RESUMO
The title compound, C15H12N2O2S, is a P21/c polymorph of a previously reported P21/n polymorph [Büyükgüngör et al. (2004 â¶). Acta Cryst. E60, o1414-o1416]. The dihedral angle between the benzo-thia-zole (r.m.s. deviation = 0.010â Å) and the benzene ring of 7.86â (6)° compares with 10.76â (10)° in the literature structure. The meth-oxy substituent is almost coplanar with the benzene ring to which it is attached [C-O-C-C torsion angle = 178.31â (14)°] and the conformation about the imine bond [1.287â (2)â Å] is E. There is an intra-molecular O-Hâ¯N hydrogen bond and the hy-droxy O and thio-ether S atoms are syn. In the crystal, columns are formed along the b axis as centrosymmetric dimeric aggregates, mediated by C-Hâ¯O inter-actions and linked by π-π inter-actions between the thia-zole and benzene rings [centroid-to-centroid distance = 3.8256â (10)â Å].
RESUMO
The compound with R=CH2CH3 in Bi(S2CNR2)3 (1) is highly cytotoxic against a range of human carcinoma, whereas that with R=CH2CH2OH (2) is considerably less so. Both 1 and 2 induce apoptosis in HepG2 cells with some evidence for necrosis induced by 2. Based on DNA fragmentation, caspase activities and human apoptosis PCR-array analysis, both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. While both compounds activate mitochondrial and FAS apoptotic pathways, compound 1 was also found to induce another death receptor-dependent pathway by induction of CD40, CD40L and TNF-R1 (p55). Further, 1 highly expressed DAPK1, a tumour suppressor, with concomitant down-regulation of XIAP and NF-κB. Cell cycle arrest at the S and G2/M phases correlates with the inhibition of the growth of HepG2 cells. The cell invasion rate of 2 is 10-fold higher than that of 1, a finding correlated with the down-regulation of survivin and XIAP expression by 1. Compounds 1 and 2 interact with DNA through different binding motifs with 1 interacting with AT- or TA-specific sites followed by inhibition of restriction enzyme digestion; 2 did not interfere with any of the studied restriction enzymes.
Assuntos
Antineoplásicos/farmacologia , Bismuto/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , NF-kappa B/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Permeabilidade da Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proteínas Quinases Associadas com Morte Celular/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
The Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with 1 being the most active. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis is demonstrated and both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. Compound 1 activates the p73 gene, whereas each of 2 and 3 activates the p53 gene. An additional apoptotic mechanism is exhibited by 2, that is, via the JNK/MAP pathway.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Compostos Organoáuricos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Humanos , Modelos Moleculares , Compostos Organoáuricos/farmacologia , Padrões de ReferênciaRESUMO
The synthesis and characterisation of R3PAu[S2CN((i)Pr)CH2CH2OH], for R = Ph (1), Cy (2) and Et (3)4, is reported. Compounds 1-3 are cytotoxic against the doxorubicin-resistant breast cancer cell line, MCF-7R, with 1 exhibiting greater potency and cytotoxicity than either of doxorubicin and cisplatin. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis by 1, and necrosis by 2 and 3, are demonstrated, by both extrinsic and intrinsic pathways. Compound 1 activates the p53 gene, 2 activates only the p73 gene, whereas 3 activates both the p53 and p73 genes. Compounds 1 and 3 activate NF-κB, and each inhibits topoisomerase I.