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

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.

Figure 1.

(Top) Structures of ulbactins F-3″S-trans (1), ulbactin G-3″R-cis (2), and pyochelin (3). Structurally novel fused heterocycle in blue. Iron chelating atoms of pyochelin in red. (Bottom) Proposed biosynthesis from putative gene annotation and retrosynthetic analysis.

Figure 2.

Fluorescence titration of ulbactin F (1) with (A) iron chloride and (B) copper chloride. (C) Metal selectivity of 1, measured on a log scale as the ratio of fluorescence of free ligand over fluorescence of ligand in the presence of one molar equivalent of metal. (D) Free energy minimization of proposed 1-Fe³⁺ structure.

Scheme 1.

Total Synthesis of Ulbactin F (1) and epi-Ulbactin F (12)

Scheme 2.. Proposed Mechanism for Stereoselectivity in Ulbactin Formation^a

^aThe reaction is selective for ulbactin F over G due to a favored chairlike transition state. A similar model applies to epi-ulbactin F over epi-ulbactin G.