Inhibition of Human Telomerase by Rubromycins: Implication of Spiroketal System of the Compounds as an Active Moiety
详细信息 查看全文
- 作者：Takamasa Ueno ; Hirotada Takahashi ; Masako Oda ; Makiko Mizunuma ; Akihisa Yokoyama ; Yuso Goto ; Yoshiyuki Mizushina ; Kengo Sakaguchi ; and Hideya Hayashi
- 刊名：Biochemistry
- 出版年：2000
- 出版时间：May 23, 2000
- 年：2000
- 卷：39
- 期：20
- 页码：5995 - 6002
- 全文大小：200K
- 年卷期：v.39,no.20(May 23, 2000)
- ISSN：1520-4995
文摘
We found that a group of rubromycins and their analogues, a class of quinone antibiotics thatpossesses benzofuran and benzodipyran rings to form a spiroketal system, strongly inhibited humantelomerase as assessed with a modified telomeric repeat amplification protocol. 
- and 
-Rubromycinsand purpuromycin appeared to be the most potent telomerase inhibitors, with 50% inhibitory concentrations(IC50) of about 3 
M, and griseorhodins A and C also showed comparable potencies for the inhibition(IC50 = 6-12 M). In contrast, opening of the spiroketal system of -rubromycin, giving rise to
-rubromycin, substantially decreased its inhibitory potency toward telomerase (IC50 > 200 M), indicatingthe essential role of the spiroketal system in telomerase inhibition. A kinetic study of the inhibition by-rubromycin revealed a competitive interaction with respect to the telomerase substrate primer, with aKi of 0.74 M, whereas a mixed type inhibition was observed with respect to the nucleotide substrate.-Rubromycin was also potent in inhibiting retroviral reverse transcriptases but had virtually no effect onother DNA/RNA-modifying enzymes including DNA and RNA polymerases, deoxyribonuclease, andtopoisomerase. Although -rubromycin showed nonspecific cytotoxicities, reducing proliferation of cancercells (IC50 ~ 20 M), we conclude that -rubromycin appears to be a lead structure for the developmentof more potent and selective inhibitors of human telomerase.
- and -Rubromycinsand purpuromycin appeared to be the most potent telomerase inhibitors, with 50% inhibitory concentrations(IC50) of about 3 M, and griseorhodins A and C also showed comparable potencies for the inhibition(IC50 = 6-12 M). In contrast, opening of the spiroketal system of -rubromycin, giving rise to-rubromycin, substantially decreased its inhibitory potency toward telomerase (IC50 > 200 M), indicatingthe essential role of the spiroketal system in telomerase inhibition. A kinetic study of the inhibition by-rubromycin revealed a competitive interaction with respect to the telomerase substrate primer, with aKi of 0.74 M, whereas a mixed type inhibition was observed with respect to the nucleotide substrate.-Rubromycin was also potent in inhibiting retroviral reverse transcriptases but had virtually no effect onother DNA/RNA-modifying enzymes including DNA and RNA polymerases, deoxyribonuclease, andtopoisomerase. Although -rubromycin showed nonspecific cytotoxicities, reducing proliferation of cancercells (IC50 ~ 20 M), we conclude that -rubromycin appears to be a lead structure for the developmentof more potent and selective inhibitors of human telomerase.