RESUMO
Cyclin dependent kinases (CDKs) along with the complementary cyclins form key regulatory checkpoint controls on the cell cycle. Flavopiridol is a synthetic flavone that shows potent and selective cyclin-dependent kinase inhibitory activity. In this paper, we report modifications of the 3-hydroxy-1-methylpiperidinyl (D ring) of flavopiridol and their effect on CDK inhibitory activity.
Assuntos
Cromonas/química , Cromonas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Antineoplásicos/química , Antineoplásicos/farmacologia , Cromonas/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/metabolismo , Flavonoides/metabolismo , Piperidinas/metabolismo , Piridinas/síntese química , Células Tumorais CultivadasRESUMO
Levuglandin E2 (LGE2), a rearrangement product derived from the prostaglandin endoperoxide, PGH2, causes repair-resistant DNA-protein cross-links and cell death (LD50 = 230 nM) in V79 Chinese hamster lung fibroblasts. The half-life for sequestration of LGE2 by covalent binding to cellular nucleophiles is at least an hour for 10 microM LG. This suggests that the in vivo production and distribution of free LGs should be measurable on this time scale. Following removal of the LGE2 and the return of the cultures to normal growth medium, additional DNA-protein cross-links continued to form over the ensuing 6-24 h. The results suggest that LG adducts to DNA or protein are not repaired, but react further at sites on protein or DNA in close proximity to the initial adducts, forming cross-links in a slow phase of the process.
Assuntos
Núcleo Celular/metabolismo , Reagentes de Ligações Cruzadas/farmacologia , DNA/metabolismo , Proteínas Nucleares/metabolismo , Prostaglandinas E/farmacologia , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Cinética , PulmãoRESUMO
Prevention by glycine of protein crosslinking which accompanies binding of levuglandin E2 (LGE2) is shown to involve binding of glycine with the protein-LGE2 adduct. With ovalbumin, the LGE2 adduct initially binds nearly 2 equivalents of glycine, but the capacity to bind glycine decreases with time reflecting a competition, inter alia, with crosslinking.
Assuntos
Reagentes de Ligações Cruzadas , Glicina/metabolismo , Ovalbumina/metabolismo , Eletroforese em Gel de Poliacrilamida , Cinética , Prostaglandinas E/metabolismoRESUMO
Levuglandin E2 (LGE2) is a gamma-keto aldehyde produced by rearrangement of the prostaglandin endoperoxide PGH2 under the aqueous conditions of its biosynthesis. We show that exogenous LGE2 enters cells and efficiently inhibits the first synchronous cell division of fertilized sea urchin eggs. We attribute this inhibition to covalent modification of tubulin and thereby to inhibition of microtubule assembly.
