Natural Products Synthesis/Translational Medicinal Chemistry
Natural products possess a long and storied history in the discovery of lead compounds and important medicines for the treatment of human disease. This is particularly notable in the area of cancer research, where, according to data published by the National Cancer Institute, 74% of the small-molecule chemical entities introduced as new drugs worldwide between 1981-2001 can be traced to or were inspired by natural products.Moreover, natural products synthesis is an integral part of the drug development process. Pharmacophore identification, optimization of lead compounds, and creating novel structural scaffolds inspired by nature are achieved by synthetic means.

An integral aspect of our research program at City of Hope involves the application of complex molecule synthesis to the generation and development of novel therapeutic agents for the molecular-targeted treatment of cancer and related conditions. Our research interests in general lie in developing new synthetic methods and strategies for the total synthesis of architecturally complex biologically active natural products (Fig. 1). Notable representatives include the oroidin-based alkaloids agelastatin A and palau'amine, cell cycle inhibitor spirotryprostatin A, the red-tide neurotoxins, saxitoxin and gonyautoxins, anti-tumor agents grossularines as well as the structurally complex alkaloids dragmacidins and diazonamide A.

Fig. 1  Representative Natural Product Targets

These and other structurally related secondary metabolites represent a collective class of molecules that elicit a myriad of potent biological responses. These include anticancer, immunosuppressive, antitumor, antiserotonergic, antiviral, and ion-channel blocking properties as well as ATPase stimulating activities of myosin and actomyosin. While completion of the total synthesis is an important goal, we are more concerned, per se, with developing novel chemistry that each target structure suggests. For example, we recently completed a biomimetic synthesis of the anti-tumor natural products, grossularines (Scheme 1). This family of secondary metobolites was isolated in minute amounts from the Britannia marine tunicate Dendrodoa grossularia (Styelidae). Grossularines represent one of the more structurally intriguing members of a relatively small but potent class of a-carboline metabolites that exhibit pronounced effects against solid human tumor cell lines. The limited material available from nature as well as synthetic sources, however, has hampered further investigations in vivo. Our lab has recently developed an exceedingly efficient biomimetic synthesis of grossularines whereby these important natural products are now readily accessible in large amounts through total synthesis.

Scheme 1  Biomimetic synthesis of grossularines-1 Angew. Chem. Int. Ed. 2005, 44, 3280-3284.

The synthesis showcases the development of new reaction methodology that leads molecular complexity in rapid fashion. In addition, preliminary work in collaboration with Prof. Jove's group at City of Hope has identified even more potent non-natural analogs against certain prostate cancer cell lines than the natural products themselves. Investigations directed at target identification and SAR studies are currently in progress. 

Another recent focus area involves the development of novel synthons and synthetic methodologies for use in indole-based natural product synthesis. Several new methodological advances have been made that include the development of an acyl cyanide approach for the practical preparation of oxotryptamine, an important tryptamine-based intermediate. We demonstrated the utility and relevance of this key intermediate in various heterocyclic bisindole natural product syntheses that involve the marine alkaloids topsentin, nortopsentin, dragmacidins, and dihydrohamacanthins. New reduction methodology was also introduced during these studies that allows rapid access to various bisindole-linked piperazines and piperizinones from readily available pyrazine and pyrazinone precursors. No protecting groups were utilized in any of these syntheses, an approach that has become a trademark of our work. The synthesis of the important cell cycle inhibitors spirotryprostatins is illustrative (Scheme 2). Again, rapid molecular complexity can be attained through the development of novel synthons such as a-substituted tryptophan and tryptamine derivatives.

Scheme 2 Preparation and synthetic applications of 2-halotryptophan methyl esters: A rapid synthesis of spirotryprostatin B. Angew. Chem. Intl. Ed. 2004, 43, 5357-5360.

We are in a unique position to advance drug discovery through synthetic organic chemistry, high-through-put screening, molecular modeling, and translation of these efforts to on-campus clinical trials. In essence, our program embodies a total translational medicinal chemistry (TMC) effort ranging from reaction development and natural products synthesis to target validation and elucidation of new biological pathways with the ultimate goal of developing new pharmacophores as novel and effective therapeutic agents. TMC at COH is an integral part of the Experimental Therapeutics Program and NCI-designated Comprehensive Cancer Center.