Total synthesis of the proposed menominin A and its stereoisomers: identification of a highly potent isomer (1a) against RM-1 prostate cancer cells.

Abstract

Menominin A is a natural cyclodepsipeptide isolated from the freshwater sponge-associated cyanobacterium Nostoc sp. UIC 10,607, and exhibits antiproliferative activity against the high-grade serous ovarian cancer cell line OVCAR3. The pronounced biological relevance and limited natural abundance have rendered menominin A a compelling target for total synthesis and biological studies. Herein, we report the total synthesis and cytotoxicity evaluation of the proposed structure of menominin A and its seven isomers. Key features of this synthesis include an Evans aldol reaction to construct the 3-hydroxy-2-methylcarboxylic acid unit, a chiral phosphonic acid-mediated asymmetric allylic addition to establish a chiral alcohol, and a ring-closing metathesis followed by hydrogenation to construct the macrocyclic framework. The mismatch between the NMR spectra of our synthetic samples and those of the natural product suggests that the originally proposed structure is incorrect. Biological evaluation indicated that three compounds (1a, 1b, and 1g) displayed moderate to potent antitumor activity against osteosarcoma, human colon cancer, and prostate cancer. The most active compound 1a exhibited antiproliferative activity against RM-1 cells in a sustained manner, yielding IC₅₀ values of 4.18 µM (48 h) and 1.15 µM (72 h).