Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.     

Synthesis and antiproliferative activity of some steroidal lactams

Using cholesterol as starting material, a series of 6-substituted-3-aza-A-homo-3-oxycholestanes and 6-substituted-4-aza-A-homo-3-oxycholestanes were synthesized by the oxidation, reduction, oximation, Beckman rearrangement and condensation reaction. These synthesized compounds displayed a distinct cytotoxicity against MGC 7901, HeLa and SMMC 7404 cancer cells. Our results revealed that the structures of functional groups at position-6 on the steroidal ring are crucial for the IC₅₀ value of antiproliferative activities of these compounds and the cytotoxic activity against MGC 7901 and SMMC 7404 cells was not significantly different between 4-N-lactams and 3-N-lactams when its 6-substituted group was a carbonyl or a hydroximino, but all 3-N-lactams showed a higher cytotoxicity against HeLa cells than 4-N-lactams. In particular, compounds 6, 8, 9 (IC₅₀6: 6.5 μmol/L; 8: 7.7 μmol/L; 9: 5.6 μmol/L) were even more cytotoxic than cisplatin to HeLa cells (positive contrast, 10.1 μmol/L). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.     

Synthesis and antiviral/antiproliferative activity of some N-sulphonylbenzimidazoles

Some benzimidazolyl sulphones were synthesized and evaluated for their antiviral and antiproliferative properties. Compound 10 displayed significant and selective activity against human cytomegalovirus (CMV), compound 14 showed activity against varicella zoster virus (VZV). The compounds were further evaluated for inhibitory effect on the proliferation of murine leukemia cells and human T-lymphocyte cells. Marked cytotoxicity was noted with different derivatives. Some structure-activity relationships are discussed.     

Synthesis and antiproliferative activity of some steroidal lactone compounds

Using cholesterol as starting material, some steroidal lactone compounds with the structures of 3-substituted-6-oxo-7-oxa-B-homo-cholestane or 3-substituted-7-oxo-6-oxa-B-homo-cholestane were synthesized by oxidation, reduction, Baeyer-Villiger reaction and condensation reaction. The cytotoxicity of these compounds against MGC 7901 (human gastric carcinoma), HeLa (human cervical carcinoma) and SMMC 7404 (human liver carcinoma) cells was investigated. Our results showed that the synthesized compounds displayed a distinct cytotoxicity against these cancer cells. In particular, compounds 8 and 9 have similar cytotoxic capability as cisplatin does. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.     

Synthesis and antiproliferative activity of some new DNA-targeted alkylating pyrroloquinolines

Two novel DNA-direct alkylating agents, consisting of aniline mustard linked to an angular 3H-pyrrolo[3,2-f]quinoline nucleus, were synthetized and assayed for their in vitro antiproliferative activity. Simple convergent synthesis, consisting of separate preparation of 9-chloro-3H-pyrrolo[3,2-f]quinoline and p-amino-aniline derivatives, and following their linkage by substitution reactions 8a, b and 10, yielded the corresponding diol derivatives 7b and 9. Biological properties were evaluated with respect to cell growth inhibition, ability to form cross-links with DNA, and capacity to give rise to a molecular complex with the macromolecule for 7b, 8b, 9 and 10.     

Synthesis and antiproliferative activity of some benzimidazole-4,7-dione derivatives

A series of benzimidazole-4,7-diones bearing at the 2-position the thiomethyl group or the 2-pyridyl moiety has been synthesized and tested in vitro on three tumor cell lines. Two of them show a very good antiproliferative effect. Compounds 1 and 2d are more active or equiactive, respectively, than MMC against human lymphoblastic leukemia. Both compounds exhibit high activity on human non-Hodgkin lymphoma. Compound 1 is non toxic at all the concentrations used in the antiproliferative assay and 2d is toxic only at high concentration.     

Synthesis and antiproliferative activity of some steroidal thiosemicarbazones,semicarbazones and hydrozones

Steroidal thiosemicarbazones, semicarbazones and hydrazones have received extensive attention of scientists recently because they exhibit some biological activities such as antibacterial, antiviral and anticancer. Using different steroids as starting materials, through different chemical methods, 24 steroidal compounds with thiosemicarbazone, semicarbazone or hydrazone groups in their structures, were synthesized, characterized by IR, NMR and MS. The antiproliferative activity of the compounds was evaluated against human gastric cancer (SGC-7901) and human liver cancer (Bel-7404) cells. The structure–activity relationship of these compounds was discussed. The results showed that compound 3 and 12a–12c exhibited significant inhibitory activity to Bel-7404 cells, and IC₅₀ values of them were 4.2, 11.0, 7.4 and 15.0 μM respectively (Cisplatin, IC₅₀: 11.6 μM).     

