Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids.
Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids.
复制标题
新型 C14-C3BzN 连接大环紫杉烷的设计、合成和生物学评价。
DOI：
10.1021/jo801713q
复制
发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Ojima,Iwao
中科院分区：
文献类型：
--
作者：
Sun,Liang;Geng,Xudong;Geney,Raphaël;Li,Yuan;Simmerling,Carlos;Li,Zhong;Lauher,JosephW;Xia,Shujun;Horwitz,SusanB;Veith,JeanM;Pera,Paula;Bernacki,RalphJ;Ojima,Iwao
Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the “REDOR-Taxol” structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and theorthoposition of C3′N-benzoyl group (C3′BzN), which are ca. 7.5 Å apart, with a short linker (4−6 atoms). 7-TES-14β-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-β-lactams were selected as key components, and the Ojima−Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure−activity relationships is also performed and discussed.
