6 RK-682エナミド誘導体の開発 : プロテインホスファターゼ阻害活性と細胞増殖抑制活性(口頭発表の部)

概要

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RK-682 (1), which was isolated from Streptomyces sp. 88-682, inhibits various enzymes such as phospholipase A_2, HIV-1 protease, heparanase, some dual-specificity phosphatases (DSP), and a protein tyrosine phosphatase (PTP), CD45. We already reported the structure-activity relationship studies of RK-682 derivatives at both enzyme and cell levels. Their cell level activity was, however, found to be weaker compared to the enzyme level activity indicating their poor membrane permeability. The 3-acyltetronic acid structure of RK-682, which exists as its anionic form under physiological conditions, is critical for the inhibition of phosphatases and proposed to act as phosphate mimic. But the observed low enzyme selectivity and poor membrane permeability also seem to be caused by this highly acidic structure. To create a more selective phosphatase inhibitor that can be effectively incorporated into cells, electronically neutral RK-682 derivatives were designed and synthesized. Among them, the RK-682 enamide (RE) derivatives were found to inhibit dual-specificity protein phosphatases, VHR and Cdc25A, but not PTP1B or heparanase. Finally, we found that some derivatives also remarkably inhibited proliferation of human leukemia HL-60 cells.
2006-09-15