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https://hdl.handle.net/2440/123301
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Type: | Journal article |
Title: | Exploiting the biosynthetic machinery of: Streptomyces pilosus to engineer a water-soluble zirconium(IV) chelator |
Author: | Richardson-Sanchez, T. Tieu, W. Gotsbacher, M.P. Telfer, T.J. Codd, R. |
Citation: | Organic and Biomolecular Chemistry, 2017; 15(27):5719-5730 |
Publisher: | Royal Society of Chemistry |
Issue Date: | 2017 |
ISSN: | 1477-0520 1477-0539 |
Statement of Responsibility: | Tomas Richardson-Sanchez, William Tieu, Michael P. Gotsbacher, Thomas J. Telfer and Rachel Codd |
Abstract: | The water solubility of a natural product-inspired octadentate hydroxamic acid chelator designed to coordinate Zr(iv)-89 has been improved by using a combined microbiological-chemical approach to engineer four ether oxygen atoms into the main-chain region of a methylene-containing analogue. First, an analogue of the trimeric hydroxamic acid desferrioxamine B (DFOB) that contained three main-chain ether oxygen atoms (DFOB-O₃) was generated from cultures of the native DFOB-producer Streptomyces pilosus supplemented with oxybis(ethanamine) (OBEA), which competed against the native 1,5-diaminopentane (DP) substrate during DFOB assembly. This precursor-directed biosynthesis (PDB) approach generated a suite of DFOB analogues containing one (DFOB-O₁), two (DFOB-O₂) or three (DFOB-O₃) ether oxygen atoms, with the latter produced as the major species. Log P measurements showed DFOB-O₃ was about 45 times more water soluble than DFOB. Second, a peptide coupling chain-extension reaction between DFOB-O₃ and the synthetic ether-containing endo-hydroxamic acid monomer 4-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-4-oxobutanoic acid (PBH-O₁) gave the water soluble tetrameric hydroxamic acid DFOB-O₃-PBH-O₁ as an isostere of sparingly water soluble DFOB-PBH. The complex between DFOB-O₃-PBH-O₁ and natZr(iv), examined as a surrogate measure of the radiolabelling procedure, analysed by LC-MS as the protonated adduct ([M + H]⁺, m/zobs = 855.2; m/zcalc = 855.3), with supporting HRMS data. The use of a microbiological system to generate a water-soluble analogue of a natural product for downstream semi-synthetic chemistry is an attractive pathway for developing new drugs and imaging agents. The improved water solubility of DFOB-O₃-PBH-O₁ could facilitate the synthesis and purification of downstream products, as part of the ongoing development of ligands optimised for Zr(iv)-89 immunological PET imaging. |
Keywords: | Streptomyces |
Rights: | This journal is © The Royal Society of Chemistry 2017 |
DOI: | 10.1039/c7ob01079f |
Grant ID: | http://purl.org/au-research/grants/arc/DP140100092 |
Published version: | http://dx.doi.org/10.1039/c7ob01079f |
Appears in Collections: | Aurora harvest 8 Molecular and Biomedical Science publications |
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