Non-charged thiamine analogs as inhibitors of enzyme transketolase.
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.
Thomas
Allen A
AA
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. athomas@arraybiopharma.com
De Meese
J
J
Le Huerou
Y
Y
Boyd
Steven A
SA
Romoff
Todd T
TT
Gonzales
Steven S
SS
Gunawardana
Indrani
I
Kaplan
Tomas
T
Sullivan
Francis
F
Condroski
Kevin
K
Lyssikatos
Joseph P
JP
Aicher
Thomas D
TD
Ballard
Josh
J
Bernat
Bryan
B
DeWolf
Walter
W
Han
May
M
Lemieux
Christine
C
Smith
Darin
D
Weiler
Solly
S
Wright
S Kirk
SK
Vigers
Guy
G
Brandhuber
Barb
B
D000818:Animals; D002384:Catalysis; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013831:Thiamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014174:Transketolase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014174:Transketolase; D013831:Thiamine