Solid-Phase synthesis of a library constructed of aromatic phosphate, long alkyl chains and tryptophane components, and identification of potent dipeptide telomerase inhibitors.
Telomerase inhibitors are expected as a new candidate of therapeutic agents for cancer. Recently, we have found novel inhibitors based on the bisindole skeleton. In this study, solid-phase synthesis was applied to construct a library of inhibitors having aromatic phosphate, long alkyl chain and tryptophane components, from which a D,D-ditryptophane derivative has been identified as a new potent telomerase inhibitor with IC(50) values of 0.3 microM. A hypothetical binding model for the new inhibitors has been proposed based on the structure-activity relationship.
Sasaki
S
S
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. sasaki@phar.kyushu-u.ac.jp
Ehara
T
T
Alam
M R
MR
Fujino
Y
Y
Harada
N
N
Kimura
J
J
Nakamura
H
H
Maeda
M
M
D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014364:Tryptophan / Q000737:chemistry*
D004151:Dipeptides; D004791:Enzyme Inhibitors; D014364:Tryptophan; D019098:Telomerase