Modified Taxols, 4. Synthesis and Biological Activity of Taxols Modified in the Side Chain

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Abstract
A number of taxol derivatives substituted at the 2'' position of the side chain have been prepared and their biological activities determined in KB cell culture and/or the P-388 in vivo assay. The 2''-(t-butyldimethylsilyl)taxol 5 is essentially inactive, indicating the need for a free hydroxyl group at the 2'' position for activity. Epimerization of the 2'' position occurred on treatment of 2''-acetyltaxol derivatives with 1,5-diazabicyclo[5.4.0]undec-7-ene, but treatment of 2''-(2,2,2-trichloroethyloxycarbonyl)taxol derivatives with DBU yielded the novel cyclization products 11 and 12 and, after deprotection at the 7 position, 13. The derivative 13 is also essentially inactive in the KB test system. Two taxols with increased H2O solubility were prepared, the 2''-(.beta.-alanyl) derivative 15 and the 2''-succinyl derivative 16. Although both these derivatives were active in vivo and in vitro, the former was too unstable and the latter not active enough to make suitable H2O-soluble derivatives of taxol.

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