The total synthesis of a variety of compounds with demonstrated cardiac activity is proposed. Our general aim is to develop new efficient synthetic procedures such that the target compounds will be available, via total synthesis, in sufficient quantities for detailed pharmacological evaluations. The general target areas are the pumiliotoxin A and gelsemium alkaloids, and the forskolin family of labdane diterpenes. Specifically we propose total syntheses for the natural products pumiliotoxins A and B; allopumiliotoxins 267A, B1, and B2; gelsemine, 1, 9-dideoxyforskolin, forskolin, and coleonol. In most cases the target compounds are to be prepared in enantiomerically pure form. The pumiliotoxin A alkaloids represent a model for developing a new class of cardiotonic and myotonic agents which act via selective calcium channel effects.
We aim to exploit synthetic technology developed during the past grant period to prepare complex members of this class, which are available in only minute quantities in nature. We moreover propose a rational program of analog synthesis and testing which should yield basic structure-activity information, and hopefully yield compounds of greater activity than natural materials. Forskolin and coleonol display positive ionotropic and antihypertensive effects in cardiac muscle, which appear to be related to their ability to activate cardiac adenylate cyclase. To date, only analogs of the natural diterpenes have been biologically evaluated.
Our aim i s to see if these complex diterpenes (and analogs thereof) can be prepared by total synthesis. Gelsemine is a hexacyclic oxindole alkaloid for which antihypertensive activity has been reported.
Our aim i s to see if this complex alkaloid (and analogs thereof) can be prepared efficiently by total synthesis. Our proposed synthetic approaches are largely founded on new cyclization and rearrangement methodology recently developed in our laboratory.
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