Synthesis of Agelasines and Analogs, and Evaluation of Their Bioactivities

Agelasines are 7,9-dialkylpurinium salts isolated from marine sponges (Agelas sp.) and asmarines are neutral purine derivatives isolated from Raspaila sp. sponges. These two classes of natural products are structurally related; they both contain terpenoid side chains. Up till now only a few agelasines and no asmarines have been synthesized. High activity against Mycobacterium tuberculosis (the bacterium that causes tuberculosis) has been found for some agelasines and analogs. Tuberculosis (TB) is the majo r cause of death from a single infectious agent among adults in developing countries and there is estimated that 30 million people will die from TB in the next 10 years. However no new drug directed specifically against TB have been introduced the last 30 years even though multi-drug resistant TB is a growing problem. In this project, we will develop selective synthesis of agelasines and analogs. Allylic rearrangements and allylic oxidations will be key-steps in the formation of the terpenoid part of the compounds. We will continue to screen the agelasines and analogs formed for antimycobacterial activity and try to determine their mode of action as antibacterials. We are also interested in potential activity against other microorganisms as well as other biological activities of agelasines. Little is known about bioactivity of asmarines. We will develop methodology for construction of the 7-membered ring in the asmarines, and work towards the first total syntheses of these compounds. The asmarines and an alogs formed will be subjected to the same bioactivity studies as described for the agelasines.