Synthetic and biological studies on new anti-tumor agents

Forty years after its discovery, Paclitaxel still offers attractive challenges for chemists and biologists. Taxol chemotherapy is associated with undesirable side effects due to the lack of specificity towards tumor cells and the development of cancers expressing MDR phenotype. More research is required to further extend the acquired knowledge and reduce those limits.; Our research is essentially focused on the further expansion of paclitaxel's existing SAR studies, and on the development of tumor targeting strategies.; A new approach has been evaluated to increase the tumor uptake of second generation taxoids, especially active against multi drug resistant cancers. Polyunsaturated fatty acids such as docosahexanoic acid, linolenic acid and linoleic acid were linked at the C2'-position of the second generation taxoids already developed in these laboratories. The new conjugates exhibited strong activity against a drug-sensitive human ovarian tumor xenograft and a human colon tumor xenograft, overexpressing Pgp glycoprotein and resistant to anticancer agents including paclitaxel and docetaxel.; The increasing interest recently devoted to the synthesis of biologically active compounds containing fluorine atoms, led us to extend our structure-activity relationship studies to C-3'-difluoro- and C-3'trifluoromethyl advanced second generation taxoids. Optimization of the synthesis and enzymatic resolution of fluorinated beta-lactam, has provided easily accessible fluorinated taxoids side chains. We synthesized paclitaxel analogs with multiple modifications, at C-2, C-3' and C-10.; SAR studies on paclitaxel over the last 15 years confirmed the importance of the baccatin core to the anticancer activity of this important drug. One of the few exceptions discovered so far is IDN5390 a novel taxoid with the C-ring of the taxane skeleton cleaved. This novel C-seco taxoid is a promising drug candidate to deal with non-MDR based resistance to paclitaxel caused by the upregulation of the class III beta-tubulin. It has been recently shown that some mammalian cells resistant to paclitaxel overexpress specific beta-tubulin classes. In particular, in ovarian tumors from cancer patients the upregulation of the class III beta-tubulin confers this type of resistance to paclitaxel. Microtubules composed of the class III beta-tubulin are by far more sensitive to IDN5390 than to paclitaxel. These results led us to design a series of IDN5390 analogs. The synthesis and SAR studies of these novel C-seco taxoids will be discussed, with a focus on their ability to interact with overexpressed class III beta-tubulin.