C Ring and Its Substitutions

Acylation of free hydroxyl at C-7 in paclitaxel usually led to the reduction and even loss of cytotoxicity of the derivatives, when steric hindrance of the acyl groups increases. Bhat et al. have used a parallel solution phase synthetic method to construct a 26-membered library of C-7 esters, and concluded that modification at C-7 were detrimental to cytotoxicity against the MCF-7 cell line. Only a few exceptions, including 10-deacetyl-lO-propionyl-7-chloroacetyl 

Previous results have shown that lO-deacetyl-7-acyl paclitaxels or docetaxels 

7-Deoxy-7p-sulfur analogs were prepared by epimerization with DBU from 7a-thiol, the latter one from 7(3-triflate upon treatment of LiSMe or KSAc. In contrast to 7a-SH and 7(3-SH analogs, which are less toxic, 7(3-MeS (76a) and 7p-MeOCH2S (76b) analogs as well as 73 are superior to paclitaxel. 

Treatment of 2 -C02Bn-paclitaxel with DAST reagent yielded 7a-F 77 and 7,19-cyclopropane 78 products, and 6,7-olefin derivative 79 derivatives, which can also be obtained through 7-triflate intermediate when treated with 

DBU and silica gel in 1,2-dichloroethane, respectively.Paclitaxel and docetaxel analogs with 7a-F are not superior to the parent compounds in both in vitro and in vivo, and those with 7,19-cyclopropane and 6,7-olefin were comparably active.  

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