This research program plans to discover the reason for the antitumor activity of certain members of a class of natural products called the cyclopentanoid monoterpenes, or iridoids. At least three iridoids, penstemide, didrovaltrate, and allamandin, all of which have some structural similarity, have significant antitumor activity in vivo against the P388 animal model of lymphocytic leukemia. Yet there was no prior precedent for such activity among the iridoids, and there is no obvious structural feature that can be used to explain the reason for this activity. We will uncover the reason by the total synthesis of these compounds and their structural analogs, using chemical methods developed already in our laboratory, and then by a comparative analysis of the antitumor activity of the parent drugs vs. their analogs. We also expect to be able to find an analog with valuable antitumor activity whose structure is simpler than the parent drug. Successful work will be followed in subsequent grant periods by the examination of the way such compounds interact with cultured tumor cells as a test of the idea that these compounds act by covalent attachment to tumor cells, thereby interfering with the function of vital biomolecules. The value of this research program is (i) the potential of finding a new mechanism of action for antitumor drugs, (ii) the possibility that in this way we will learn something new about how to control the growth of tumor cells, and (iii) the high probability that we will find a clinically active antitumor drug from the synthetic and medicinal chemistry studies.
