Diospyrin, a bisnaphthoquinone: a novel inhibitor of type I DNA topoisomerase of Leishmania donovani.
Diospyrin is a plant product that has significant inhibitory effect on the growth of Leishmania donovani promastigotes. This compound inhibits the catalytic activity of DNA topoisomerase I of the parasite. Like camptothecin, it induces topoisomerase I mediated DNA cleavage in vitro. Treatment of DNA with diospyrin before addition of topoisomerase I has no effect. Preincubation of topoisomerase I with diospyrin before the addition of DNA in the relaxation reaction increases this inhibition. Our results suggest that this bis-naphthoquinone compound exerts its inhibitory effect by binding with the enzyme and stabilizing the topoisomerase I-DNA "cleavable complex." Diospyrin is a specific inhibitor of the parasitic topoisomerase I. It does not inhibit type II topoisomerase of L. donovani and requires much higher concentrations to inhibit type I topoisomerase of calf thymus. The potent inhibitory effect of diospyrin on type I DNA topoisomerase from L. donovani can be exploited for rational drug design in human leishmaniasis.
Ray
S
S
Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Calcutta 700 032, India.
Hazra
B
B
Mittra
B
B
Das
A
A
Majumder
H K
HK
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000302:isolation & purification; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007893:Leishmania donovani / Q000201:enzymology*; D009285:Naphthoquinones / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C043546:diospyrin