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Computational investigations of cytochrome P450 aromatase catalysis and biological evaluation of isoflavone aromatase inhibitors

Hackett, John C
http://rave.ohiolink.edu/etdc/view?acc_num=osu1101247030

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Pharmacy.
Density functional theory calculations are used to unravel the mysterious third step of aromatase catalysis. The feasibility of mechanisms in which the reduced ferrous dioxygen intermediate mediates androgen aromatization are explored and determined to be unlikely. Mechanisms for the aromatization/deformylation sequence which are initiated by 1beta-hydrogen atom abstraction by P450 Compound I are considered. 1beta-Hydrogen atom abstraction from substrates in the presence of the 2,3-enol encounters strikingly low barriers,whereas barriers for this same process are higher in the keto tautomer. Transition states for 1beta-hydrogen atom abstraction from enolized substrates in the presence of the 19-gem-diol decayed directly to the experimentally observed products. If the C19 aldehyde remains unhydrated, aromatization occurs with concomitant decarbonylation, and therefore does not support dehydration of the C19 aldehyde prior to the final catalytic step. Ab initio molecular dynamics on the confirmed that the 1beta-hydrogen atom abstraction and deformylation or decarbonylation occur in a non-synchronous, coordinated manner. These calculations support a dehydrogenase behavior of aromatase in the final catalytic step, which can be summarized by 1beta-hydrogen atom abstraction followed by gem-diol deprotonation. Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone-dependent breast cancer. There are several classes of natural products that exert potent activities in aromatase inhibition, with the flavonoids being most prominent. Previous studies have exploited flavone and flavanone scaffolds for the development of new aromatase inhibitors. In this dissertation, we describe design, synthesis, and biological evaluation of a novel series of 2-(4-pyridylmethyl)thioisoflavones as the first example of synthetic isoflavone-based aromatase inhibitors. The biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the P450 heme.
Robert Brueggemeier (Advisor)
290 p.
Cytochrome P450; Aromatase; Density Functional Theory; Molecular Dynamics; Isoflavones

Recommended Citations

Citations

  • Hackett, J. C. (2004). Computational investigations of cytochrome P450 aromatase catalysis and biological evaluation of isoflavone aromatase inhibitors [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1101247030

    APA Style (7th edition)

  • Hackett, John. Computational investigations of cytochrome P450 aromatase catalysis and biological evaluation of isoflavone aromatase inhibitors. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1101247030.

    MLA Style (8th edition)

  • Hackett, John. "Computational investigations of cytochrome P450 aromatase catalysis and biological evaluation of isoflavone aromatase inhibitors." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1101247030

    Chicago Manual of Style (17th edition)

osu1101247030
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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.