Differential antiproliferative activity of new benzimidazole-4,7-diones

Ten benzimidazole-4,7-diones were synthesized and tested in vitro on two tumor cell lines. Several compounds showed a significant antiproliferative activity on K562 cells, although to a different extent, whereas compound 1i showed a highly significant activity on SW620 cells, comparable to that of doxorubicin. Both the substituents in the quinone ring and the position of the nitrogen atom in the pyridine moiety play a crucial role for the biological activity.     

Synthesis and antiproliferative activity in vitro of 2-aminobenzimidazole derivatives

A novel series of Schiff bases 1-11, the derivatives of 2-aminobenzimidazole and substituted aromatic aldehydes, has been synthesised. Compounds 1-11 reduced by NaBH(4) formed 2-benzylaminobenzimidazoles 12-21. 2-(o-Bromobenzylamino)benzimidazole (15) acylated by cinnamoyl chloride gave 2-(o-bromobenzylamino)-1-cinnamoylbenzimidazole (22). Long heating of 15 and 19 with p-nitrocinnamoyl or cinnamoyl chloride led to the formation of pyrimido[1,2-a]benzimidazol-4-ones 23 and 24. The structures of 1-24 were identified by the results of elemental analysis and their IR, (1)H NMR and MS spectra. Among the compounds 1-24 evaluated for their antiproliferative activity in vitro, 16, 19, 20 and 22 exhibited cytotoxic activity against the cells of human cancer cell lines, namely SW707 (rectal), HCV29T (bladder), A549 (lung) and T47D (breast cancer).     

Synthesis of 1H-pyrazole-1-carboxamide derivatives and their antiproliferative activity against melanoma cell line

Synthesis of a new series of 1H-pyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375 human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The pharmacological results indicated that most of the newly synthesized compounds showed moderate activity against A375, compared with sorafenib. Among all of these derivatives, compound IIe which has N-methylpiperazinyl and phenolic moieties showed the most potent antiproliferative activity against A375 human melanoma cell line.     

Synthesis and antiproliferative in-vitro activity of natural flavans and related compounds

The total synthesis of natural flavan racemates (+/-) 1, (+/-) 2 and natural flavones 3, 4 had thus been achieved. A straightforward synthetic procedure of flavans via the Pd-C catalyzed hydrogenation/hydrogenolysis of corresponding flavones was developed. Furthermore, the antiproliferative activities of racemic flavans (+/-) 1, (+/-) 2, flavones 3, 4, and five synthetic intermediates toward human SGC-7901, BEL-7402, HeLa, and HL-60 cell lines in vitro were evaluated by MTT assay, and the racemic flavans (+/-) 1 were found to have significant antiproliferative activity against all four cell lines.     

Design, synthesis, and antiproliferative activity of 3,4-diarylpyrazole-1-carboxamide derivatives against melanoma cell line

Synthesis of a new series of 3,4-diarylpyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E-b-Raf and the binding mode was studied.     

Design and synthesis of isoindoloquinoline derivatives as potential antitumor agents

A series of isoindoloquinoline derivatives was synthesized and evaluated in vitro cytotoxicity against four human cancer cell lines (HCT15, SK-OV-3, MDA-MB-468 and T-47D).     

A field‐based disparity analysis of new 1,2,5‐oxadiazole derivatives endowed with antiproliferative activity

A series of 1,2,5‐oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT‐116 cancer cell line. The field‐based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure–activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization.     

1,5-Benzodiazepines XIV. Synthesis of new substituted 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepines and relate compounds endowed with in vitro cytotoxic properties

A series of 11 new 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepine derivatives 8e-o was synthesized. Ten of these compounds (8e-m,o), along with four analogues (8a-d) (previously synthesized by us) were tested in vitro in order to evaluate their cytotoxic and anti-HIV-1 properties. In this connection other six original compounds, i.e., five 9-substituted compounds prepared starting from the 6,12-diphenylderivative 8c (compounds 10, 11, 12, 13a,b) and the bis-triazolone derivative 14, were synthesized and tested for the same purpose. While none of the 20 compounds tested exhibited any appreciable anti-HIV-1 activity, some of them exhibited interesting cytotoxic properties, the best results being shown by compounds 8c,d,k and 11 (CC(50) range=3-12 microM). Therefore, these four compounds were further evaluated for their antiproliferative activity against a panel of human tumor cell lines; actually, compounds 8d, 8k and 11 showed antiproliferative properties against either or both leukemia- and lymphoma-derived cell lines in the low micromolar range.     

In vivo evaluation of substituted 2,3-diaryl acrylophenone amide derivatives as anti-implantation agents

A series of substituted 2,3-diaryl acrylophenone amide derivatives was evaluated for their anti-implantation activity in mature female Sprague-Dawley rats. Compounds 11, 14, 15, and 19 showed significant activity in preventing implantation in rats at 10 mg kg⁻¹.     

Synthesis and cytotoxic activity of 1,3-benzodioxole derivatives. Note II

A series of 1,3-benzodioxoles (2-12) were synthesized and evaluated for their in vitro ability to inhibit the growth of three human tumor cell lines. No cytotoxic effects were noticed with any of the test compounds at a concentration of 10(-4) M.     

