Synthesis and biological action of novel 4-position-modified derivatives of D-myo-inositol 1,4,5-trisphosphate

ORGN 684

Stuart J. Conway, sjc16@st-andrews.ac.uk1, Davide Bello1, Tashfeen Aslam1, Geert Bultynck2, Alexandra M. Z. Slawin, amzs@st-andrews.ac.uk1, H. Llewellyn Roderick3, and Martin D. Bootman3. (1) School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, United Kingdom, (2) Laboratory of Molecular Signalling, K.U. Leuven, Campus Gasthuisberg O/N1, Herestraat 49 – Bus 802, Leuven, B-3000, Belgium, (3) Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, CB2 1PD, United Kingdom
D-myo-Inositol 1,4,5-trisphosphate (InsP3) is a ubiquitous intracellular Ca2+-releasing second messenger, which exerts its actions by activation of specific receptors (InsP3Rs), located predominantly on the endoplasmic- or sarcoplasmic reticulum. Activation of the InsP3Rs leads to a plethora of intracellular signaling events. The biochemical importance of InsP3 has prompted many syntheses of InsP3 and related unnatural derivatives. These compounds have proved vital in establishing the structural requirements for agonist activity at InsP3Rs. However, there are very few compounds that act as antagonists of the InsP3Rs and those that do exist are non-selective, interacting with several cellular targets. In order to elucidate the structural requirements for InsP3R antagonist activity, we have used the X-ray crystal structure of the mouse type 1 InsP3R to design a range of novel compounds that are based on InsP3 and modified at the 4-position. Herein the enantioselective synthesis and initial biological evaluation of these compounds is reported.

 

Biologically-Related Molecules and Processes
8:00 AM-12:00 PM, Wednesday, August 22, 2007 BCEC -- 258B, Oral

Division of Organic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007