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Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

Sun, Alexander W. and Bulterys, Philip L. and Bartberger, Michael D. and Jorth, Peter A. and O'Boyle, Brendan M. and Virgil, Scott C. and Miller, Jeff F. and Stoltz, Brian M. (2019) Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity. Bioorganic and Medicinal Chemistry Letters, 29 (18). pp. 2686-2689. ISSN 0960-894X. PMCID PMC6711789 . https://resolver.caltech.edu/CaltechAUTHORS:20190718-083115245

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Abstract

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.bmcl.2019.07.024DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6711789/PubMed CentralArticle
ORCID:
AuthorORCID
Sun, Alexander W.0000-0001-6639-4469
Bartberger, Michael D.0000-0002-5167-3139
Jorth, Peter A.0000-0002-0981-740X
Virgil, Scott C.0000-0001-8586-5641
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2019 Elsevier Ltd. Received 7 April 2019, Revised 8 July 2019, Accepted 13 July 2019, Available online 16 July 2019. A.W.S. and B.M.S conceived of the project. A.W.S., B.M.O, M.D.B., and S.C.V. performed experimental chemistry. P.L.B., P.A.J., and WuXi AppTec performed biological assays. M.D.B. performed VCD experiments. A.W.S., P.L.B., M.D.B., P.A.J., B.M.O., J.F.M., and B.M.S. wrote the manuscript. The NIH-NIGMS (R01GM080269), Caltech, the Paul and Daisy Soros Foundation, the Cystic Fibrosis Foundation, and the UCLA-Caltech Medical Scientist Training Program are thanked for support of our research program. (Grants R01GM080269 to B.M.S., F30GM120836 and T32GM008042 to A.W.S., F30AI118342, T32GM008042 and P.D. Soros Fellowship to P.L.B., and a Cystic Fibrosis Foundation Fellowship to P.A.J.). Dr. David VanderVelde is thanked for assistance with structural assignments via NMR analysis. Dr. Justin Hilf is thanked for helpful discussions. Professor Dianne K. Newman is thanked for MIC testing. The CO-ADD is thanked for MIC testing. The UCLA Microbiology Laboratory is thanked for providing bacterial strains.
Funders:
Funding AgencyGrant Number
NIHR01GM080269
CaltechUNSPECIFIED
Paul and Daisy Soros FoundationUNSPECIFIED
Cystic Fibrosis FoundationUNSPECIFIED
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
NIHR01GM080269
NIH Postdoctoral FellowshipF30GM120836
NIH Predoctoral FellowshipT32GM008042
NIH Postdoctoral FellowshipF30AI118342
NIH Predoctoral FellowshipT32GM008042
Subject Keywords:Antibiotic; Mitochondria; Allylic Alkylation; Heterocycle; Linezolid
Issue or Number:18
PubMed Central ID:PMC6711789
Record Number:CaltechAUTHORS:20190718-083115245
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190718-083115245
Official Citation:Alexander W. Sun, Philip L. Bulterys, Michael D. Bartberger, Peter A. Jorth, Brendan M. O'Boyle, Scott C. Virgil, Jeff F. Miller, Brian M. Stoltz, Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity, Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 18, 2019, Pages 2686-2689, ISSN 0960-894X, https://doi.org/10.1016/j.bmcl.2019.07.024. (http://www.sciencedirect.com/science/article/pii/S0960894X1930469X)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:97229
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Jul 2019 16:05
Last Modified:03 Apr 2020 23:16

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