Synthesis of asymmetric, heavy chalcogen tetramethylrosamine derivatives: Micromolar inhibition at the “R” site of P-Glycoprotein

MEDI 52

Jason J. Holt1, Gregory Tombline2, and Michael R. Detty, mdetty@buffalo.edu1. (1) Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, (2) Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642
The transmembrane protein P-glycoprotein (Pgp) is often closely associated with multidrug resistance (MDR). Pgp is an efflux pump, and is known to couple drug export to ATP binding and hydrolysis, however little is known about the detailed mechanism of action on the molecular level. We have recently shown that a library of thio- and seleno-derivatives of tetramethylrosamine, modified at the 9 position, show significant variation in the extent of ATPase stimulation. Herein we describe the synthesis and properties of thio- and seleno- TMR derivatives bearing an asymmetric xanthylium core. The synthesis, highlighted by microwave assisted Willgerodt-Kindler, and directed ortho-metallation reactions, is conducive to significant variation at the 9 position via Grignard reaction. Evaluation of Pgp ATPase stimulation, and competition behavior with verapamil is also discussed.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006