Recent advances in the chemistry and biology of new generation taxoids

Among the numerous chemotherapeutic drugs, paclitaxel and docetaxel are among the most widely used against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop "taxane" anticancer agents with better pharmacological properties and improved activity especially against drug-resistant cancers. Several laboratories have performed extensive SAR studies on paclitaxel. Our SAR studies have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3' positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the new generation taxoids also exhibited excellent cytotoxicity against pancreatic cell lines expressing multidrug-resistant genes. We have also designed taxoids with strategic fluorine incorporation to investigate their effects on the cytotoxicity and the blockage of known metabolic pathways. Furthermore, we have successfully employed computational biology analysis to design novel macrocyclic taxoids to mimic the bioactive conformation of paclitaxel. This account describes our work on the design, synthesis, and biological evaluation of these novel taxoids, which has led to the discovery of very promising candidates for further preclinical studies