RESUMO
The brain isoform of creatine kinase has been implicated in cellular transformation processes. Cyclocreatine, a creatine kinase substrate analog, was previously shown to be cytotoxic to a broad spectrum of solid tumors. We have synthesized, enzymatically characterized, and evaluated the antitumor activity of a series of substrate analogs of creatine kinase. Using in vitro assays, we demonstrate that several of these analogs are cytotoxic to the human ME-180 cervical carcinoma, the MCF-7 breast adenocarcinoma and the HT-29 colon adenocarcinoma cell lines at low mM concentrations. Analogs that were active in vitro delayed the growth of a subcutaneously implanted rat 13,762 mammary adenocarcinoma. Tumor growth delays of 6-8 days were achieved, which is comparable to effects seen with standard regimens of currently used anticancer drugs. These studies further establish the creatine kinase system as a promising and novel target for anticancer chemotherapy drug design.
Assuntos
Antineoplásicos/farmacologia , Creatina Quinase/metabolismo , Creatina/análogos & derivados , Fosfocreatina/análogos & derivados , Adenocarcinoma/tratamento farmacológico , Animais , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Creatina/química , Creatina/farmacocinética , Creatinina/análogos & derivados , Creatinina/farmacologia , Feminino , Humanos , Neoplasias Experimentais/tratamento farmacológico , Fosfocreatina/química , Fosfocreatina/farmacocinética , Ratos , Células Tumorais Cultivadas/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
The four-component Ugi reaction was utilized to prepare a library of dipeptidic compounds in order to explore the binding requirements of the key cell cycle phosphatase, Cdc25. Several phosphate surrogates were incorporated into the Ugi product to mimic either the mono- or bis-phosphorylated substrate.