Anti-MRSA-acting carbamidocyclophanes H-L from the Vietnamese cyanobacterium Nostoc sp. CAVN2

Abstract

The methanol extract of the Vietnamese freshwater cyanobacterium Nostoc sp. CAVN2 exhibited cytotoxic effects against MCF-7 and 5637 cancer cell lines as well as against nontumorigenic FL and HaCaT cells and was active against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. High-resolution mass spectrometric analysis indicated the presence of over 60 putative cyclophane-like compounds in an antimicrobially active methanol extract fraction. A paracyclophanes-focusing extraction and separation methodology led to the isolation of 5 new carbamidocyclophanes (1-5) and 11 known paracyclophanes (6-16). The structures and their stereochemical configurations were elucidated by a combination of spectrometric and spectroscopic methods including HRMS, 1D and 2D NMR analyses and detailed comparative CD analysis. The newly described monocarbamoylated [7.7] paracyclophanes (1, 2, 4 and 5) differ by a varying degree of chlorination in the side chains. Carbamidocyclophane J (3) is the very first reported carbamidocyclophane bearing a single halogenation in both butyl residues. Based on previous studies a detailed phylogenetic examination of cyclophane-producing cyanobacteria was carried out. The biological evaluation of 1-16 against various clinical pathogens highlighted a remarkable antimicrobial activity against MRSA with MICs of 0.1-1.0 μM, and indicated that the level of antibacterial activity is related to the presence of carbamoyl moieties.