Many current cancer chemotherapy drugs suffer from a lack of specificity; upon injection into the bloodstream, the drugs immediately begin killing both normal and cancerous cells causing unwanted side effects. The purpose of this project is to create taxoid-fatty acid conjugates in an effort to reduce some of these side effects. Some fatty acids are expected to increase the specificity of the drug since cancerous cells uptake significantly more than normal cells. The "n-3" fatty acids have been shown to slow down or prevent the growth of cancers. The esterification of a taxoid with a fatty acid at the 2' position also renders the taxoid harmless until it is cleaved within the cell, allowing for a more concentrated, specific treatment and longer sustained release.

Upon synthesis of the second-generation taxoid SB-T-1103 from 10-deacetylbaccatin III through a series of five steps (88% average yield), three different fatty acids (docosanoic acid [22:0], ?-linolenic acid [18:3n-3], docosahexaenoic acid [22:6n-3]) were coupled to the 2' position to afford three different conjugates. Due to the instability of conjugated fatty acids for air oxidation, high performance liquid chromatography (HPLC) is currently being used for stability tests to determine the rate of decomposition of each conjugate. Advanced second-generation taxoid SB-T-11033 is currently being synthesized, a nine step process that will culminate in the coupling of the fatty acids to the 2' position to afford three additional conjugates. The efficacy of the six final compounds will be evaluated by in vivo antitumor activity testing in an animal model at the Roswell Park Cancer Institute. This research was supported by a fellowship (to S.F.) from the Simons Foundation and a grant from National Institute of Health (to I.O.).