RESUMO
[structure: see text] Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F(0)F(1)-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels-Alder adduct, were analyzed for antiproliferative activity in E1A-transformed rat fibroblasts. Potent F(0)F(1)-ATPase inhibition was not a sufficient determinant of antiproliferative activity for several analogues, suggesting the existence of a secondary biological target or more complex mode of action for apoptolidin.
Assuntos
Antineoplásicos , Macrolídeos , ATPases Translocadoras de Prótons/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Macrolídeos/síntese química , Macrolídeos/química , Macrolídeos/farmacologia , Modelos Moleculares , Estrutura Molecular , Ratos , Células Tumorais Cultivadas , Leveduras/enzimologiaRESUMO
Our screening for antitumor antibiotics against transformed cells resulted in the isolation of a new active metabolite, oximidine III, from Pseudomonas sp. QN05727. This substance selectively inhibited the growth of rat 3Y1 fibroblasts transformed with various oncogenes. In ras- or src-transformed cells, oximidine III arrested the cell cycle at G1 phase and increased the expression of p21WAF1.
Assuntos
Antibióticos Antineoplásicos/isolamento & purificação , Compostos de Epóxi/isolamento & purificação , Lactonas/isolamento & purificação , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Transformada , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fermentação , Fibroblastos/efeitos dos fármacos , Citometria de Fluxo , Lactonas/química , Lactonas/farmacologia , Pseudomonas , RatosRESUMO
The structure of oximidine III, a new antitumor antibiotic against transformed cells from Pseudomonas sp. QN05727, was determined to be a benzolactone enamide containing an O-methyloxime moiety as shown in Fig. 1 by NMR spectral analysis including a variety of two-dimensional techniques.
