Design, synthesis and biological evaluation of novel taxane-based anticancer agents and their tumor targeting delivery

Paclitaxel (TaxolRTM) and docetaxel (Taxotere RTM) are the most important drugs in modern cancer chemotherapy. These drugs were approved by the FDA for treatment of advanced ovarian cancer, metastatic breast cancer, AIDS-related Kaposi's Sarcoma, and non-small cell lung cancer. TaxolRTM and TaxotereRTM are currently undergoing Phase II and III clinical trials worldwide for a variety of other cancers.; Although these drugs have very promising anticancer activity, they have a number of undesirable side effects as well as inherent weakness against drug-resistant cancer cells expressing multi-drug resistance (MDR) phenotypes. The development of new analogs, which are expected to have higher potency and better pharmacological properties than the parent drugs is an avenue to overcome the problems.; The introduction of fluorine(s), difluoromethyl, trifluoromethyl, or difluorovinyl group can modulate the properties of bioactive molecules and lead to substantially improved pharmacological profile due to increased membrane permeability, enhanced hydrophobic binding, and stability against metabolic oxidation. The synthesis of fluorine containing second generation taxoids, utilizing the beta-Lactam Synthon Method (beta-LSM), was used as one of the approaches. The synthesized fluorine-containing taxane-based anticancer agents exhibited 2-3 orders of magnitude higher potency against drug-resistant and 1 order of magnitude higher potency against drug-sensitive human breast cancer cell lines compared with paclitaxel.; The synthesis of tumor-specific drug delivery system was used as another approach to overcome undesirable severe side effects. In order to achieve effective delivery to tumor cell the conjugates containing polyunsaturated fatty acids (PUFA) were synthesized and evaluated. The tumor-targeting conjugates showed complete tumor regression demonstrating the exceptional efficacy of PUFAs---second-generation taxoid conjugates against drug-sensitive and drug-resistant human tumor xenografts.