Cytotoxic Naphthoquinone Analogues, Including Heterodimers, and Their Structure Elucidation Using LR-HSQMBC NMR Experiments

Approximately 1700 naphthoquinones have been reported from a range of natural product source materials, but only 283 have been isolated from fungi, fewer than 75 of those were dimers, and only 2 were heterodimers with a head-to-tail linkage. During a search for anticancer leads from fungi, a series of new naphthoquinones (1-4), including two heterodimers (3 and 4), were isolated from Pyrenochaetopsis sp. (strain MSX63693). In addition, the previously reported 5-hydroxy-6-(1-hydroxyethyl)2,7-dimethoxy-1,4-naphthalenedione (5), misakimycin (6), 5hydroxy- 6-[1-(acetyloxy)ethyl]-2,7-dimethoxy- 1,4-naphthalenedione (7), 6-ethyl-2,7-dimethoxyjuglone (8), and kirschsteinin (9) were isolated. While the structure elucidation of 1-9 was achieved using procedures common for natural products chemistry studies (high-resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D NMR), the elucidation of the heterodimers was facilitated substantially by data from the long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) experiment. The absolute configuration of 1 was established by analysis of the measured vs calculated ECD data. The racemic mixture of 4 was established via X-ray crystallography of an analogue that incorporated a heavy atom. All compounds were evaluated for cytotoxicity against the human cancer cells lines MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovarian), where the IC50 values ranged between 1 and 20 mu M.

Automated summary

A series of new naphthoquinones, including two heterodimers, were isolated from Pyrenochaetopsis sp. During the study, the structure of these compounds was elucidated using various experimental methods, and their cytotoxicity against human cancer cell lines was evaluated, with IC50 values ranging from 1 to 20 μM.