The Taxanes The Compounds Sinenxan A Chemical, Structural Modification And Structure-activity Relationship Study

Sinenxan A (SIA) is a new biosynthetic taxoid with a simplified structure and some cytotoxicity.Our studies are focussed on the following research related to SIA by SAR correlation in the searching for new antitumor agents. (1)Five side chains of taxol and its analogues were steroselectively synthesized. Arndt-Eistert wolff rearrangement is firstly introduced to prepare the side chain SC-33A sterospecifically. The key intermediate diazoketon e was isolated and identified by IR and ¹H-NMR. (2) The chemical character of SIA including selective deacetylation, deacetoxylation, acylation, epimerization and oxidation was investegated. At the same time, SIA was modified mainly at its C₁₄, C₁₀ and C₂ positions. The new compounds with skeletal modification including some key intermediates such as 14β-OH SI-22 and its epimerized counterpart 14α-OH SI-203 were obtained. It is also observed and investegated in detail that bases and acids can bring some special reactions to SIA and SI-200. Some new interesting derivatives from SI-200 were identified and synthesized. (3) Several side chains were successfully introduced into C₁₄ and C₁₀ of modified SIA skeletons. Proper esterfications with side chains and stereohampered SI-203 were found. Twenty-six new taxol and taxotere analogues were synthesized. Cytotoxicity of sixteen of which is tested on three kinds of cell lines. A rough SAR has come out. (4) All new structures are identified by ¹H-NMR. Most of them are also proved by ¹³C-NMR Some of them are further charaterized by FAB-MS, DEPT and UV. Very few of them are verified by C-H COSY, HMBC, IR or x-ray.