P-56 海綿Dysidea arenaria由来の抗腫瘍性デプシペプチドarenastatin A : 類縁体合成と活性(ポスター発表の部)

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During the course of our investigations in search of new biologically active substances from marine organisms, we have isolated a very potent cytotoxic depsipeptide named arenastatin A (1) from the Okinawan marine sponge Dysidea arenaria through bioassay-guided separation. In this paper, we present an improved asymmetric total synthesis of 1 and its structure-activity relationship. Further investigation on the final cyclization for building up 15 led us to find that the macrolactamization proceeds in favorable yield. Segment A (7) was synthesized starting from transstyrylacetic acid by taking advantage of Evans asymmetric aldol reactions. Then, in order to study structure-cytotoxicity relationship concerning arenastatin A (1), we further synthesized following four stereoisomers 24-27 in the analogous manner. Among these synthesized allied compounds, only 1 showed extremely potent cytotoxicity (IC_<50> 5pg/ml for KB cell), while others as 15,16 and 24-27 didn't show any potent cytotoxicity at the concentration of below 0.1μg/ml. Arenastatin A (1) inhibited the in vitro polymerization of microtubule proteins, while 16, 24, and 26 didn't show effect on the in vitro microtubule assembly. Furthermore, we examined the conformation of arenastatin A (1) and its stereoisomers 16 and 26.
天然有機化合物討論会の論文
1995-09-01