Synthesis andin vitro cytotoxicity of 2-alkylaminosubstituted quinoline derivatives

Eight 2-alkylaminosubstituted 5,8-dimethoxy-4-methylquinolines and nine 2-alkylaminosubstituted or 2,6-disubstituted 4-methylquinoline-5,8-diones were synthesized and evaluated in vitro cytotoxicity against four human cancer cell lines (HOP62, SK-OV-3, HCT15 and SF295).     

Synthesis and in vitro antileukemic activity of new 4-triazenopyrazole derivatives

Several new 4-(3,3-dimethyltriazeno)-5-benzamidopyrazole derivatives were prepared by reacting 4-diazo-5-benzamidopyrazole derivatives with dimethylamine. The compounds were tested at 10 microM for their vitro antileukemic activity against K562 (Human chronic myelogenous leukemia) and Raji (human Burkitt limphoma ) cell lines. Dacarbazine and methotrexate were used for comparative purpose. The 3-methyl-4-(3,3-dimethyltriazeno)-5-(substituted benzamido)pyrazoles, bearing the pyrazole nucleus free at 1 position, resulted more active than the 1-(substituted phenyl)-3-methyl-4-(3,3-dimethyltriazeno)-5-benzamidopyrazoles. Dacarbazine at 10 microM showed no activity in the above tests. The observed difference among Dacarbazine and the active 4-triazenopyrazoles migth be explained admiting that these last compounds, differently by Dacarbazine, did not follow a mechanism of action based on the cytochrome P-450 induced demethylation. The most active compound 2d showed growth inhibition values of 97.8 and 99.4% against K562 and Raji cell lines respectively. Methotrexate inhibition values at 0.2 microM against the above cell lines were 86.7 and 75.1% respectively.     

Synthesis and antiproliferative activity of new mycophenolic acid conjugates with adenosine derivatives

New conjugates of mycophenolic acid (MPA) and adenosine derivatives were synthesized and assessed as potential immunosuppressants on Jurkat cell line and peripheral blood mononuclear cells (PBMC) from healthy donors. As compared to MPA, all compounds were found to be more active against Jurkat cell line. The antiproliferative activities were compared with MPA and adenosine, in both 2′,3′-O-isopropylidene protected and free hydroxyl groups possessing forms. The obtained results were also discussed in terms of selectivity index, defined as SI = IC₅₀/EC₅₀.     

Biological approach of anticancer activity of new benzimidazole derivatives

BackgroundA series of new benzimidazole derivatives, earlier synthesized, was tested in vitro as new bioreductive prodrugs with the potential anticancer activity. Their effect on the DNA destruction and growth inhibition into selected tumor cell lines at normoxia and hypoxia conditions was determined.MethodsThe human lung adenocarcinoma A549 cell line was used to determine the anticancer activity of the analyzed compounds by using WST-1 assay. The apoptosis test (caspase 3/7 assay) was used to define the cytotoxic way of tumor cells death. Additionally test In situ DNA Damage Assay Kit was applied to recognize the DNA destruction.ResultsFour of the examined compounds (1, 3, 7, 9) show a very good antiproliferative effect and three of them are specific for hypoxia conditions (2, 4, 8).ConclusionCompound 8 is the most cytotoxic against human lung adenocarcinoma A549 cells at hypoxic conditions. Hypoxia/normoxia cytotoxic coefficient of compound 8 (4.75) is close to hypoxia/normoxia cytotoxic coefficient of tirapazamine (5.59) – reference substance in our experiments and this parameter locates it between mitomycin C and 2-nitroimidazole (misonidazole). The screening test of the caspase-dependent apoptosis proved that the exposure of compounds 1–2 and 7–8 against A549 cells for a 48 h promote apoptotic cell death. Additionally, the test of the DNA damage established that compounds 1, 2, 7, 8 are specific agents for the hypoxia-selective cytotoxicity of nitrobenzimidazoles [6], [26].     

Chromophore-modified bis-benzo[g]indole carboxamides: synthesis and antiproliferative activity of bis-benzo[g]indazole-3-carboxamides and related dimers

Tricyclic pyrazole dimers that comprise two kinds of CONH-(CH(2))(n)-N(CH(3))-(CH(2))(n)-NHCO bridges to which are linked potential DNA-intercalating groups such as 1H-benzo[g]indazole, 2H-benzo[g]indazole and 1,4-dihydroindeno[1,2-c]pyrazole were designed, synthesized and some of them evaluated in vitro by NCI (Bethesda, USA) against nine types of cancer cells. Compounds 2a, 2f-i and 2o-r demonstrated significant antiproliferative activity, all with GI(50) values in the low micromolar range. Preliminary analysis of the structure-activity relationship for dimers 2 indicated that: (i) in the ground terms (2a and 2k) antitumor activities were strongly related to the type of chromophore, (ii) in contrast, either 1H-benzo[g]indazole- or 1,4-dihydroindeno[1,2-c]pyrazole-dimers when bore a N(1)-aryl group (2g, 2h, 2i, 2o, 2p, 2q and 2r) generally showed a good level of antitumor potency and (iii) for the most representative compounds (pairs of compounds: 2g,2h; 2o,2p and 2q,2r) the length of the bridges did not significantly contribute to the variations in cytotoxicity. Two members of this series, 2f and 2q, were selected and tested in the hollow fiber cell assay to evaluate in a preliminary fashion their in vivo antitumor activity. Finally, viscosity measurement of 2f with poly(dA-dT)(2), confirmed that these promising compounds behaved as typical DNA-intercalating agents.     

