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
Oxidative cleavage of the C-20/C-21 bond in apoptolidin (1) provides two fragments of similar complexity, facilitating a divide-and-diversify strategy for the determination of the structural basis for apoptolidin's biological activity, the remarkably selective induction of apoptosis in sensitive cell lines. The ability of compounds derived from this cleavage to inhibit mitochondrial F(0)F(1)-ATPase is reported. [structure: see text]
Assuntos
Macrolídeos/química , Macrolídeos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Metanol/química , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , OxirreduçãoRESUMO
[reaction: see text] To investigate the structural basis for the exceptional selectivity and activity of apoptolidin (1), a strategy has been devised that allows for selective functionalization of seven of its eight hydroxyl groups based on progressive silyl protection, derivatization, and deprotection. The syntheses of these derivatives and their ability to inhibit F(0)F(1)-ATPase are reported.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Macrolídeos , Animais , Humanos , Hidroxilação , Concentração Inibidora 50 , Proteínas Mitocondriais , ATPases Translocadoras de Prótons/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
[formula: see text] Apoptolidin (1) is a novel oncolytic lead that induces apoptosis in transformed cell lines with exceptional selectivity. We report the isolation and characterization of a ring-expanded macrolide isomer of apoptolidin: isoapoptolidin (2). The solution conformation of isoapoptolidin is described. The rate of isomerization was measured under biologically relevant conditions and found to approach equilibrium within the time frame of most cell-based assays. Isoapoptolidin's ability to inhibit mitochondrial F0F1-ATPase is over 10-fold less than that of apoptolidin.
