| Cancer remains the leading cause of death among Americans, second only to heart disease. Of all cancer subtypes, lung and prostate cancer are two of the most deadly that also consistently beckon the largest number of new diagnoses. Clearly, there is a serious unmet demand for therapies targeting these cancer subtypes. Because many of the clinically useful drugs for lung and prostate cancer target topoisomerase II (topo II) and β-tubulin, we have chosen these proteins as molecular targets for our research.; Within the topo II realm, our laboratory has for many years been interested in developing derivatives of azatoxin, a dual topo II/tubulin inhibitor containing an indole core. Considering the structural similarities between azatoxin and the tryprostatin class of natural products, we have designed and synthesized over 30 compounds within three subclasses: (1) amino-acid (AA) functionalized carbolines, (2) AA-functionalized diketopiperazines, and (3) diketopiperazine-based carboline homodimers. In this work, our synthetic triumphs and challenges will be outlined. The resulting structure-activity relationships (SARs) in lung (NCI-H520) and prostate (PC-3) cancer subtypes will be discussed with particular emphasis on proposed refinements to the topo II-model pharmacophore.; During the course of this research, we have also focused considerable attention on proving that biaryl colchicinoids targeting the α/β-tubulin heterodimer may be viable agents for chemotherapy. 2-methoxy-5-(2,3,4-trimethoxyphenyl)cyclohepta-2,4,6-trien-1-one, the biaryl equivalent of colchicine, retains most of the biological properties of colchicine itself. Towards further understanding of the SAR and therapeutic potential of this class, we have designed, synthesized, and evaluated 34 biaryl colchicinoids. We have discovered five agents possessing submicromolar activity in the NCI-H520 and PC-3 lines examined. Overall, we will discuss our SAR conclusions as we begin to answer the question: “Is the trimethoxy motif on AC's core essential for biological activity?”... |
