Design, synthesis and biological evaluation of new-generation taxoid-based tumor-targeting drug conjugates

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Zuniga, Edison S.
The Graduate School, Stony Brook University: Stony Brook, NY.
Over the past decades, chemotherapy has transitioned to an age of "targeted therapy." The development of Gleevec (Novartis) and Tarceva (Genentech and OSI Pharmaceuticals) has revolutionized the treatment of certain cancers, such as chronic myelogenous leukemia (CML), non-small cell lung cancer (NSCLC) and pancreatic cancer. Gleevec specifically targets the cancer cell-overexpressed Abl tyrosine kinase, and Tarceva targets the epidermal growth factor receptor that is mutated in different types of cancers. However, the use of these modern targeted-therapies is limited to specific cancer types. Therefore, considerable efforts have been made to find cancer-specific markers which can be exploited for tumor-specific delivery of more traditional chemotherapeutic drugs. A promising approach along this line is the development of tumor-targeting drug conjugates, which consists of one or multiple cytotoxic drugs (warheads) connected to a tumor-targeting module (TTM) via cleavable covalent bonds or cleavable linkers. The drug conjugates have been designed to remain inactive until they are specifically delivered to the tumor site, guided by the TTM and internalized, where the warhead is released from the carrier, restoring its original activity. New-generation taxoids have been developed by the Ojima laboratory via the Β-lactam synthon method. These taxoids show orders of magnitude greater potency in a number of cancer cell lines compared to the parent compound paclitaxel. Thus, new-generation taxoids are promising candidates as warheads for tumor-targeting drug conjugates. Accordingly, a number of new-generation taxoid-based drug conjugates have been developed that contain polyunsaturated fatty acids (PUFAs), vitamins and monoclonal antibodies (mAbs) as TTM. The synthesis and biological evaluation of these novel drug conjugates will be discussed.
432 pg.