Synthesis of Hsp90 inhibitor dimers as potential antitumor agents

Structure-based drug design was used to systematically synthesize PU3-dimers. The cytotoxicity of PU3 dimers 6 against breast cancer cell lines was evaluated, and their potency increased as the length of the bridging linker increased. Among the compounds tested, 6e with a C-20 linker was the most potent and exhibited a 20- to 30-fold increase in activity compared with that of the parent compound 5. Western blot analyses of the cell lysates treated with 6c revealed that 6c resulted in the concentration-dependent degradation of the Hsp90 client protein Her2, which is consistent with other Hsp90 inhibitors.     

Synthesis of azole nucleoside analogues of D-pinitol as potential antitumor agents

A convenient strategy is reported for the synthesis of azole nucleoside analogues of D-pinitol (=3-O-methyl-D-chiro-inositol). The key intermediate 3-O-methyl-4,5-epoxy-D-chiro-inositol was obtained in excellent yield via an epoxidation from mono-methanesulfonate of D-pinitol. The process of opening of the epoxy ring by azole-bases appeared strongly regioselective in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. All newly synthesized carbocyclic azole nucleosides were assayed against lung and bladder cancer in vitro. Only the triazole and benzotriazole nucleoside analogues inhibited the growth of human lung cancer cell lines (PG) with EC(50) of 11.3 and 22.6 microM, respectively, and showed much less inhibitory activity against human bladder cell lines (T(24)).     

Bacterial endotoxins as potential antitumor agents

Natural and modified preparations of lipopolysaccharides and lipopolysaccharide-protein complexes isolated from the S- and R-form of Shigella dysenteriae serovar 1 were found to markedly inhibit the initial growth of mouse solid tumors derived from Németh-Kellner lymphoma, Gardner 6C3HED lymphoma, an ill-defined syngeneic lymphoma of DBA mice (Skalsky lymphoma) and LP-2 plasmacytoma. The biopreparations were given intraperitoneally, most frequently at a dose range from 50 to 200 micrograms per mouse; significant inhibitory effects on tumor growth were evidenced even in mice bearing tumors weighing 113 to 507 mg.     

Synthesis of novel potential antitumor agents: 2,6-dimethoxyhydroquinone-3-mercapto-acetyl peptide conjugates.

This paper reports on an ongoing study of the use of short chain peptides as carriers of a potential anti-tumor agent: 2,6-dimethoxyhydroquinone-3-mercaptoacetic acid (DMQ-MA). In an effort to carry out anti-cancer drug design, we synthesized three new peptide-DMQ-MA conjugates: DMQ-MA-Arg-Arg-Ome, DMQ-MA-Lys(Cbz)-Arg-Ome, DMQ-MA-Lys(Cbz)-Arg-Arg-Ome; two new DMQ-MA-peptide-Chlorambucil (CRB) derivatives: DMQ-MA-Lys(CRB)-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Lys(CRB)-Arg-Ome and four tripeptide-cytotoxic agent conjugates: DMQ-MA-Lys(DMQ-MA)-Phe-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Ile-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Val-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Lys(Cbz)-Arg-Ome. These conjugates were synthesized by coupling protected amino acid residues according to Pfp/DCC methods (Pfp: Pentafluorophenol, DCC:N,N'-Dicyclohexyl-carbodiimide) in solution. After deblocking the Boc- group of the Lysine, the conjugation was achieved by reaction with the pentafluorophenyl ester of DMQ-MA in DMF. The CRB in the side chain was coupled by deblocking the lysylcarbobenzyloxy protecting group Cbz and then reacting with the pentafluorophenyl ester of Chlorambucil(CRB). Further studies on cytotoxicity and sequence specificity of DNA alkylation of these five new conjugates are being investigated.     

Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents

We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI₅₀ values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.     

