A novel pyrazolone, 4,4-dichloro-1-(2,4-dichlorophenyl)-3-methyl-5-pyrazolone, as a potent catalytic inhibitor of human telomerase.
A new derivative of 1-phenyl-3-methyl-5-pyrazolone, 4,4-dichloro-1-(2,4-dichlorophenyl)-3-methyl-5-pyrazolone, named TELIN, was chemically synthesized and identified as a potent inhibitor of human telomerase in the cell-free telomeric repeat amplification protocol. TELIN inhibited telomerase activity at submicromolar level with IC50 of approximately 0.3 microM. Kinetic studies revealed that TELIN does not bind to DNA but to telomerase protein, and the mode of inhibition by this substance was competitive-noncompetitive mixed-type with respect to the TS primer, whereas it was uncompetitive or noncompetitive-uncompetitive mixed-type with respect to the three deoxyribonucleosides. These results demonstrate that TELIN is a specific potent catalytic blocker of telomerase,and is considered to be a valuable substance for medical treatment of cancer and related diseases.
Kakiuchi
Yasutaka
Y
Department of Biology, Faculty of Science, Ochanomizu University, Tokyo, Japan.
Sasaki
Narie
N
Satoh-Masuoka
Mieko
M
Murofushi
Hiromu
H
Murakami-Murofushi
Kimiko
K
D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism*; D047069:Pyrazolones; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D011720:Pyrazoles; D047069:Pyrazolones; C038362:pyrazolone; D019098:Telomerase