Synthesis and biological evaluation of natural products and their analogs as new cancer chemotherapeutic agents

Abstract

Cancer is a leading cause of death in the world and there is a continual search for new anti cancer drugs. Today, more than half of the clinically available drugs are either natural products or derived from natural products. This is not surprising as natural products have been used for centuries as medicine and it is clear that Nature will continue to be a source for many new drug leads. The use of natural product scaffolds to synthesize analogs has already produced many new drugs for cancer chemotherapy. Here the aim of this thesis is to develop different classes of natural product analogs as potential new chemotherapeutic agents.

In Chapter 2, we described the first reported synthesis of a class of polyenylpyrrole natural products and their analogs. The compounds were evaluated for the cell cytotoxicity against human lung cancer cells A549 and structure-activity studies showed that the 3-chloropyrrole moiety is essential as replacement of the group with other 2 or 3-chloro aromatic rings led to a complete loss of activity. 2 of these compounds displayed excellent cytotoxicity with IC50 of 0.6 µM and 0.01 µM respectively. In addition, these 2 compounds proved to be non-toxic to normal human lung cells Beas-2b at up to 80 µM. These results indicated that these 2 compounds have the potential to be developed as anticancer agents due to their high selectivity against A549 cells.

In Chapter 3, the synthesis of lignan natural products as potential anti-tumor agents was described. After the synthesis of racemic isochaihulactone and nemerosin was achieved, asymmetric synthetic technique was introduced to afford all 4 lignan isomers: isochaihulactone, slyvestrin, nemerosin and its enantiomer. Of these 4 compounds synthesized, isochaihulactone and slyvestrin are natural products which had been isolated previously but never synthesized. Nemerosin is a natural product which had previously been synthesized while there are no reports on the isolation or synthesis of the enantiomer of nemerosin. Both isochaihulactone and slyvestrin displayed cytotoxicity against various cancer cells.

Chapter 4 described the microwave assisted synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones through a modified Biginelli procedure. Under microwave irradiation, the reaction time was shortened from 12 h to 15 min. These results further demonstrate the value of microwave-assisted synthesis in increasing yield, shortening reaction time and streamlining high throughput synthesis. This also represents the first reported synthesis of such a class of 5-unsubstituted 3,4-dihydropyrimidin-2-thiones.