摘要：

Macrosphelides, 16-membered natural macrolide compounds, have been reported to exhibit potent cell-cell adhesion inhibitory activity, immunosuppressive activity, and anti-tumor activity. We have recently discovered that some of natural macrosphelides and analogues (1-5, Scheme 1) can activate apoptotic program in human lymphoma U937 cells, albeit rather weak potency. Although detailed mechanism of action remains to be elucidated, the structural characteristics of macrosphelides are associated with natural macrolide, epothilones, possessing the same 16-membered lactone framework. Epothilones have been reported to inhibit microtubule dynamics in living cells and consequently exhibit extraordinarily potent cytotoxicity. In addition, epothilones are known to induce apoptotic cell death, which is suggested to have close correlation with the tumor cell growth inhibitory effects. Thus, we designed novel hybrid compounds (8-13, Scheme 1) composed of the 16-membered trilactone core structure of macrosphelides and the thiazole-containing side chain of epothilones, aiming at discovery of new efficient apoptosis inducing agents. The synthesis of the hybrid compounds 8-13 were achieved based on a ring-closing metathesis (RCM) strategy, which has been developed by us for the total syntheses of natural macrosphelides A, B, and E. Details are summarized in Scheme 3-5. Examination of the apoptosis inducing activity of the hybrid compounds synthesized in this study brought about results of great interest, whose results are depicted in Figure 1. The hybrid 9 exhibited the most potent activity with negligible secondary necrosis at 1μM concentration after 6h incubation, and the hybrids 13 and 11 also induced apoptosis slightly. It is an important note that the parent macrosphelides 1-5 did not display any apoptosis inducing ability at the same concentration. These results indicate that the thiazole-containing substituent installed at a suitable position can give rise to significant interactions with a living substance controlling an apoptotic program.

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