Water-soluble platinum phthalocyanines as potential antitumor agents

Breast cancer represents the second cause of death in the European female population. The lack of specific therapies together with its high invasive potential are the major problems associated to such a tumor. In the last three decades platinum-based drugs have been considered essential constituents of many therapeutic strategies, even though with side effects and frequent generation of drug resistance. These drugs have been the guide for the research, in last years, of novel platinum and ruthenium based compounds, able to overcome these limitations. In this work, ruthenium and platinum based phthalocyanines were synthesized through conventional techniques and their antiproliferative and/or cytotoxic actions were tested. Normal mammary gland (MCF10A) and several models of mammarian carcinoma at different degrees of invasiveness (BT474, MCF-7 and MDA-MB-231) were used. Cells were treated with different concentrations (5–100 μM) of the above reported compounds, to evaluate toxic concentration and to underline possible dose–response effects. The study included growth curves made by trypan blue exclusion test and scratch assay to study cellular motility and its possible negative modulation by phthalocyanine. Moreover, we investigated cell cycle and apoptosis through flow cytometry and AMNIS Image Stream cytometer. Among all the tested drugs, tetrasulfonated phthalocyanine of platinum resulted to be the molecule with the best cytostatic action on neoplastic cell lines at the concentration of 30 μM. Interestingly, platinum tetrasulfophtalocyanine, at low doses, had no antiproliferative effects on normal cells. Therefore, such platinum complex, appears to be a promising drug for mammarian carcinoma treatment.     

Synthesis of 5-azacytidine nucleosides with rigid sugar moiety as potential antitumor agents

The bicyclic 3'-O,5'-C-methylene-linked and 2'-O,5'-C-methylene-linked 5-azacytidine derivatives were readily synthesized from 1,2;5,6-di-O-isopropylidene-D-glucose and evaluated against several cancer cell lines.     

Synthesis and biological evaluation of imidazol-2-one derivatives as potential antitumor agents

A new series of aryl substituted imidazol-2-one derivatives structurally related to combretastatin A-4 (CA-4) were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines including MDR cell line. The cytotoxic effects of compounds 7b and 7i proved to be similar to or greater than that of docetaxel. The highly active compound 7b also exhibited excellent inhibitory activity on tumor growth in vivo.     

Synthesis and cytotoxicity evaluation of novel indolylpyrimidines and indolylpyrazines as potential antitumor agents

Novel indolylpyrimidines and indolylpyrazines have been synthesized as potential antitumor agents. They were screened in a panel of 60 human tumor cell lines in vitro. Compounds 7, 9, 10, 15, 21 exhibited efficiently cytotoxic activities with GI(50) values in the low micromolar range against a variety of human cancer cell lines. 2,4-Bis(3'-indolyl)pyrimidine 8 displayed selective cytotoxic activity against IGROV1 tumor cell line with the GI(50) value below 0.01 microM.     

Novel naphthalimide polyamine derivatives as potential antitumor agents

A novel series of naphthalimide polyamine conjugates were designed, synthesized and evaluated for in vitro antiproliferative activity against human leukemia (Jurkat), human cervical adenocarcinoma (HeLa), human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549) cell lines. From the six derivatives, the new I1 and A3 exhibited highest antiproliferative activity with the IC₅₀ values of 5.67–11.02 μmol·L^?1. Cell cycle analysis of Jurkat cells exposed to I1 at a concentration of 30 μmol × L^?1 for 24 h exhibited a mild increase in S and G₂/M fraction caused by accumulation of cells. This arrest was followed by an increase in sub-G₀/G₁ after 48 h of incubation. Jurkat cells exposed to A3 at a concentration of 30 μmol × L^?1 for 24 h showed an increase in G₀/G₁ fraction and after 48 h an increase in G₂/M fraction followed by an increase in sub-G₀/G₁ after 72 h of incubation. Moreover, the A3 compound was observed to displace the intercalating agent ethidium bromide from calf thymus DNA using fluorescence spectroscopy. The apparent binding constant was estimated to be 3.1 × 10⁶ M^?1 what indicates non-intercalating mode of DNA binding. On the other hand, we found no inhibitory effect of studied compounds on topoisomerase I and topoisomerase II activity. Finally, the localization of these compounds in the cells due to their inherent fluorescence was investigated with the fluorescence microscopy. Our results suggest that the naphthalimide polyamine conjugates rapidly penetrate to the cancer cells. Further studies are necessary to investigate the precise mechanism of action and to find out the relationship between the structure, character and position of substituents of naphthalimide polyamine conjugates and their biological activities.     

Substituted cyclic imides as potential anti-gout agents

N-substituted cyclic imides of phthalimide, 2,3-dihydrohalazine-1,4-dione, and diphenimide were shown to reduce the serum uric acid levels in normal and hyperuric mice at 20 mg/kg/day I.P. for 14 days. The agents were potent inhibitors of commercial xanthine dehydrogenase and xanthine oxidase enzyme activities with IC50 values from 10(-7) to 10(-8) M concentrations of drug.     

