Platensimycin (PTM), produced by several strains of Streptomyces platensis, is a promising drug lead for infectious diseases and diabetes. The recent pilot-scale production of PTM from S. platensis SB12026 has set the stage for the facile semi-synthesis of a focused library of PTM analogues. In this study, gram-quantity of platensic acid (PTMA) was prepared by the sulfuric acid-catalyzed ethanolysis of PTM, followed by a mild hydrolysis in aqueous lithium hydroxide. Three PTMA esters were also obtained in near quantitative yields in a single step, suggesting a facile route to make PTMA aliphatic esters. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU)-catalyzed coupling of PTMA and 33 aminobenzoates resulted in the synthesis of 28 substituted aminobenzoate analogues of PTM, among which 26 of them were reported for the first time. Several of the PTM analogues showed weak antibacterial activity against methicillin-resistant Staphylococcus aureus. Our study supported the potential utility to integrate natural product biosynthetic and semi-synthetic approaches for structure diversification.
Several sulfur-containing platensimycin (PTM) and platencin (PTN) analogues, with activities comparable to the parent natural products, have recently been discovered from microorganisms, implying a biomimetic route to diversify the PTM and PTN scaffolds for structure-activity relationship study. We present here a substrate-directed and scaleable semisynthetic strategy to make PTM and PTN sulfur analogues with excellent diasteroselectivity, without using any chiral catalysts. Most of the sulfur analogues showed strong activities against clinical Staphylococcus aureus isolates, with minimum inhibitory concentrations of 0.5-2 μg mL. Density functional theory calculations were in agreement with the observed selectivity for these analogues and suggest that the conformation restraints of the terpene cages of PTM and PTN on the transition states determine the si-face attack selectivity.
Platensimycin (PTM) is an excellent natural product drug lead against various gram‐positive pathogens, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant enterococci. In this study, twenty PTM derivatives with varying aminobenzoic acids were semisynthesized. In contrast to all the previous reported inactive aminobenzaote analogues, a few of them showed moderate antibacterial activities against S. aureus. Our study suggested that modification of the conserved aminobenzoic acid remains a viable approach to diversify the PTM scaffold.
Bioinspired cascade reactions involving sulfa-Michael/aldol reactions have been developed for the step-economical construction of thia-ring analogues of platensimycin and platencin.
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