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Synthesis of Spirolide-Activators of L-type Calcium Channels

Institution: University of California, Santa Barbara
Investigator(s): Craig Stivala, BS
Award Cycle: 2009 (Cycle 18) Grant #: 18DT-0002 Award: $60,000
Subject Area: Cardiovascular Disease
Award Type: Dissertation Awards

Initial Award Abstract
The American Heart Association has reported that of the 2.4 million annual premature deaths in the United States, smoking and smoking related illnesses account for approximately one-sixth of this astounding number. Cigarette smoking along with high blood pressure (hypertension) are two of the six major factors that contribute to coronary heart disease. Currently, there are several types of therapeutics that are used to treat hypertension which include ACE (angiotension-converting enzyme) inhibitors, ARBs (angiotension receptor blockers), diuretics, beta-blockers, and calcium channel blockers.

The calcium channel blockers (CCBs) are presumed to work by inhibiting the movement of calcium into the cells of the heart and walls of the blood vessels. As a result, this will widen blood vessels and reduce blood pressure since the heart does not have to work as hard to circulate blood. The L-type calcium channel dominates the activity of the cardiovascular system whereas other calcium channel types contribute little to its mechanical activity. This infers that auxiliary knowledge of channel structure and function may assist in the production of more effective therapeutics.

CCBs have been an important pharmacological target in the treatment of a number of conditions however they have had controversial success. It is through a comprehensive investigation of known calcium channel activators that will aid in the identification of key binding sites that will optimize the mechanical activity of therapeutic agents.

The research proposed in this application focuses on the synthesis of the marine natural product spirolide. Marine natural products have long served as leading compounds for new therapeutic agents; however, utilization is often extremely limited due to poor availability. Therefore, exploration of new synthetic techniques offers shortcuts in the production of such agents and the opportunity to discover new applications. A synthetic strategy for the L-type calcium channel activator, 13-desmethyl-spirolide C is described in detail. Understanding the various mechanisms through which calcium channel activation occurs will enable scientists to produce more effective therapeutics to treat hypertension.