This proposal focuses on the synthesis and reactivity of transition metal porphyrinoid complexes that are designed to model key aspects of structure and function in heme enzymes. A subset of heme enzymes react with O2 and/or the related small molecules H2O2 and O2-, including Cytochrome P450 (CYP), dioxygenases such as tryptophan dioxygenase or indoleamine dioxygenase, peroxidases such as chloroperoxidase and myeloperoxidase, aromatic peroxygenase, catalases, heme oxygenases, and cytochrome c oxidase. Although these enzymes carry out a diverse array of critical functions, their proposed mechanisms of action have multiple intermediates in common. These intermediates include high-valent metal-oxo and metal-hydroxo species, such as FeIV(O)(porphyrin-radical-cation) (Compound-I) and FeIV(OH)(porphyrin) (protonated Compound-II) identified in CYP, as well as metal-dioxygen species such as FeIII(superoxo)(porphyrin). The factors that control the generation, stability, and reactivity of these species remains poorly understood in many cases, as do the overall mechanisms of action in which these species are proposed to play key roles. The proposed efforts focus on developing synthetic porphyrinoid analogs of M=O, M-OH, and M-O2 intermediates, and studying their reactivity in H-atom transfer (HAT), proton-coupled electron-transfer (PCET), O-atom transfer (OAT), and rebound processes. Catalytic oxidations of substrates with C-H bonds and O2 as oxidant will also be investigated. These analogs will also provide needed spectroscopic benchmarks (rR, Mssbauer, EPR, XAS) for comparison with, and identification of, the relevant biological species. A new series of Fe and Mn porphyrinoid complexes will be synthesized with corrole (Crl) and corrolazine (Cz) ligands. These porphyrinoid compounds are modified by ring contraction of the porphyrin nucleus, and are designed to stabilize metal-oxygen species such as high-valent M=O and M-OH complexes. In the previous funding period our group has shown that the Cz scaffold yields new M=O and M-OH complexes of biological relevance, and the study of these systems led to discoveries regarding the influence of oxidation state, spin state, coordination environment, and proximal and distal effects on HAT, PCET, and OAT reactivity. New corrole and corrolazine complexes will be prepared in this proposal that are designed to address two main goals 1) answer fundamental questions related to heme enzyme structure, function and mechanism and 2) gain fundamental knowledge regarding transition metal porphyrinoid complexes for the design and synthesis of new catalysts. Heme enzymes are of central importance to a range of disease states. The new knowledge to be gained regarding the mechanisms of action of these systems should help in the development of novel therapeutic and/or diagnostic strategies that target these enzymes.

Public Health Relevance

Heme enzymes that utilize dioxygen and its derivatives are essential for a number of life processes, and they are implicated in many disease states. The proposed research will examine the reactivity of synthetic analogs of heme enzyme active sites, contributing to our understanding of mechanistic events in these systems, which should aid in the long-term design of therapeutic and diagnostic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101153-06
Application #
9523423
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Anderson, Vernon
Project Start
2013-09-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Zaragoza, Jan Paulo T; Siegler, Maxime A; Goldberg, David P (2018) A Reactive Manganese(IV)-Hydroxide Complex: A Missing Intermediate in Hydrogen Atom Transfer by High-Valent Metal-Oxo Porphyrinoid Compounds. J Am Chem Soc 140:4380-4390
Zaragoza, Jan Paulo T; Yosca, Timothy H; Siegler, Maxime A et al. (2017) Direct Observation of Oxygen Rebound with an Iron-Hydroxide Complex. J Am Chem Soc 139:13640-13643
Joslin, Evan E; Zaragoza, Jan Paulo T; Siegler, Maxime A et al. (2017) meso-N-Methylation of a porphyrinoid complex: activating the H-atom transfer capability of an inert ReV(O) corrolazine. Chem Commun (Camb) 53:1961-1964
Baglia, Regina A; Zaragoza, Jan Paulo T; Goldberg, David P (2017) Biomimetic Reactivity of Oxygen-Derived Manganese and Iron Porphyrinoid Complexes. Chem Rev 117:13320-13352
Yang, Tzuhsiung; Quesne, Matthew G; Neu, Heather M et al. (2016) Singlet versus Triplet Reactivity in an Mn(V)-Oxo Species: Testing Theoretical Predictions Against Experimental Evidence. J Am Chem Soc 138:12375-86
Baglia, Regina A; Krest, Courtney M; Yang, Tzuhsiung et al. (2016) High-Valent Manganese-Oxo Valence Tautomers and the Influence of Lewis/Brönsted Acids on C-H Bond Cleavage. Inorg Chem 55:10800-10809
McQuilken, Alison C; Matsumura, Hirotoshi; Dürr, Maximilian et al. (2016) Photoinitiated Reactivity of a Thiolate-Ligated, Spin-Crossover Nonheme {FeNO}(7) Complex with Dioxygen. J Am Chem Soc 138:3107-17
Joslin, Evan E; Zaragoza, Jan Paulo T; Baglia, Regina A et al. (2016) The Influence of Peripheral Substituent Modification on P(V), Mn(III), and Mn(V)(O) Corrolazines: X-ray Crystallography, Electrochemical and Spectroscopic Properties, and HAT and OAT Reactivities. Inorg Chem 55:8646-60
Zaragoza, Jan Paulo T; Siegler, Maxime A; Goldberg, David P (2016) Rhenium(V)-oxo corrolazines: isolating redox-active ligand reactivity. Chem Commun (Camb) 52:167-70
Jung, Jieun; Neu, Heather M; Leeladee, Pannee et al. (2016) Photocatalytic Oxygenation of Substrates by Dioxygen with Protonated Manganese(III) Corrolazine. Inorg Chem 55:3218-28

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