Synthesis of 2-thiohydantoins and their S-glucosylated derivatives as potential antiviral and antitumor agents

A series of 3-alkyl-5-((Z))-arylidene-2-thiohydantoins 4a-1 were synthesized from the direct condensation of the aromatic aldehydes with 3-alkyl-2-thiohydantoins 3a-c, which in turn were prepared from the reaction of glycine (1) and alkyl isothiocyanates 2a-c. The alkylation of 4a-1 with methylthioethyl chloride gave 5-((Z))-arylidene-3-alkyl-S-(2-methylthioethyl)-2-thiohydantoins 5a-e. S-Glucosylation took place on the reaction of 4a-1 with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide under anhydrous alkaline conditions. These structures have been confirmed from a model study of the coupling of 4a with methylthioethyl chloride and alpha-D-glucose pentaacetate, respectively under Lewis acid conditions.     

Ligand-based design of GLUT inhibitors as potential antitumor agents

Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC₅₀s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.     

Structure-activity studies of phenanthroindolizidine alkaloids as potential antitumor agents

Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structure-activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7) were among the most active compounds against tumor growth both in vitro and in vivo. In the hepatocellular carcinoma cell line HepG2, the GI(50)s of DCB-3503 and PA-7 were 35+/-5 nM and 11+/-5 nM, respectively. DCB-3503 and PA-7 significantly inhibited HepG2 tumor growth in nude mice at a dose of 9 mg/kg given by intraperitoneal (ip) injections twice a day every third day for a total of four cycles (P<0.05 for DCB-3503 and P<0.01 for PA-7). Their potent antitumor activities correlated with their potent NF-kappaB-inhibitory effects and their cyclin D1 down-regulatory effects.     

The usefulness of cyclic diamidines with different core-substituents as antitumor agents

A series of related polycationic compounds has been screened for potential antitumor activity by the NCI’s in vitro testing (one dose primary anticancer assay and the NCI-60 full panel screening). The GI₅₀ values of triazines 3 and 4 are on average 1.9 μM and 2.4 μM, respectively. Furan 8 deserves mention too (1.9 μM). The biological test results showed that carbazole 10 possessed cytotoxic activity in the nanomolar range, much better than the other compounds tested, only against several cancer cell lines: CCRF-CEM, HL-60(TB), MOLT-4, NCI-H522, COLO 205, SF-268, but the average GI₅₀ value was higher (15 μM). The activity appears closely dependent on the core-shape and length of the bisimidazoline molecules (important for both high cytotoxicity and DNA binding). The mechanism of DNA minor-groove binding of diamidines 1-12, based on the anticancer parameters, is highly probable.     

Synthesis and biological evaluation of a novel phenyl substituted sydnone series as potential antitumor agents

A series of compounds containing an N-(4'-substituted-3'-nitrophenyl)sydnone moiety with potential antitumor activity was prepared based on active analogues. The rationale behind the design of these compounds is presented along with the 4-step synthetic route to the derivatives in the 4'-position of the phenyl sydnone framework. Out of the six novel compounds, the 4'-fluoro derivative has an improved activity against all three cell lines as compared to the earlier leads.     

Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents

As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC₅₀ = 0.88–1.1 μM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED₅₀ values obtained against P-gp over-expressing KBvin (0.0146 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line.     

Synthesis of new nucleoside analogues comprising a geminal difluorocyclopropane moiety as potential antiviral/antitumor agents

Geminal difluorocyclopropane analogues of nucleosides 7a-7e were synthesized. Compounds 7a and 7c-7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane+ ++ (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a-7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.     

Quinazoline-sulfonamides as potential antitumor agents: synthesis and biological testing

Abstract

New series of quinazoline containing sulfonamide derivatives were prepared and screened for their antitumor activity. Four human cancer cell lines, namely, hepatoma cancer cell line (HepG2), breast cancer cell line (MCF-7), cervix cancer cell line (HeLa) and colon cancer cell line (HCT-8), were used to measure the cytotoxic activity. Compounds 8 and 21 exhibited remarkable antitumor activity almost similar to that of the standard drug (doxorubicin). Six compounds 16, 22, 23, 29, 30 and 33, showed considerable activity and few compounds were totally inactive.     

Synthesis and biological evaluation of indolyl chalcones as antitumor agents

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against three human cancer cell lines. Compounds 3b–d, 3h, 3j, 3l, 3m, 4g, and 4j showed significant cytotoxicity, particularly, indolyl chalcones 3l and 3m were identified as the most potent and selective anticancer agents with IC₅₀ values 0.03 and 0.09 μM, against PaCa-2 cell line, respectively.