Design, synthesis, and structure-activity relationship (SAR) of novel taxane anticancer agents

Paclitaxel holds great promise for the treatment of various types of cancers. However, the use of paclitaxel is associated with several undesirable side effects including the development of multi-drug resistance (MDR) expressing cancers. Although there have been numerous SAR studies which have produced several very promising compounds that show activities far superior to that of the parent compound, more research is clearly needed before the taxane class of compounds can reach their full potential in the fight against cancer.; One of the major areas of research in this dissertation is centered on the further development of paclitaxel's existing SAR. These new taxoids, developed in part using the information gathered from the previous SAR studies, incorporate new functionalities that will hopefully result in drugs with decreased undesirable side effects and increased biological activities. The information gained from these studies will undoubtedly influence the future development of taxane anti-cancer agents.; Another area of research discussed is the determination of the active conformation of taxane anticancer agents. Through the design and synthesis of novel photoaffinity labels and conformationally restricted macrocyclic taxoids we have taken important steps towards achieving this goal. These macrocyclic compounds were designed based on our common pharmacophore model and are the first step on the road to denovo taxane like anticancer agents.; The development of drug resistance is a major obstacle in cancer chemotherapy. The continuing SAR study of non-cytotoxic taxane MDR reversal agents, which have been shown to be potent inhibitors of the protein responsible for MDR, is also explored.; Finally, our initial research on tumor targeting taxoid conjugates is described. These compounds are designed to bring the taxoid directly to the tumor thereby drastically reducing the undesirable side effects observed for the parent compound.