Abstract
Cancer is the second major cause of death in the United States and is the leading cause of death of patients below the age of 85. Traditional chemotherapeutics, such as paclitaxel (Taxol ¶©) and docetaxel (Taxotere ¶©) have had a significant impact in the field of chemotherapy because of their unique mechanism of action of inducing apoptosis by stabilizing microtubules during mitotic cell division. However, studies have indicated that these drugs are not active in multi-drug resistant (MDR) cancer cells. MDR arises from the overexpression of ATP-binding cassette proteins which enable the cancer cell to remove cytotoxic agents from the cell via ATP dependent efflux pumps, resulting in the loss of efficacy of the drug. In addition to the problem of MDR, traditional chemotherapeutics have little or no specificity, which leads to systemic toxicity, causing severe and harmful side effects. Therefore, it is important to develop next generation taxoids with increased potency and activity in MDR expressing cancers, as well as to incorporate these cytotoxic agents to tumor-targeting delivery systems to ensure selective cytotoxicity and reduce systemic toxicity. In general, these delivery systems include a tumor-targeting module (TTM) and a cytotoxic agent. Highly potent next generation taxanes, SB-T-1214, SB-T-121602, and SB-T-121302, were synthesized via Ojima-Holton coupling protocol using enantiopure Beta-lactam and modified 10-Deacetyl-Baccatin III (10-DAB). The Beta-lactam required for the Ojima-Holton coupling protocol was afforded via two synthetic routes; Staudinger [2+2] cycloaddition followed by enzymatic resolution protocol and by the chiral ester enolate-imine cyclocondensation. In addition, tumor-targeting drug conjugates were synthesized using linolenic acid (LNA) as the tumor-targeting module. LNA is an essential fatty acid which plays a crucial role in many metabolic processes. Polyunsaturated fatty acids, such as LNA, are greedily taken up by tumor cells as biochemical precursors, making them effective tumor-targeting agents. Several LNA drug conjugates were synthesized, including LNA-SB-T-1214 and LNA-SB-T-121602 as well as a tumor targeting drug conjugate that incorporates a methyl-branched disulfide linker.
