The Yoshimoto research laboratory at UTSA harnesses the power of synthetic chemistry to solve challenging problems relevant to human health.
Artemisinin, one of the topics of the 2015 Nobel Prizes in Medicine, is an endoperoxide-containing sesquiterpenoid plant natural product used to treat malaria. The biosynthesis of the endoperoxide functional group, which gives the natural product its antimalarial activities, has been controversial. Using isotope-labeling strategies, we have elucidated the mechanism of the nonenzymatic endoperoxide forming cascade reaction that converts the precursor, dihydroartemisinic acid, to artemisinin in four steps: (i) first oxygen incorporation, (ii) C-C bond cleavage, (iii) second oxygen incorporation, (iv) and polycyclization to form artemisinin (1,2). Analogs of DHAA have been synthesized to probe endoperoxide formation, which led to the elucidation of the mechanism of the formation of the aromatic ring in serrulatene, an antibiotic plant natural product (3).
Secondly, human cytochrome P450 8B1, the oxysterol-12a-hydroxylase enzyme implicated in bile acid biosynthesis, is a therapeutic target to treat obesity. Preliminary studies involving the synthesis of a rationally designed inhibitor of P450 8B1 through the incorporation of a C12-pyridine in the steroid backbone, will be discussed (4).
1. Varela, K., Arman, H. D., and Yoshimoto, F. K. (2020) Synthesis of [3,3-2H2]-Dihydroartemisinic Acid to Measure the Rate of Nonenzymatic Conversion of Dihydroartemisinic Acid to Artemisinin. J. Nat. Prod. 83, 66-78
2. Varela, K., Arman, H. D., and Yoshimoto, F. K. (2021) Synthesis of [15,15,15-2H3]-Dihydroartemisinic Acid and Isotope Studies Support a Mixed Mechanism in the Endoperoxide Formation to Artemisinin J. Nat. Prod. 84, 1967-1984
3. Varela, K., Al Mahmud, H., Arman, H. D., Martinez, L. R., Wakeman, C. A., and Yoshimoto, F. K. (2022) Autoxidation of a C2-Olefinated Dihydroartemisinic Acid Analogue to Form an Aromatic Ring: Application to Serrulatene Biosynthesis. J. Nat. Prod. 85, 951-962
4. Chung, E., Offei, S. D., Jia, U. A., Estevez, J., Perez, Y., Arman, H. D., and Yoshimoto, F. K. (2022) A synthesis of a rationally designed inhibitor of cytochrome P450 8B1, a therapeutic target to treat obesity. Steroids 178, 108952