Over the past three decades, 28% of all new FDA approved drugs have been natural products, or derived from natural products, while 27% have been entirely synthetic in origin. Thus, the pursuit of new synthetic methods and strategies to access complex molecules is not only a worthy pursuit, but a critical component of biomedical research and drug development that also contributes novel elements of synthetic strategy and methods to the lexicon of synthetic chemistry. The studies proposed within this application describe the pursuit of six different natural products that fall into three general classes (diketopiperazine, alkaloid, and terpenoid). These compounds possess a range of biological activities including: leishmanicidal, NO production inhibition, anti- inflamatory, antiinsectan, antifungal, antiviral, cytotoxicity against a variety of cancer cell lines, as well as anti- proliferative activity. For the diketopiperazine and alkaloid projects we are aiming to develop ring expansion technology that will enable efficient access to imbedded hydroxamic acid intermediates. More specifically:
Aim 1, entails syntheses of the N-hydroxy-2,5-diketopiperazine-derived (NHDKP) natural products haenamindole, raistrickindole A, and 14-hydroxyterezine D.
This aim also includes the development of a regioselective ring expansion of tetramic acids that will enable the direct acces of to highly functionalized NHDKP?s.
Aim 2 focuses on syntheses of phyllantidine and flueggeacosine B, two members of a securinega alkaloid subset that contain N-O bonds. The scope of the optimized ring-expansion chemistry developed in Aim-1 will be expand in this aim to deliver key intermediates in both syntheses.
Aim 3 is a departure from aims 1 and 2 and turns toward further development of keteniminium chemistry by its application in a complex synthetic setting. At present, work toward each aim is at a different stage of development and this development will continue to evolve over the course of the grant period. As with all of our synthetic endeavors, collections of intermediates will be submitted to the NIH for SAR studies and once materials are in hand further collaborations are sought. In addition to direct contributions to biomedical science afforded by the latter, our synthetic efforts have (and will continue to) educate graduate students and postdoctoral researchers in the planning and execution of complex molecule synthesis.
From 1981 to 2014, approximately 28% of all new drugs approved for use were derived directly or indirectly from natural products. This application proposes studies that will enable the laboratory synthesis of six natural products in three different classes of molecules. All of the targeted compounds possess potential as useful therapeutics. In addition, the researchers involved in this project will learn the techniques needed to manipulate molecules with atomic resolution, thereby endowing skills that will enable them to prepare nearly any type of drug or drug-like molecule.
