Synthesis and pKa values of stereoelectronically diverse methylenebisphosphonic acids: A nucleotide analog toolkit to probe nucleic acid polymerase structure and function

ORGN 278

Thomas G. Upton, tupton@usc.edu1, Jorge Osuna1, Boris A. Kashemirov1, Charles E. McKenna1, Myron F. Goodman, mgoodman@usc.edu2, Christopher A. Sucato, csucato@usc.edu1, Samuel H. Wilson, wilson5@niehs.nih.gov3, Vinod K. Batra3, Lars C. Pedersen3, and William A. Beard3. (1) Department of Chemistry, University of Southern California, Los Angeles, CA 90089, (2) Departments of Biological Sciences and Chemistry, University of Southern California, 835 W. 37 St., University Park, Los Angeles, CA 90089-1340, (3) Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709
Structurally modified nucleoside triphosphates are useful probes of nucleic acid polymerases. Replacement of the Pα-O-Pβ bridging oxygen by carbon prevents hydrolysis, whereas in Pβ-CXY-Pγ analogues the leaving group properties depend on the nature of the substituents X and Y. We describe the practical synthesis of a stereoelectronically varied series of α-substituted methylenebisphosphonic acids (X,Y = H, F, Cl, Br, CH3) which can be used to prepare the dNTP α,β- and β,γ-CXY analogues. The corresponding pKa values were determined under self-consistent conditions, generating a “toolkit” for use in kinetic and structural studies of DNA polymerase catalysis mechanisms.
 

Biologically Active Molecules
8:00 AM-12:00 PM, Tuesday, April 8, 2008 Morial Convention Center -- Rm. R05, Oral

Division of Organic Chemistry

The 235th ACS National Meeting, New Orleans, LA, April 6-10, 2008