage. The compounds showed selective cytotoxicity against cancer cell lines, with (E)-2-(2-(5-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl)vinyl)-4H-chromen-4-one (compound 2 a ) being more potent in non-metastatic T-47D cells (IC₅₀ 0.65 μM). Replacing the hydrogen by a methyl group on the triazole ring in compound 2 b enhanced the cytotoxic activity up to IC₅₀ 0.24 μM in PC3, 0.32 μM in MDA-MB-231 and 0.52 μM in T-47D. Compound 2 b was 3-fold more potent than doxorubicin in PC3 (IC₅₀ 0.73 μM) and 4-fold in MDA-MB-231 (IC₅₀ 1.51 μM). The addition of tetrahydroisoindole-1,3-dione moiety in compound 5 did not improve its effectiveness in any of the cell lines but it exerted the lowest cytotoxic effect in HuMEC (IC₅₀ 221.35 μM). The compounds revealed different cytotoxic mechanisms: 2 a and 2 b induced G2/M arrest, and compound 5 did not affect the cell cycle.     

Antimetabolites: Design,synthesis, and cytotoxic evaluation of novel dihydropyridine thioglycosides and pyridine thioglycosides

A convenient synthesis of a novel series of dihydropyridine and pyridine thioglycosides was developed. The evaluation of anti-proliferative activity against HepG-2 cell lines (liver carcinoma cell lines) shows that most of the compounds have antitumor activity, especially 5b, 5f, 5j, 5n, 7b, 7f, 7j, 7n, 8b, 8f, and 8j. The results of molecular docking reveal that these compounds have high binding affinity by hydrogen bond formation with the binding pocket of thymidylate synthase dihydrofolate reductase (TS-DHFR).     

Synthesis, structural characterization, and in vitro antitumor activity of novel N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides

A new series of N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23-48 have been synthesized as potential anticancer agents. All compounds were screened for their cytotoxic activity against six human tumor cell lines. The selected compounds 23-27, 30, 31, 33, 35, 38, 42, 45, and 46 were further tested at the US National Cancer Institute for their in vitro activities against a panel of 53-59 human tumor cell lines. The compounds 23-26, 30, 31, 33, 38, 42, 45, and 46 showed 50% growth inhibitory activity in low micromolar concentration (GI(50)=0.03-4.9 microM) against one or more human tumor cell lines (Table 3). The prominent compound with remarkable activity (GI(50)=0.03 microM, TGI=1.3 microM) and selectivity toward melanoma UACC-257 cell line was N-(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)-N-(phenyl)-5-bromothiophene-2-sulfonamide 46.     

Synthesis, crystal structure and biological activities of copper(II) complexes with chelating bidentate 2-substituted benzimidazole ligands

A series of Cu(II) coordination compounds with benzimidazole-derived bidentate chelating ligands have been prepared and characterized by X-ray crystallography. The 2-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzimidazole CuCl2 complex 8 showed very potent superoxide dismutase (Cu,Zn-SOD) activity in vitro with IC50 of 0.09 microM, comparable to those described in the literature for best low molecular weight CuZnSOD mimics. Cytotoxicity studies with seven different human tumor cell lines in vitro showed that the most active 2-(4,5-dihydro-1H-imidazol-2-yl)-5-nitro-1H-benzimidazole CuCl2 complex 10 inhibited the growth of cancer cells with IC50 between 4.76 and 10.84 microM.