Synthesis of a bisubstrate analogue targeting estrogen sulfotransferase.
Sulfotransferases catalyze the transfer of a sulfuryl group from the eukaryotic sulfate donor 3'-phosphoadenosine 5'-phosphosulfate to an acceptor biomolecule. Sulfotransferases have been linked with several disease states, prompting our investigation of specific sulfotransferase inhibitors. Presented herein is the synthesis and evaluation of a bisubstrate analogue designed to inhibit estrogen sulfotransferase. The synthesis utilizes a novel, orthogonally protected 3'-phosphoadenosine 5'-phosphate (PAP) derivative allowing the selective functionalization of the 5'-phosphate with a sulfate acceptor mimic. Kinetic studies revealed significant inhibitory activity and provide guidance for improved inhibitor design.
Armstrong
Joshua I
JI
Department of Chemistry, University of California, Berkeley, California 94720, USA.
Verdugo
Dawn E
DE
Bertozzi
Carolyn R
CR
D000244:Adenosine Diphosphate / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D004791:Enzyme Inhibitors; D000244:Adenosine Diphosphate; C010840:adenosine 3'-phosphate-5'-phosphate; D015238:Sulfotransferases; C020122:estrone sulfotransferase