Cytotoxicity and L-amino acid oxidase activity of crude insect drugs

The cytotoxicity of crude insect drugs was measured using HeLa cells originating from human cervix and uterine cancer, using the dye uptake assay in order to find potential anticancer agents. Three kinds of extracts (buffer, methanol and ethylacetate) were prepared from 26 insects and used as raw materials for the activity assay. Among these, the buffer extracts from Tabanus, Mylabris and Huechys showed a potent anticancer activity, and those from Catharsius, Red ant, Scorpion, Tabanus and Vespae Nidus showed a strong L-amino acid oxidase (AAO) activity as well as cytotoxicity. In contrast, buffer extracts from Gryllotalpa orientalis and Apriona germari larvae showed greater/more rapid Hela cell growth than that of other insects.     

Curcumin analogues and derivatives with anti-proliferative and anti-inflammatory activity: Structural characteristics and molecular targets

ABSTRACT

Introduction: Curcumin (Diferuloylmethane) is a natural phenolic compound, which belongs to the curcuminoid family, presenting pleiotropic activity and low bioavailability. A lot of recent research is focused on the design and synthesis of curcumin analogs as antiproliferative and anti-inflammatory agents improving the bioavailability and target selectivity. Their structural characteristics and functional groups seem to define the extent of the biological activity.

Areas covered: Publications (2008–2018), describing curcumin analogs and curcumin derivatives are analyzed. Structural characteristics, functional groups, modelling studies, structure activity relationships, biological evaluation in vitro/in vivo as antiproliferative and anti-inflammatory agents are included. Furthermore, a wide range of biological results derived from different targets are also summarized.

Expert opinion: Several curcumin analogs and derivatives appear to have a high biological impact as well as promising antiproliferative and anti-inflammatory activities. Their clinical evaluation will be critical to assess therapeutic utility. Compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.     

Differential effects of tautomycetin and its derivatives on protein phosphatase inhibition, immunosuppressive function and antitumor activity

In the present work, we studied the structure-activity relationship (SAR) of tautomycetin (TMC) and its derivatives. Further, we demonstrated the correlation between the immunosuppressive fuction, anticancer activity and protein phosphatase type 1 (PP1) inhibition of TMC and its derivatives. We have prepared some TMC derivatives via combinatorial biosynthesis, isolation from fermentation broth or chemical degradation of TMC. We found that the immunosuppressive activity was correlated with anticancer activity for TMC and its analog compounds, indicating that TMC may home at the same targets for its immunosuppressive and anticancer activities. Interestingly, TMC-F1, TMC-D1 and TMC-D2 all retained significant, albeit reduced PP1 inhibitory activity compared to TMC. However, only TMC-D2 showed immunosuppressive and anticancer activities in studies carried out in cell lines. Moreover, TMC-Chain did not show any significant inhibitory activity towards PP1 but showed strong growth inhibitory effect. This observation implicates that the maleic anhydride moiety of TMC is critical for its phosphatase inhibitory activity whereas the C1-C18 moiety of TMC is essential for the inhibition of tumor cell proliferation. Furthermore, we measured in vivo phosphatase activities of PP1 in MCF-7 cell extracts treated with TMC and its related compounds, and the results indicate that the cytotoxicity of TMC doesn't correlate with its in vivo PP1 inhibition activity. Taken together, our study suggests that the immunosuppressive and anticancer activities of TMC are not due to the inhibition of PP1. Our results provide a novel insight for the elucidation of the underlying molecular mechanisms of TMC's important biological functions.     

4-氨基嘧啶取代的双芳基脲类化合物的合成及抗肿瘤细胞增殖活性

目的设计并合成含有不同取代苯环结构的双芳基脲类化合物,初步评价其体外抗肿瘤细胞增殖活性。方法以ABT-869为先导化合物,利用生物电子等排原理,将其3-氨基-1H-吲唑结构改造为氨基嘧啶环设计新目标化合物;以对硝基苯乙腈为起始原料,经与N,N-二甲基甲酰胺二甲缩醛(DMF-DMA)缩合、环合、还原、酰化、成脲共5步反应合成目标化合物;以索拉非尼(sorafenib)为阳性对照药,采用MTT法,测试目标化合物对乳腺癌细胞株MDA-MB-231的抗增殖活性。结果与结论合成了18个未见报道的双芳基脲类化合物,其结构经1H-NMR和MS谱确证;6个化合物显示较好的体外活性,其中,化合物5r活性突出,为对照药索拉非尼的1.8倍;并且初步探讨了目标化合物的构效关系。