RESUMO
Cell-based assays for evaluation of the anticancer potential of a focused small molecule library have identified a few potential hit molecules. Among the hits identified, Torrubiellutins (3a) showed good anticancer potential across the cells used in screening assays. Torrubiellutins are isolated from fungal insects Torrubiella luteorostrata and diverse pharmacological effects for these have been reported. However, it is not known as to how Torrubiellutins act through signaling pathways inhibiting the growth of eukaryotic cells. The current study aimed to determine the anticancer potential of Torrubiellutins by defining the molecular mechanism of cytotoxicity using DU145 cells. The results showed that the inhibition of prostate cancer cell growth by 3a was associated with inhibition of anchorage-independent growth, cell migration, and, to a small extent, apoptosis-mediated cell death by caspase activation. The growth-inhibitory effects of 3a are supported by inactivation of prosurvival pathways. Immunoblot analysis showed that the treatment of DU145 cells with 3a resulted in specific downregulation of AKT/mammalian target of rapamycin (mTOR) and its downstream effector proteins p70S6K, GSK3ß, and STAT3. On the basis of these findings, we propose that the changes observed in the AKT/mTOR signaling axis are new targets of 3a that are involved in its inhibitory activity on the proliferation of prostate cancer cells, suggesting its potential for further investigation as a promising anticancer agent.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Fenilalanina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Masculino , Fenilalanina/farmacologia , Neoplasias da Próstata , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
A practical and stereoselective synthesis of the tubuvaline-tubuphenylalanine (Tuv-Tup) fragment of tubulysin is achieved involving the opening of aziridine, crucial MacMillan alpha-hydroxylation on both fragments, and an epoxide-opening reaction.
Assuntos
Oligopeptídeos/química , Oligopeptídeos/síntese química , Fragmentos de Peptídeos/síntese química , Fenilalanina/química , Valina/química , Monoterpenos Acíclicos , Antineoplásicos/síntese química , Antineoplásicos/química , Aziridinas/química , Compostos de Epóxi/química , Hidroxilação , Monoterpenos/química , Fragmentos de Peptídeos/química , Fenilalanina/síntese química , Estereoisomerismo , Valina/síntese químicaRESUMO
A three-component 3+2 cycloaddition reaction followed by Suzuki coupling reaction was carried out to synthesize a library of compounds using automation (parallel synthesizer). Scaffolds that are unexplored in literature were used for the synthesis of library. The iodo-triazoles formed by 3+2 cycloaddition reaction were coupled with boronic acids to get tri-substituted triazoles.