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|Title:||Reverse biosynthesis: generating combinatorial pools of drug leads from enzyme-mediated fragmentation of natural products|
|Citation:||ChemBioChem: a European journal of chemical biology, 2017; 18(4):368-373|
|Tomas Richardson-Sanchez, William Tieu, and Rachel Codd|
|Abstract:||A combinatorial pool of hydroxamic acid fragments as potential metalloprotein drug leads was generated from the enzymatic hydrolysis of the natural product desferrioxamine B (DFOB). DFOB is a metabolite produced by Streptomyces pilosus for iron acquisition, and can be selectively catabolised by Niveispirillum irakense to access carbon for growth. The supernatant of a DFOB-supplemented culture of N. irakense was analysed by LC-MS at intervals over 168 h. This identified a mixture of endo-hydroxamic acid fragments that contained reactive terminal groups. The supernatants from two cultures (at 48 h and 168 h) were reacted with 1,8-naphthalic anhydride in a microwave synthesiser to generate pools of scriptaid analogues, which were screened against ZnII -containing histone deacetylases (HDACs) and FeIII -containing 5-lipoxygenase (5-LO). Compound S2 showed relative potency against 5-LO (IC50 =59 μm; BWA4C, 17 μm); it was 28-fold more selective towards 5-LO than HDAC1. Compound S1 inhibited HDAC1 but not 5-LO. Enzyme-mediated reverse biosynthesis could yield new benefits from structurally complex natural products in drug design.|
|Description:||Final Article published: January 16, 2017|
|Rights:||© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim|
|Appears in Collections:||Aurora harvest 4|
Molecular and Biomedical Science publications
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