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(IC
50) of about 3
M, and griseorhodins A and C also showed comparable potencies for the inhibition(IC
50 = 6-12
M). In contrast, opening of the spiroketal system of
-rubromycin, giving rise to
-rubromycin, substantially decreased its inhibitory potency toward telomerase (IC
50 > 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 a
Ki 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 (IC
50 ~ 20
M), we conclude that
-rubromycin appears to be a lead structure for the developmentof more potent and selective inhibitors of human telomerase.