Yoshiteru Eikyu

Synthesis and evaluation of nitro 5-deazaflavins as novel bioreductive antitumor agents

Abstract A series of nitro 5-deazaflavins, 5-deazaflavins possessing a nitro group at C(6)–C(9) position, has been designed and synthesized as a novel class of bioreductive nitrohetero-aromatic compounds and their cytotoxicities towards L1210 and KB cells were evaluated. It has been found that the nitro 5-deazaflavins undergo one electron reduction on the nitro group and undergo two electrons or “(net) hydride” reduction on the C(5)-C(4a)-C(10a)-N(1) redox system. They showed much more potent antitumor activities than the other 5-deazaflavins bearing no nitro group. These results suggest that an activation of nitro group by biological one electron reduction is crucial for an expression of cytotoxicity.

Structure-Based de novo design of non-nucleoside adenosine deaminase inhibitors

We searched for non-nucleoside inhibitors of adenosine deaminase by rational structure-based de novo design and succeeded in the discovery of 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide (FR221647: K(i)=5.9 microM to human ADA) as a novel inhibitor with moderate activity and good pharmacokinetics compared with the known inhibitors pentostatin and EHNA.

Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins

Abstract Cytotoxicities of nitro 5-deazaflavins were evaluated in vitro towards hypoxic and oxic Chinese hamster cells (V79). 6-Nitro and 8-nitro derivatives were generally more toxic towards hypoxic cells than oxic cells, showing marked hypoxic selectivity. In contrast, 7-nitro and 9-nitro derivatives showed no significant hypoxic selectivity. Electrochemical study using cyclic voltammetry (CV) revealed that 6-nitro and 8-nitro derivatives generate a stable two electrons reduction product as well as a stable one electron reduction product and that 7-nitro and 9-nitro derivatives afford an unstable one electron reduction product. These results strongly support that not solely electron affinity but also stability of the one electron reduction products is crucial for the differential hypoxic cytotoxicities of nitro 5-deazaflavins.