A5070615711- Steroid Chemistry and Biochemistry
- Chemical Synthesis and Analysis
- Microbial Natural Products and Biosynthesis
- Carbohydrate Chemistry and Synthesis
- Estrogen and related hormone effects
- Click Chemistry and Applications
- Biochemical and Structural Characterization
- RNA and protein synthesis mechanisms
- Organic Chemistry Cycloaddition Reactions
- Fluorine in Organic Chemistry
- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Sulfur-Based Synthesis Techniques
- Plant biochemistry and biosynthesis
- Glycosylation and Glycoproteins Research
- Synthesis and Reactions of Organic Compounds
- Synthesis and Catalytic Reactions
- Ubiquitin and proteasome pathways
- Synthetic Organic Chemistry Methods
- Phytochemical compounds biological activities
- Natural product bioactivities and synthesis
- Genomics and Phylogenetic Studies
- Cancer-related gene regulation
- Inflammatory mediators and NSAID effects
- Antimicrobial Peptides and Activities
University of North Carolina at Chapel Hill
2016-2025
UNC Lineberger Comprehensive Cancer Center
2019-2024
University of North Carolina Health Care
2024
Communities In Schools of Orange County
2014-2019
Segeberger Kliniken
2019
Colorado State University
2008-2013
Purdue University West Lafayette
2012
Harvard University
2008-2010
Noble (United States)
2010
Los Alamos National Laboratory
2010
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNotes - The Direct Conversion of Steroidal Δ5-3β-Alcohols to Δ5- and Δ4-3-KetonesCarl. Djerassi, R. Engle, A. BowersCite this: J. Org. Chem. 1956, 21, 12, 1547–1549Publication Date (Print):December 1, 1956Publication History Published online21 February 2003Published inissue 1 December 1956https://pubs.acs.org/doi/10.1021/jo01118a627https://doi.org/10.1021/jo01118a627research-articleACS PublicationsRequest reuse permissionsArticle...
A. Bowers, T. G. Halsall, E. R. H. Jones and J. Lemin, Chem. Soc., 1953, 2548 DOI: 10.1039/JR9530002548
The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite thiol (2) is described. required eight linear steps proceeded in 37% overall yield. It demonstrated that a pro-drug activated by removal octanoyl residue from 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate 2, which an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic 2 have been evaluated side-by-side with FK228 SAHA for inhibition HDACs 1, 3, 6....
Sactipeptides are ribosomally synthesized peptides that contain a characteristic thioether bridge (sactionine bond) is installed posttranslationally and absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires unique family of radical SAM enzymes, which multiple [4Fe-4S] clusters, to form the requisite between cysteine α-carbon an opposing amino acid through radical-based chemistry. Here we present structure sactionine bond-forming enzyme CteB, from Clostridium...
Thiocillins from Bacillus cereus ATCC 14579 are members of the well-known thiazolyl peptide class natural product antibiotics, biosynthesis which has recently been shown to proceed via post-translational modification ribosomally encoded precursor peptides. It long hypothesized that final step involves a formal [4 + 2] cycloaddition between two dehydroalanines, unique transformation had eluded enzymatic characterization. Here we demonstrate TclM, single enzyme thiocillin biosynthetic pathway,...
Glycosyl triflates, which serve as important intermediates in glycosylation reactions, were generated and accumulated by the low-temperature electrochemical oxidation of thioglycosides such thioglucosides, thiogalactosides, thiomannosides presence tetrabutylammonium triflate (Bu4NOTf) a supporting electrolyte. Thus-obtained solutions glycosyl triflates (glycosyl pools) characterized NMR measurements. The thermal stability their reactions with acceptors also examined.
A 2-O-benzyl-3,5-O-benzylidene-alpha-d-thioarabinofuranoside was obtained by reaction of the corresponding diol with alpha,alpha-dibromotoluene under basic conditions. On activation 1-benzenesulfinyl piperidine, or diphenyl sulfoxide, and trifluoromethanesulfonic anhydride in dichloromethane at -55 degrees C, glycosyl acceptors affords anomeric mixtures little no selectivity. The analogous 2-O-benzyl-3,5-O-(di-tert-butylsilylene)-alpha-d-thioarabinofuranoside also showed significant...
Bacillus cereus ATCC 14579 converts the C-terminal 14 residues of a 52-mer prepeptide into related set eight variants thiocillin subclass thiazolyl peptide antibiotics by cascade post-translational modifications that alter 13 those residues. We have introduced gene knockout strain to conduct an alanine scan all progenitor residues, as well serine six cysteine are converted thiazoles in mature natural product. No scaffolds were detected for S1A and S10A mutants, consistent with their roles...