Synthesis and antiproliferative activity of some 4'-C-hydroxymethyl-alpha- and -beta-D-arabino-pentofuranosyl pyrimidine nucleosides

A suitably protected 4-C-hydroxymethyl-arabino-pentofuranose was prepared and condensed with the following nucleobases: uracil, 5-fluorouracil and thymine. The corresponding cytosine and 5-fluorocytosine derivatives have also been obtained respectively from the uracil and 5-fluorouracil nucleosides. Separation of the anomeric mixtures followed by deprotection afforded the target compounds that were found to be non-cytotoxic to CCRF-CEM leukemia cells.     

Synthesis and antiproliferative activity of alkylphosphocholines

Alkylphosphocholines (APC) with one or more methylene groups in the alkyl chain replaced by oxygen atoms or carbonyl groups, or both have been assembled modularly using omega-diols as central building blocks. Out of 25 new compounds of this kind, 11 were evaluated for their antiproliferative activity on four cell lines and compared with miltefosine to evaluate their hemolytic activity (HA) and cytotoxicity on non-tumoral cells (MT2), used as markers of adverse effects. Compound 13 was more active on cancer cell lines than on non-tumoral cells and the data were similar for MTT and thymidine incorporation assays. It had less HA than miltefosine. Compound 13 could therefore be a candidate for the preparation of compounds with higher cytotoxicity on cancer cells and lower general toxicity.     

Synthesis and antiproliferative activity of retroetoposide

Retro-4'-demethyl-4-epipodophyllotoxin 6 was synthesized in eight steps and 10% overall yield from 4'-demethyl-4-epipodophyllotoxin 12. Subsequent coupling of 22 with 1-O-trimethylsilyl-4,6-O-ethylidene-beta-D-glucoside 26 afforded retroetoposide 5 which is 10-fold less cytotoxic than etoposide against L1210 cell line.     

Synthesis and antiproliferative activity of some novel derivatives of diospyrin, a plant-derived naphthoquinonoid

Derivatisation of diospyrin, a bisnaphthoquinonoid isolated from Diospyros montana Roxb., led to the modification of its inhibitory activity, in vitro, towards a murine tumour model, Ehrlich ascites carcinoma (EAC), and two human cancer cell lines, viz., malignant skin melanoma (A375) and epidermoid laryngeal carcinoma (Hep2). Among the novel derivatives, an epoxide exhibited the maximum antiproliferative activity (IC(50) values in the range of 0.03-0.21 microM) and a comparatively lower toxicity (IC(50) approximately 98 microM) in normal human peripheral blood mononuclear cells (PBMC). This compound might provide a novel 'lead' for the development of clinically effective antiproliferative agents against cancer.     

Synthesis and antiproliferative activity of threo-5-fluoro-L-dihydroorotate

Fluorinated compounds play an important role in enzymology as well as clinical medicine. Based on the stereochemical preferences of dihydroorotate oxidase and enzymes that use fluoroaspartate, it was anticipated that threo-5-fluoro-L-dihydroorotate (t-FDHO) would have the properties of an antimetabolite. Thus, t-FDHO was synthesized via the reduction of 5-fluoroorotate using NADH and dihydroorotate dehydrogenase that was free of dihydroorotase. When the product was purified and studied by high field proton and carbon 13 NMR, the fluorine, the five carbons, and all the nonexchangeable protons were readily observed. Confirmation of threo configuration was obtained by examining the vicinal coupling constants between the substituents on carbon 5 and carbon 6 of the newly synthesized compound. Additionally, t-FDHO could be reoxidized to 5-fluoroorotate in the presence of dihydroorotate dehydrogenase and NAD+. Treatment of t-FDHO with dihydroorotase generated N-carbamyl-threo-3-fluoro-L-aspartate (CTF-ASP) which was also purified and characterized by NMR. The antiproliferative activity of t-FDHO was determined against a diploid human fibrosarcoma cell line (HT-1080). Fifty microM t-FDHO caused 50% inhibition of HT-1080 cell proliferation. During the 48-h toxicity study, extracellular t-FDHO underwent significant hydrolysis to CTF-ASP. Further extracellular degradation to fluoroaspartate was not seen. The antiproliferative activity of t-FDHO was not due to extracellular degradation since CTF-ASP itself was essentially nontoxic.     

