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Spoxazomicin D and Oxachelin C, Potent Neuroprotective Carboxamides from the Appalachian Coal Fire-Associated Isolate Streptomyces sp. RM-14‑6

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journal contribution
posted on 28.12.2016, 18:20 by Khaled A. Shaaban, Meredith A. Saunders, Yinan Zhang, Tuan Tran, Sherif I. Elshahawi, Larissa V. Ponomareva, Xiachang Wang, Jianjun Zhang, Gregory C. Copley, Manjula Sunkara, Madan K. Kharel, Andrew J. Morris, James C. Hower, Matthew S. Tremblay, Mark A. Prendergast, Jon S. Thorson
The isolation and structure elucidation of six new bacterial metabolites [spoxazomicin D (2), oxachelins B and C (4, 5), and carboxamides 68] and 11 previously reported bacterial metabolites (1, 3, 912a, and 1418) from Streptomyces sp. RM-14-6 is reported. Structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry data analysis, along with direct comparison to synthetic standards for 2, 11, and 12a,b. Complete 2D NMR assignments for the known metabolites lenoremycin (9) and lenoremycin sodium salt (10) were also provided for the first time. Comparative analysis also provided the basis for structural revision of several previously reported putative aziridine-containing compounds [exemplified by madurastatins A1, B1, C1 (also known as MBJ-0034), and MBJ-0035] as phenol-dihydrooxazoles. Bioactivity analysis [including antibacterial, antifungal, cancer cell line cytotoxicity, unfolded protein response (UPR) modulation, and EtOH damage neuroprotection] revealed 2 and 5 as potent neuroprotectives and lenoremycin (9) and its sodium salt (10) as potent UPR modulators, highlighting new functions for phenol-oxazolines/salicylates and polyether pharmacophores.