RESUMO
A new cephalostatin/ritterazine analogue was prepared from the commercially available hecogenin acetate and the natural cytotoxic steroid 22-epi-hippuristanol. The method involved the reductive dimerization of enaminoketones (condensation of alpha-aminoketones) and condensation between an enaminoketone and an alpha-hydroxyketone. The new analogue showed higher cytotoxic activity than the cytotoxic 22-epi-hippuristanol against MDA-MB-231, A-549 and HT-29 cultured tumor cell lines.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Fenazinas/química , Fenazinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Esteroides/química , Esteroides/farmacologia , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Fenazinas/síntese química , Sapogeninas/química , Compostos de Espiro/síntese química , Esteroides/síntese química , Esteróis/químicaRESUMO
Three unusual new steroid thioesters, parathiosteroids A-C (1a-3a), were isolated from the 2-propanol extract of the soft coral Paragorgia sp. collected in Madagascar. Their structures, determined by detailed spectroscopic analysis, were confirmed by synthesis and represent the first isolation of natural steroids bearing a C22 thioester in their side chain. These compounds displayed cytotoxicity against a panel of three human tumor cell lines at the micromolar level. The preparation of several analogues revealed structure/activity relationships in this type of steroids, for example, that the XCH2CH2NHCOCH3 moiety (X = S, O, NH) in the side chain is essential for the antiproliferative activity, and a low degree of oxidation in the A-ring results in higher bioactivity. These natural products could be biosynthetic intermediates in the steroid side chain degradation pathway involving activation with CoA and beta-oxidations.
