Molecules from nature have been a major source for medications including cancer, malaria, and antiarrhythmic agents. Many clinical drugs are either directly inspired or derived from natural products. As a result, natural product based drug discovery is of great importance in modern drug discovery. Natural molecules or compounds from natural sources are usually chiral molecules which are the secondary metabolites that are used in the defense mechanism of the plants or organisms. The organisms have evolved to produce only one of the enantiomers. As a result, it is possible to isolate and screen for biological activity only of the enantiomers, i.e., the natural enantiomer. Logically, the unnatural enantiomer might actually be as good as the natural enantiomer or even better in activity, as well as in toxicity profile depending on the metabolism. In our group, we have developed an efficient and practical method for the total synthesis of a number of sarpagine - related bioactive indole alkaloids. We are using the same strategy for the total synthesis of the unnatural enantiomers of a number of C - 19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids. N4 - Methyltalpinine showed very strong NF-kB inhibition1. Talcarpine was found active against Plasmodium falciparum2. N4 -methyl- N4, 21 -secotalpinine exhibited antileishmanial activity against Leishmania mexicana1. Talpinine exhibited cytotoxicity in reversing multidrug resistance in drug resistant KB/VJ300 cells3. Rauvomine B showed significant activity in inhibiting macrophage RAW 264.7 cell line4. Total synthesis of the unnatural enantiomers of these alkaloids will be presented.

Total synthesis of unnatural enantiomers of bioactive C – 19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids

2019 Spring National Meeting

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