Inhibition of human telomerase by rubromycins: implication of spiroketal system of the compounds as an active moiety.
Biochemistry
; 39(20): 5995-6002, 2000 May 23.
Article
em En
| MEDLINE
| ID: mdl-10821671
ABSTRACT
We found that a group of rubromycins and their analogues, a class of quinone antibiotics that possesses benzofuran and benzodipyran rings to form a spiroketal system, strongly inhibited human telomerase as assessed with a modified telomeric repeat amplification protocol. beta- and gamma-Rubromycins and purpuromycin appeared to be the most potent telomerase inhibitors, with 50% inhibitory concentrations (IC(50)) of about 3 microM, and griseorhodins A and C also showed comparable potencies for the inhibition (IC(50) = 6-12 microM). In contrast, opening of the spiroketal system of beta-rubromycin, giving rise to alpha-rubromycin, substantially decreased its inhibitory potency toward telomerase (IC(50) > 200 microM), indicating the essential role of the spiroketal system in telomerase inhibition. A kinetic study of the inhibition by beta-rubromycin revealed a competitive interaction with respect to the telomerase substrate primer, with a K(i) of 0.74 microM, whereas a mixed type inhibition was observed with respect to the nucleotide substrate. beta-Rubromycin was also potent in inhibiting retroviral reverse transcriptases but had virtually no effect on other DNA/RNA-modifying enzymes including DNA and RNA polymerases, deoxyribonuclease, and topoisomerase. Although beta-rubromycin showed nonspecific cytotoxicities, reducing proliferation of cancer cells (IC(50) approximately 20 microM), we conclude that beta-rubromycin appears to be a lead structure for the development of more potent and selective inhibitors of human telomerase.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinonas
/
Compostos de Espiro
/
Telomerase
/
Inibidores da Transcriptase Reversa
/
Antibacterianos
Limite:
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2000
Tipo de documento:
Article