RESUMO
Tetrahydrobenzo[b]thiophene derivatives were well known to be biologically active compounds and many of them occupy a wide range as anticancer agent drugs. One of our main aim of this work was to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of novel 1,2,4-triazines as efficient anticancer drugs with low cytotoxicity and good bioavailability properties using cyclohexane-1,3-dione and 3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-diazonium chloride to give the 2-(2-(2,6-dioxocyclohexylidene)hydrazinyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) as the key starting material for many heterocyclization reactions. Compound 3 was reacted with phenylisothiocyanate to give the tetrahydrobenzo[e][1,2,4]triazine derivative 5 which reacted with hydrazines to give dihydrazone derivatives. In addition, it underwent multi-component reactions with aromatic aldehydes and either malononitrile or ethyl cyanoacetate in the presence of triethylamine or ammonium acetate to produce fused pyran and fused pyridine derivatives, respectively. Compounds obtained in this work were evaluated for their c-Met kinase inhibitory potency as well as in-vitro cytotoxic activity against the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). Molecular modeling studies were carried out for the most active compounds 5, 7a, 7b, 10c, 10e, 11c and 11f using Molecular Operating Environment (MOE) software. It was found that all the tested compounds displayed potent c-Met enzymatic activity with IC50 values ranging from 0.24 to 9.36 nM. Ten of them (5, 7a, 7b, 10c, 10e, 10f, 11b, 11c, 11d and 11f) exhibited higher potency with IC50 values less than 1.00 nM compared with foretinib (IC50 = 1.16 nM). Also those compounds possessed moderate to strong cytotoxicity against the six tested cancer cell lines in the single-digit µM range. The synthesized compounds 5, 7a, 7b, 10c, 10e, 11c and 11f were fit on the active site of c-Met kinase, with almost the same binding pattern as foretinib and higher binding energy scores (from -16.38 to -18.21 kcal/mol) compared to foretinib (-16.37 kcal/mol). A series of novel 1,2,4-triazines were synthesized and displayed potent bioactivities, indicating that these compounds could be considered as a new lead for more investigation in the future.
Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Cicloexanos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade , Triazinas/síntese químicaRESUMO
A simple and efficient method has been developed for the synthesis of 4,5-dihydro-2-mercapto-4-oxo-6-substituted arylpyrimidine derivatives (2a-e) and their fused rings (3b, 4b, 5b & 6b) and also 1,4-dihydro-2-mercaptopyrimidine derivatives (7a-e) & (9a-e) using triethylamine as a catalyst. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analysis. All the synthesized compounds were evaluated for their in vitro anticancer activity against six human cancer cell lines and normal fibroblasts. Thirteen of the tested compounds: 2a-e, 3b, 4b, 5b, 7d, 8, 9a, 9c and 9d exhibited significant cytotoxicity against most cell lines. Among these derivatives compounds 2a, 3b and 9c are the most potent, they exhibited cytotoxic effect against the six cancer cell lines with IC(50) values < 330 nM compared to the standard CHS 828. Normal fibroblast cells (WI38) were affected to a much lesser extent (IC(50) >10,000 nM).
RESUMO
A series of new N-substituted-3-mercapto-1,2,4-triazoles (3a,b and 7a-d), triazolo[1,3,4]thiadiazines (5a,b) and triazolo[1,3,4]thiadiazoles (4a-d, 6 and 8a-d) have been synthesized starting from isonicotinic acid hydrazide. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against 6 human cancer cell lines and normal fibroblasts. Seven of the tested compounds (3a,b, 4c, 5a and 8b-d) exhibited significant cytotoxicity against most cell lines. Among these derivatives compound 4c exhibited equivalent cytotoxic effect to the standard CHS 828 against gastric cancer cell line (IC50 = 25 nM). Normal fibroblast cells (WI38) were affected to a much lesser extent (IC50 > 10,000 nM).