| Autor: |
Khopade TM; Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh 517507, India., Ajayan K; Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh 517507, India., Vincent DM; Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh 517507, India., Lane AL; Department of Chemistry, University of North Florida, Jacksonville, Florida 32224, United States., Viswanathan R; Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh 517507, India.; Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh 517507, India. |
| Abstrakt: |
Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from Nocardiopsis , with a desymmetrized cyclo -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 exo - 12a , exo - 12b , and exo - 12c (>19:1). Evidence shows that N 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. |
