Biomimetic Total Synthesis of (+)-Nocardioazine B and Analogs
Biological Products (pharmacology); Biomimetics; Diketopiperazines; Prenylation
Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from , with a desymmetrized -d-Trp-d-Trp DKP core. Based on our deeper biosynthetic understanding, a biomimetic total synthesis of (+)-nocardioazine B is accomplished in merely seven steps and 23.2% overall yield. This pathway accesses regio- and stereoselectively C3-isoprenylated analogs of (+)-nocardioazine B, using the same number of steps and in similar efficiency. The successful strategy mandated that the biomimetic C3-prenylation step be executed early. The use of an unprotected carboxylic acid of Trp led to high diastereoselectivity toward formation of key intermediates -, -, and - (>19:1). Evidence shows that 1-methylation causes the prenylation reaction to bifurcate away to result in a C2-normal-prenylated isomer. Nocardioazine A, possessing an isoprenoidal-epoxide bridge, inhibits P-glycoprotein (P-gp)-mediated membrane efflux, in multidrug-resistant mammalian colon cancer cells. As several P-gp inhibitors have failed due to their toxicity effects, endogenous amino-acid-derived noncytotoxic inhibitors (from the nocardioazine core) are worthy leads toward a rejuvenated strategy against resistant carcinomas. This total synthesis provides direct access to Trp-derived isoprenylated DKP natural products and their derivatives.
The Journal of organic chemistry
Digital Object Identifier (DOI)
Khopade, Tushar M.; Ajayan, Kalyani; Vincent, Dona Mariya; Lane, Amy L.; and Viswanathan, Rajesh, "Biomimetic Total Synthesis of (+)-Nocardioazine B and Analogs" (2022). UNF Faculty Research and Scholarship. 3188.