Design, Synthesis and Evaluation of Novel Taxane-Based Anticancer Agents

Abstract

Taxol¶© (paclitaxel) and TaxotÇùre¶© (docetaxel) are the most widely used pharmaceuticals in cancer chemotherapy. These drugs have been approved by the FDA for the treatment of advanced ovarian cancer, metastatic breast cancer, Kaposi Sarcoma, non-small cell lung cancer, etc. Both drugs are also under clinical development for additional cancer indications. Although established great success in the clinic, paclitaxel and docetaxel have exhibited a number of undesirable side effects as well as low efficiency against drug-resistant cancerphenotypes. Therefore the development of new analogs, which are expected to have higher potency and better pharmacological properties but fewer side effects, is of high value from the cancer chemotherapy perspective. The dissertation will present the design, synthesis and biological evaluation of the following novel taxane-based anticancer agents: (1) New generation taxoids: via the highly efficient β-Lactam Synthon Method, the design and synthesis of a large number of novel taxoids with systematic modifications has led to the development of highly potent second- and third-generation taxoids. In parallel, taxoids against multi-drug resistance cell lines have also been developed to create the dual functions (the cytotoxicity and the MDR reversal activity) into one molecule. (2) Macrocyclic taxoids: paclitaxel takes effect by inducing microtubule stabilization, G2/M block and apoptosis. Although this classic mechanism of action has been known for almost 30 years, the binding conformation of paclitaxel to β-tubulin is yet to be fully understood. Structurally constrained macrocyclic taxoids were designed, synthesized and evaluated to help identify the bioactive conformation(s). (3) Novel taxoid conjugates: the undesirable side effects in conventional cancer chemotherapy are generally resulted from the lack of tumor-specificity. Omega-3 fatty acids have been shown to be beneficial for tumor-targeting drug delivery. Novel tumor-targeting conjugates of new generation taxoids were hence designed and synthesized using omega-3 polyunsaturated fatty acids.