Design, synthesis, and biological evaluations of novel taxane-based and taxane-free anticancer agents

TaxolRTM (paclitaxel) is a major success in cancer chemotherapy and currently the bestselling anticancer drug worldwide. It acts by its unique mechanism of action, i.e., promoting polymerization of tubulins and stabilizing the microtubules. This thesis consists of the structure-activity relationship (SAR) studies of paclitaxel and its analogs (taxoids), the investigation of the bioactive conformation of paclitaxel through the synthesis of macrocyclic taxoids as well as the synthesis of taxane-free taxol-mimicking anticancer agents.; beta-Lactam Synthon Method utilizes enantio-pure beta-lactam as the precursor for the C-13 side chains of taxoid analogs. The semi-synthesis of paclitaxel and its analogs could be successfully accomplished by beta-lactam ring-opening coupling reactions with properly modified baccatins.; Second-generation taxoids are analogs with modifications at the C-10, C-3' and C3'N positions. Advanced second generation taxoids combine second-generation taxoids with C2 phenyl group modifications and resulted in analogs which virtually overcome multi-drug resistance. Most of these taxoids exhibited one order of magnitude higher potency than that of paclitaxel against drug-sensitive cancer cell lines, and some of these taxoids showed 2--3 orders of magnitude higher potency than that of paclitaxel against the drug-resistant cell lines, which makes them highly promising clinical candidates for cancer chemotherapy.; Taxane has a unique tetra-cyclic framework that renders a distinct steric environment which could differentiate the two enantiomers of beta-lactams, providing the basis for kinetic resolution. Accordingly, highly potent second-generation taxoids could be synthesized in high diasteroselectivities through coupling reactions of baccatins with racemic beta-lactams.; The presence of hypoxic (poorly oxygenated) tumor cells causes solid tumor to respond badly to radiation therapy. A series of dual functional radio-sensitizing taxoids bearing nitro groups were designed and synthesized and their biological activities assayed. In the current cancer chemotherapy, therapeutic drugs usually lack selectivity towards cancer cells, causing severe damage to the healthy tissues. The utilization of tumor-specific monoclonal antibodies as vehicles to deliver chemotherapeutic agents specifically to cancer cells will target tumor cells without affecting normal tissues. A novel taxoid analog bearing a methyldisulfanylalkanoyl group was designed, synthesized and conjugated with monoclonal antibodies. The taxoid-antibody conjugates showed promising in vitro as well as in vivo biological activities. (Abstract shortened by UMI.)...