Current cancer chemotherapy suffers a lack of specificity of the chemotherapeutic drugs for cancer cells; the drugs, taxoids, arrest the mitotic process and induce apoptosis in any actively propagating cells, both cancer cells and non-malignant cells alike. This causes many undesired effects, and nearly guarantees that in the event of a complete remission, non-malignant tissues will be severely damaged by the taxoids. Therefore, any differences between cancer cells and healthy cells must be exploited in order to protect the healthy cells. One notable difference between cancer cells and non-malignant cells is that on the surface of cancer cells is an overexpression of the epidermal growth factor receptor, an antigen. Monoclonal antibodies (MAbs) have demonstrated a high binding specificity for this tumor cell-specific antigen; therefore, MAbs could be used as media for selectively administering taxoids to the tumor cells through conjugation of taxoids to the MAbs. While conjugated to the MAbs, the taxoids would be inactive, but when the taxoid-MAb conjugate reached
a tumor cell, the MAb would bind to the tumor cell-specific antigen, the conjugate would be internalized through endocytosis, and it is believed that the disulfur bond linking the taxoid to the MAb would be cleaved by an intracellular thiol, releasing the taxoid in its active form. In this sense, the conjugates could be considered tumor-activated prodrugs (TAPs). While theoretically this means of delivering cytotoxic drugs to tumor cells seems ideal, conjugation of the taxoid to the MAb requires that the water-solubility of the taxoid be improved. The purpose of this project, thus, was to design and synthesize potent second-generation taxoids with increased water-solubility. First, taxoids SB-T-12136 and SB-T-1213601, two second-generation taxoids with great cytotoxicities, were synthesized from 10-Deacetylbaccatin III over seven steps, with an average yield of 90%, stepwise. From these second generation taxoids, four novel water-soluble taxoids will be synthesized. Both taxoids were coupled with diglycolic anhydride and thiodiglycolic anhydride. One carboxylic acid functional group was introduced onto the C-2\u8217\'92 position of the taxoids; hence, their water solubilities should be increased. Although the blocking of the C-2\u8217\'92 position of the taxoids will decrease the taxoids' cytotoxicity, either basic conditions or an enzymatic reaction within the cell should cleave the ester bond releasing the parent compounds in their cytotoxic forms. Once coupling of SB-T-12136 and SB-T-1213601 with diglycolic anhydride and thiodiglycolic anhydride is completed, the novel taxoids' water solubilities will be determined by high performance liquid chromatography. The structures of the synthesized compounds were confirmed by proton NMR, carbon NMR, and high-resolution mass spectrum. This research was supported by grants from the National Institutes of Health (NIH GM42798).