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Total Synthesis of Delavatine A and its Structural Analogues

Institution: University of California, Berkeley
Investigator(s): Vignesh Palani, B.S.
Award Cycle: 2019 (Cycle 28) Grant #: 28DT-0007 Award: $159,924
Subject Area: Cancer
Award Type: Dissertation Awards

Initial Award Abstract

Recently, two natural products, delavatine A and (–)-incarviatone A, were isolated from  plants of the Incarvillea genus, which have attracted considerable interest among scientists due to their medicinal properties and role in traditional Chinese herbal medicine (e.g., to treat anemia and dizziness). Delavatine A showed cytotoxicity against a number of human cancer cell lines (breast, colon, ovarian, liver, and cervical) and (–)-incarviatone A showed potential as a novel monoamine oxidase (MAO) A inhibitor. It has been demonstrated that MAO-A plays a significant role in cancer and that inhibition of MAO-A reduces tumor proliferation. Therefore, these two molecules are highly relevant for addressing cancer treatment by new mechanisms of action that will combat recalcitrant tumors. However, the functional group responsible for biological activity in these natural products was not studied/identified. Additionally, further biological studies of (–)-incarviatone A that could be relevant to combating cancer were not reported. The low natural abundance of (–)-incarviatone A, together with both natural products' intriguing biological activities make these compounds highly attractive synthetic targets for total synthesis.

Partially inspired by the proposed biosynthesis of these natural products, we designed a unified approach, to access both natural products from a common intermediate. The planned synthetic route is expected to be efficient and modular to facilitate the syntheses of structural analogues to be utilized in studying their anti-cancer properties. Structure–activity relationship (SAR) studies on the synthesized analogues will ultimately guide us in the design of novel chemotherapeutic drugs. Additionally, a synthesis of the unique MAO inhibitor incarviatone A will set the stage for more in-depth studies into the connections between MAO inhibition and cancer progression.