This proposal aims at the development of H-phosphinic acids (RP(O)(OH)H) as synthetic intermediates for the preparation of biologically-active phosphorus-containing compounds. Recent advances in phosphorus-carbon bond formation are the stepping stone for novel applications. Focus is placed on two different health related areas which were chosen to show the synthetic flexibility of H-phosphinic acids: 1) the preparation and evaluation of gamma-aminobutyric acid (GABA) analogs relevant to the treatment of disorders of the central nervous system, where the phosphinic acid functionality is exploited as a carboxylate replacement; and 2) the development of a novel approach for the preparation of bisphosphonates under mild conditions relevant to the treatment of bone-related and other diseases, where the phosphinic acid functionality is a precursor to phosphonic acids. Compounds displaying promising in vitro biological activity will also be evaluated in vivo through consultants. While phosphinic acids are becoming popular pharmacophores in many other medicinal applications, their use in the above two areas has been largely unrealized. Thus, beyond the scope of this proposal, some of the chemistry detailed therein should make a significant contribution to the realm of phosphorus-based medicinal chemistry in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067610-04
Application #
7227048
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$162,746
Indirect Cost
Name
Texas Christian University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043807882
City
Fort Worth
State
TX
Country
United States
Zip Code
76129
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Abrunhosa-Thomas, Isabelle; Coudray, Laƫtitia; Montchamp, Jean-Luc (2010) Synthesis and Reactivity Studies of ?,?-Difluoromethylphosphinates. Tetrahedron 66:4434-4440
Queffelec, Clemence; Montchamp, Jean-Luc (2010) Facile P,N-heterocycle synthesis via tandem aminomethylation-cyclization of H-phosphinate building blocks. Org Biomol Chem 8:267-73
Coudray, Laƫtitia; Kantrowitz, Evan R; Montchamp, Jean-Luc (2009) Submicromolar phosphinic inhibitors of Escherichia coli aspartate transcarbamoylase. Bioorg Med Chem Lett 19:900-2
Coudray, Laetitia; Pennebaker, Anne F; Montchamp, Jean-Luc (2009) Synthesis and in vitro evaluation of aspartate transcarbamoylase inhibitors. Bioorg Med Chem 17:7680-9
Jiang, Ke; Fan, Dongmei; Belabassi, Yamina et al. (2009) Medicinal surface modification of silicon nanowires: impact on calcification and stromal cell proliferation. ACS Appl Mater Interfaces 1:266-9
Coudray, Laetitia; Montchamp, Jean-Luc (2009) Temporary Protection of H-Phosphinic Acids as a Synthetic Strategy. European J Org Chem 2009:
Antczak, Monika I; Montchamp, Jean-Luc (2008) Mild synthesis of organophosphorus compounds: reaction of phosphorus-containing carbenoids with organoboranes. Org Lett 10:977-80
Bravo-Altamirano, Karla; Abrunhosa-Thomas, Isabelle; Montchamp, Jean-Luc (2008) Palladium-catalyzed reactions of hypophosphorous compounds with allenes, dienes, and allylic electrophiles: methodology for the synthesis of allylic h-phosphinates. J Org Chem 73:2292-301

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