Biomimetic Total Synthesis of (+)-Nocardioazine B and Analogs

Document Type

Article

Publication Date

9-2-2022

Subject Area

Biological Products (pharmacology); Biomimetics; Diketopiperazines; Prenylation

Abstract

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.

Publication Title

The Journal of organic chemistry

Volume

87

Issue

17

First Page

11519

Last Page

11533

Digital Object Identifier (DOI)

10.1021/acs.joc.2c01120

PubMed ID

35960860

E-ISSN

1520-6904

Language

eng

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