@article{bf1f70825a304e2e9c80d68aa7a30a7c,
title = "A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C–H oxidation of carbocyclic N-heterocycles",
abstract = "An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (N-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative. A chemoinformatic analysis underscored limited structural diversity of N-heterocyclic substrates oxidized using chemical methods relative to pharmaceutical chemical space. Here, we describe a preparative chemical method for direct aliphatic oxidation that tolerates a wide range of nitrogen functionality (chemoselective) and matches the site of oxidation (site-selective) of liver CYP450 enzymes. Commercial small-molecule catalyst Mn(CF3-PDP) selectively effects direct methylene oxidation in compounds bearing 25 distinct heterocycles including 14 out of 27 of the most frequent N-heterocycles found in U.S. Food and Drug Administration (FDA)-approved drugs. Mn(CF3-PDP) oxidations of carbocyclic bioisostere drug candidates (for example, HCV NS5B and COX-2 inhibitors including valdecoxib and celecoxib derivatives) and precursors of antipsychotic drugs blonanserin, buspirone, and tiospirone and the fungicide penconazole are demonstrated to match the major site of aliphatic metabolism obtained with liver microsomes. Oxidations are demonstrated at low Mn(CF3-PDP) loadings (2.5 to 5 mol%) on gram scales of substrate to furnish preparative amounts of oxidized products. A chemoinformatic analysis supports that Mn(CF3-PDP) significantly expands the pharmaceutical chemical space accessible to small-molecule C–H oxidation catalysis.",
keywords = "C–H activation, CYP450 mimic, metabolism, bioisosteres, Oxidation chemistry",
author = "Chambers, {Rachel K.} and Weaver, {Jacob D.} and Jinho Kim and Hoar, {Jason L.} and Krska, {Shane W.} and {Christina White}, M.",
note = "Funding Information: ACKNOWLEDGMENTS. Financial support for this work was provided by the National Institute of General Medical Sciences (NIGMS) Maximizing Investigators{\textquoteright} Research Award (MIRA R35GM122525) and from a grant from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to study metabolite synthesis. We thank the Molecule Maker Lab Institute (An AI Research Institutes program supported by the NSF, under award no. 2019897) for support for chemoinformatic analysis. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect those of the NIGMS or the NSF.J.K.,Associate Professor at Incheon National University,acknowledges the Fulbright Visiting Scholar Program from the Korean-American Educational Commission, funded by the US and Korean governments. We thank L. Zhu and the University of Illinois School of Chemical Science NMR laboratory for assistance with NMR spectroscopic analysis, Z. Firestein for checking the procedure in Fig. 2, compound 12,and J.Wolf for substrate synthesis.We thank Ron Ferguson (Merck & Co., Inc., Rahway, NJ, USA) for assistance with prep-HPLC purification of compounds 58 andS53/S54,Kristina McNab (Merck&Co.,Inc.,Rahway,NJ,USA)for assistance with compound registration and distribution to assays, Scott Borges (Merck & Co., Inc., Rahway, NJ, USA) for assistance with purification of compounds 58 and S53/S54, Dr. Peter Nizner (Merck & Co., Inc., Rahway, NJ, USA) for assistance with obtaining Blonanserin D2L binding assay data, and Richard W. Gundersdorf (Merck & Co., Inc., Rahway, NJ, USA) for assistance with metabolite ID studies and analyses. We thank Prof. Tobias Ritter for helpful discussions on deoxyfluorination. The Bruker 500-Mz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, IA, USA. Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",
year = "2023",
month = jul,
day = "18",
doi = "10.1073/pnas.2300315120",
language = "English (US)",
volume = "120",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "29",
}