Reverse Biosynthesis: Generating Combinatorial Pools of Drug Leads from Enzyme‐Mediated Fragmentation of Natural Products. (16th January 2017)

• Record Type: Journal Article
• Authors: Richardson‐Sanchez, Tomas; Tieu, William; Codd, Rachel
• Is Part Of: Chembiochem. Volume 18:Number 4(2017)
• Page Start: 368
• Page End: 373
• Publication Date: 2017-01-16
• Subjects: bacterial interspecies interactions -- combinatorial drug discovery -- inhibitors -- natural products -- reverse biosynthesis; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201600636
• Languages: English
• ISSNs: 1439-4227

Abstract

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 Zn II ‐containing histone deacetylases (HDACs) and Fe III ‐containing 5‐lipoxygenase (5‐LO). CompoundS2 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. Abstract : Constructive destruction : Enzyme‐mediated fragmentation of the natural product desferrioxamine B (1 ) gave a pool of catabolites; subsequent derivatisation yielded a 5‐lipoxygenase inhibitor. This top‐down approach to generate new drug leads from a natural product, "reverse biosynthesis", provides a new perspective on natural products as a resource for drug discovery.