抄録
Pladienolide B (2) and D (3) are 12-membered macrolide isolated from Streptomyces platensis Mer-11107 by way of a cell-based assay that evaluated the suppression of hypoxia-induced gene expression controlled by the human VEGF promoter. They also inhibit the growth of a variety of cancer cell lines in vitro with low nanomolar IC_<50> values. COMPARE analysis indicated that the compounds have a unique mode of antitumor action. Pladienolides B and D also cause in vivo tumor regression in several human cancer xenograft models. After intensive studies, we discovered E7107 (4). Treatment of several tumor xenograft models with E7107 has led to complete remission as well as tumor shrinkage in a variety of tumor xenografts. Recently E7107 has entered Phase I clinical trial. To verify the structure of Pladienolides, and to facilitate the discovery of novel analogues with advantageous pharmaceutical profiles we have executed the first total syntheses of pladienolides B and D. In conclusion, we have achieved the first total synthesis of pladienolides B (2) and D (3), through longest linear sequences of 22 and 19 steps, respectively, in overall yields of 2.1% and 2.2 %, respectively. These syntheses confirmed the absolute stereochemistry of pladienolides B and D. Our synthetic approaches involve the first example of ring-closing metathesis for the construction of a sterically hindered aliphatic 12-membered macrolide structure and also exhibit an effective application of cross-metathesis to the synthesis of natural products. The exploitation of cross-metathesis at the culmination of our total synthesis is quite efficient and versatile because the fragments can be assembled without protecting groups to directly provide the final target in sufficient yield. We believe that this synthetic effort provides a practical route to novel pladienolide analogues that could not be obtained from natural resources.
