Author/Authors :
Allen A. Thomas، نويسنده , , J. De Meese، نويسنده , , Y. Le Huerou، نويسنده , , Steven A. Boyd، نويسنده , , Todd T. Romoff، نويسنده , , Steven S. Gonzales، نويسنده , , Indrani Gunawardana، نويسنده , , Tomas Kaplan، نويسنده , , Francis Sullivan، نويسنده , , Kevin Condroski، نويسنده , , Joseph P. Lyssikatos، نويسنده , , Thomas D. Aicher، نويسنده , , Josh Ballard، نويسنده , , Bryan Bernat، نويسنده , , Walter deWolf، نويسنده , , May Han، نويسنده , , Christine Lemieux، نويسنده , , Darin Smith، نويسنده , , Solly Weiler، نويسنده , , S. Kirk Wright، نويسنده , , et al.، نويسنده ,
Abstract :
Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.
Keywords :
Thiazolone , Pyrazolothiamine , Transketolase , Thiamine , Deazathiamine , pyrophosphokinase , pyrophosphate
