Biologically Inspired Total Synthesis of Ulbactin F, an Iron-Binding Natural Product

• Type of Material: Article
• Authors: Justin A. Shapiro, Emory University; Kelly R. Morrison, Emory University; Shreya S. Chodisetty, Emory University; Djamaladdin Musaev, Emory University; William Wuest, Emory University
• Language: English
• Date: 2018-09-21
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2018 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/acs.orglett.8b02599
• Title of Journal or Parent Work: Organic Letters
• ISSN: 1523-7060
• Volume: 20
• Issue: 18
• Start Page: 5922
• End Page: 5926
• Grant/Funding Information: We gratefully acknowledge funding from the National Institute of General Medical Sciences (GM119426 for W.M.W.) and the National Science Foundation (CHE1755698 for W.M.W., CHE-0958205 for D.G.M.), the use of the resources of the Cherry Emerson Center for Scientific Computation, and CHE1531620 for the NMR instrumentation used in this work.
• Keywords: PSEUDOMONAS-AERUGINOSA; SIDEROPHORE; Chemistry; Science & Technology; PYOCHELIN; Chemistry, Organic; MIGRATION-INHIBITORY ACTIVITY; Physical Sciences
• Research Categories: Chemistry, Biochemistry

Abstract

Natural products from environmental microbiomes provide exquisite templates for elucidating biological activity in the search for new drugs. A recently discovered marine Brevibacillus sp. metabolite, ulbactin F, was found to inhibit tumor cell migration and invasion at IC50 < 3 μM. Herein, we disclose the first total synthesis of ulbactin F and epi-ulbactin F, which was modeled after the biosynthetic pathway. The scaffold bears structural similarity to siderophores of human pathogens but contains a novel tricyclic ring system derived from cysteine. We have found that ulbactin F forms low-affinity metal complexes, with a preference for Fe3+ and Cu2+, which may hint both at its environmental role and its antimetastatic mechanism of action.