Synthesis and antiproliferative activity of basic thioanalogues of merbarone

Three series of 5-substituted 1,3-diphenyl-6-(omega-dialkyl- and omega-cyclo-aminoalkyl)thio-2-thiobarbiturates (11-13) were synthesized as polysubstituted thioanalogues of merbarone, a topoisomerase II inhibitor acting on the catalytic site. To better understand pharmacophore requirements, a forth series of conformationally constrained analogues 14 was also prepared. Derivatives 11b,e, 14b,e,h,i,j were active in the low micromolar concentration range (IC(50): 3.3-4.3 microM), whereas compounds 11a,c,d,f,h,j and 13a,b,d,g,j and 14a,d,f showed IC(50) values between 10 and 15.5 microM. In contrast, compounds 12a-c,g-j, 13e,f,h and 14k were inactive. Cytotoxicity data provided from N.C.I. on selected compounds provided evidence that 11b,d, 13d,g and 14b,d,f,h,i,j were endowed with potent antiproliferative activity against leukemia and prostate cell lines (GI(50) up to 0.01 microM). In general, bicyclic derivatives 14 were up to 10-fold more potent than monocyclic counterparts against solid tumor-derived cell lines. SAR studies indicated that, in general, a certain tolerability in length of the alkyl side chains and in shape of distal amines is allowed in the four series, but in the monocyclic derivatives (11-13) antiproliferative activity was strongly affected by the nature of the 5-substituents (COOC(2)H(5)>COCH(3)>C(6)H(5)). Compounds 11b and 14b were also evaluated against KB cell subclones expressing altered levels of topoisomerases or the multidrug resistance phenotype (MDR). In both cases the above compounds showed a decrease in potency. In enzyme assays, 11b and 14b turned out to be inhibitors of topoisonerase II as merbaron.     

Synthesis,antiproliferative and pro-apoptotic activity of 2-phenylindoles

Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC₅₀ values of 2.71 μM and 1.86 μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.     

Synthesis and antiproliferative activity of 2-chlorophenyl carboxamide thienopyridines

3-Amino-2-arylcarboxamide-thieno[2,3-b]pyridines are a known class of antiproliferative compounds with activity against the phospholipase C enzyme. To further investigate the structure activity relationships of these derivatives a series of analogues were prepared modifying key functional groups. It was determined that modification of the 3-amino and 2-aryl carboxamide functionalities resulted in complete elimination of activity, whilst modification at C-5 allowed compounds of greater activity to be prepared.     

Synthesis and antiproliferative activity of sulfonamide-based peptidomimetic calpain inhibitors

The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ–calpain and m-calpain are the most widely distributed in mammalian cells. Calpains have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, and cancer. Therefore, calpain inhibitors are of interest as potential therapeutic agents. We have synthesized four new sulfonamide-based peptidomimetic compounds 2–5 as inhibitors of μ-calpain that incorporate (E)-1-(phenyl)-2-phenyldiazene and (E)-1-(phenyl)-2-phenylethene functionalities as the N-terminal capping groups of the inhibitors. Compound 5 with K_i value of 9 nM versus μ-calpain was the most potent member of the group. The compounds were predicted to be more lipophilic compared to MDL28170 based on CLogP estimation. They displayed moderate to good antiproliferative activity versus melanoma cell lines (A-375 and B-16F1) and PC-3 prostate cancer cells in vitro. Additionally, one member of the group (compound 3) inhibited DU-145 cell invasion by 80% at 2 μM concentration in the Matrigel cell invasion assay.     

Synthesis and antiproliferative activity of novel steroidal dendrimer conjugates

We describe the synthesis of steroidal dendrimer conjugates of first and second generation with tetramethylene core and 5-hydroxy-isophtalic acid dimethyl ester as branching unit modified to incorporate ethynylestradiol or 17α-estradiol as terminal units. The steroidal dendrimer conjugates, the free drug (steroids) and dendrimer were tested against a panel of cancer cell lines (CEM, MCF7, HeLa) and normal human fibroblast (BJ). The steroidal dendrimer conjugates of first generation exhibited cytotoxic activity and induced apoptosis in chronic leukemia (CEM) as resultant activation of caspase cascade which is mainly provoked in G2/M arrested cells.     

Synthesis and antiproliferative activity of thiazolidine analogs for melanoma

We have previously described 2-aryl-thiazolidine-4-carboxylic acid amides as a novel class of antiproliferative agents for prostate cancer. Screening these compounds with melanoma cell lines revealed that several of them have potent antiproliferative activity and selectivity against melanoma. To further improve the potency and selectivity, we synthesized a new series of analogs and tested them in two melanoma cell lines and fibroblast cells (negative controls). Comparison of anticancer effects of these compounds with a standard chemotherapeutic agent, sorafenib, showed that they are very effective in killing melanoma cells with low micromolar to nanomolar antiproliferative activity and provide us a new lead for developing potential drugs for melanoma.     

Synthesis and in vitro antiproliferative evaluation of some ring B abeo-sterols

Using cholesterol, β-sitosterol, dehydroisoandrosterone and pregnenolone as starting materials, a series of 5(6→7)abeo-sterols with different substituted groups and various side chains were synthesized and the antiproliferative activity of these compounds against HeLa, SMMC 7404 and MGC 7901 cells was investigated. The results revealed that the presence of a cholesterol-type side chain was very important for their cytotoxicity, and in particular a thiosemicarbazone at the C-6 position significantly enhanced the antiproliferative activity of these compounds. Although the elimination of 5-hydroxyl has no an obvious effect on their cytotoxic function, removal of the hydroxyl at the C-3 position decreased markedly the antiproliferative activity of the compounds. Some compounds have similar cytotoxic capability as cisplatin does.