The principal goal of this new research program is to design, synthesize, and deliver a series of Pilot-Scale Libraries composed of structurally diverse and unique boronic acids and their derivatives to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). While boronic acids have been reported to act as enzyme inhibitors through mimicking transition states, their use as probes of biological systems has been limited. The recent introduction of the boronic acid Velcade as a proteasome inhibitor approved for treatment of certain cancers has renewed interest in using this unconventional functional group in probe and drug development efforts. Toward this end, the PI has assembled an experienced interdisciplinary team of collaborators, including synthetic, medicinal, and computational chemists to assure these novel compounds possess """"""""lead-like"""""""" or """"""""drug-like"""""""" properties and cover broad areas of structural space not currently represented in the NIH MLSMR, while at the same time possessing the requisite physicochemical and pharmacokinetic properties to be of value as probes for the exploration of biological systems at the molecular level. The specific synthetic tactics to be employed have their foundation in exciting chemistry being developed in our laboratory concerning the utilization of organotrifluoroborates as protected forms of boronic acids. Organotrifluoroborates have been demonstrated to be resistant to oxidation, acids, bases, nucleophiles, and iminium ion chemistry to which boronic acids have various susceptibilities. This flexibility allows processing of ancillary functional groups incorporated within the organotrifluoroborates, while retaining the valuable boron carbon bonds. In this manner, small, readily available organotrifluoroborates can be elaborated in a highly efficient manner, increasing molecular complexity and diversity in a manner that is incompatible with the boronic acid moiety. Subsequently, the key boronic acid functional group can be unveiled through a simple deprotection protocol of the trifluoroborate. This will facilitate the construction and assembly of carefully designed libraries that have absolutely no precedent in the NIH MLSMR, thus significantly expanding the diversity of small molecules with the potential to be valuable probes for the exploration of biological systems at the molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
5P41GM086209-03
Application #
7884270
Study Section
Special Emphasis Panel (ZRG1-BCMB-R (50))
Program Officer
Hagan, Ann A
Project Start
2008-09-05
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$363,898
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Molander, Gary A; Cavalcanti, Livia N (2012) Nitrosation of aryl and heteroaryltrifluoroborates with nitrosonium tetrafluoroborate. J Org Chem 77:4402-13
Molander, Gary A; Cavalcanti, Livia N (2011) Oxidation of organotrifluoroborates via oxone. J Org Chem 76:623-30
Molander, Gary A; Cavalcanti, Livia N (2011) Metal-free chlorodeboronation of organotrifluoroborates. J Org Chem 76:7195-203
Molander, Gary A; Febo-Ayala, Wilma; Jean-GĂ©rard, Ludivine (2009) Condensation reactions to form oxazoline-substituted potassium organotrifluoroborates. Org Lett 11:3830-3
Molander, Gary A; Canturk, Belgin (2009) Organotrifluoroborates and monocoordinated palladium complexes as catalysts--a perfect combination for Suzuki-Miyaura coupling. Angew Chem Int Ed Engl 48:9240-61
Molander, Gary A; Cavalcanti, Livia N; Canturk, Belgin et al. (2009) Efficient hydrolysis of organotrifluoroborates via silica gel and water. J Org Chem 74:7364-9
Cho, Young Ae; Kim, Dong-Su; Ahn, Hong Ryul et al. (2009) Preparation of potassium azidoaryltrifluoroborates and their cross-coupling with aryl halides. Org Lett 11:4330-3