Description
The overall objective of this research is to synthesize new analogs of tryprostatins A and B to be evaluated for use as anticancer agents. Tryprostatins A and B are natural products that have been shown to have anticancer potential. Tryprostatin A exhibits cytotoxicity in cancer cells via microtubule inhibition. Tryprostatin B is more potent, but its mechanism of action has not been studied. However, the potency of these compounds is too low to make them valuable clinical trial candidates. Therefore, we are in the process of creating novel tryprostatin analogs to find a lead compound with increased potency. The design of these analogs is based on the results of previous studies including structure activity relationship studies and computational studies. The synthesis of these analogs will be done using a route that we are working on publishing. This route is shorter and therefore more efficient than our published 2019 tryprostatin A synthesis. Additionally, our new route provides two sets of two diastereomers which will allow us to synthesize more analogs in the same amount of time. The synthesized analogs will then be evaluated to determine their potency.
Tasks and Responsibilities
To help us reach this goal, the student will be synthesizing and purifying building blocks for our synthesis which will allow us to expedite the synthesis of a library of analogs. The key building blocks are a C2 alkylated gramine and a diketopiperazine. These two are then coupled together to form the penultimate products which are biologically active compounds. Those products are then converted to the final tryprostatin analogs. The chemical transformations involved in the synthesis of the C2 alkylated gramine are Boc protection and alkylation while those involved in the formation of the diketopiperazine are amide coupling, Fmoc deprotection and thermal cyclization. Typical reaction set ups involves adding starting materials to a flask followed by dissolution in appropriate solvent. To the solution of starting material, one or more reagents are carefully added. The reaction mixture is then allowed to react while reaction progress is monitored by thin-layer chromatography (TLC). Once complete, the reaction is quenched, and an aqueous organic extraction is performed to give the crude product. The synthesized compounds will then be purified via column chromatography and crystallization. Analysis of the products will be done by TLC, nuclear magnetic resonance, and mass spectroscopy.