Fourteen analogs of the marine natural product largazole have been prepared and assayed against histone deacetylases (HDACs) 1, 2, 3, 6. Olefin cross-metathesis was used to efficiently access six variants side-chain zinc-binding domain, while adaptation our previously reported modular synthesis allowed probing macrocyclic cap group.
The peptide isosteres (10 and 11) of the naturally occurring potent histone deacetylase (HDAC) inhibitors FK228 largazole have been synthesized evaluated side-by-side with FK228, largazole, SAHA for inhibition class I HDACs 1, 2, 3, 6.
Visible light catalysis allows the efficient construction of single electron transfer (SET) redox cycles that result in minimal formation byproducts and proceed under exogenous control a removable source. The O-glycosylation thioglycosides via visible photoredox chemistry is reported. Mechanistic studies show reaction fully responsive support mechanism involving decomposition an oxidatively generated sulfur radical cation propagation reduction thiol side product.
Thiopeptides are a growing class of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. Many biosynthetic enzymes for RiPPs, especially thiopeptides, promiscuous can accept wide range substrates with different amino acid sequences; thus, these have been used as tools to generate new product derivatives. Here, we explore an alternative route molecular complexity by engineering thiopeptide tailoring do or non-native chemistry. We cytochrome P450...
Thiopeptides are natural antibiotics that fashioned from short peptides by multiple layers of post-translational modification. Their biosynthesis, in particular the pyridine synthases form macrocyclic antibiotic core, has attracted intensive research but is complicated challenges reconstituting multiple-pathway enzymes. By combining select RiPP enzymes with cell free expression and flexizyme-based codon reprogramming, we have developed a benchtop biosynthesis thiopeptide scaffolds. This...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSTEROIDS. CXXVII.1 6-HALO PROGESTATIONAL AGENTSH. J. Ringold, E. Batres, A. Bowers, Edwards, and ZdericCite this: Am. Chem. Soc. 1959, 81, 13, 3485–3486Publication Date (Print):July 1, 1959Publication History Published online1 May 2002Published inissue 1 July 1959https://pubs.acs.org/doi/10.1021/ja01522a090https://doi.org/10.1021/ja01522a090research-articleACS PublicationsRequest reuse permissionsArticle Views212Altmetric-Citations55LEARN ABOUT...
Merck & Co. recently reported one of the first mRNA display-derived clinical candidates in a bioavailable inhibitor proprotein convertase subtilisin/kexin type 9 (PCSK9). Herein, we discuss chemical and pharmacological challenges surmounted bringing this compound to trials current outlook for display-based therapeutic development.
Peptides have historically been underutilized for covalent inhibitor discovery, despite their unique abilities to interact with protein surfaces and interfaces. This is in part due a lack of methods screening identifying peptide ligands. Here, we report method identify cyclic inhibitors mRNA display. We combine co- post-translational library diversification strategies create libraries reactive dehydroalanines (Dhas), which employ selections against two model targets. The most potent hits...
mRNA display is revolutionizing peptide drug discovery through its ability to quickly identify potent binders of therapeutic protein targets. Methods expand the chemical diversity libraries are continually needed increase likelihood identifying clinically relevant ligands. Orthogonal aminoacyl-tRNA synthetases (ORSs) have proven utility in cellular genetic code expansion, but relatively underexplored for vitro translation (IVT) and display. Herein, we demonstrate that promiscuous ORS...
mRNA display of macrocyclic peptides has proven itself to be a powerful technique discover high-affinity ligands for protein target. However, only limited number cyclization chemistries are known compatible with display. Tyrosinase is copper-dependent oxidase that oxidizes tyrosine phenol an electrophilic o-quinone, which readily attacked by cysteine thiol. Here we show containing and rapidly cyclized upon tyrosinase treatment. Characterization the reveals it widely applicable multiple...
The thiocillins are natural-product antibiotics derived from ribosomally encoded peptides that undergo extensive posttranslational modifications to yield the mature trithiazolylpyridine-containing macrocyclic compound. Poor pharmacokinetic properties have prevented clinical use of these highly potent antibiotics. Through in vivo manipulation gene responsible for production thiocillin precursor peptide, we generated 65 novel variants, allowing us explore structure−activity relationships...
The pyridine core of the thiocillins has long been postulated to arise from a late-stage tail-to-tail condensation two dehydroalanines. Genetic disruption tclM, proposed "Diels-Alderase", allowed isolation acyclic precursors this ring. isolated products possess full cohort post-translational modifications that are normally displayed by thiocillins, including dehydrobutyrines, thiazoles, C-terminal decarboxylation, and previously unconfirmed Additionally, leader peptides have undergone...