Vol. 54, Issue 6, 994-999, December 1998

Diospyrin, A Bisnaphthoquinone: A Novel Inhibitor of Type I DNA Topoisomerase of Leishmania donovani

Sutapa Ray,¹ Banasri Hazra, Bidyottam Mittra, Aditi Das, and Hemanta K. Majumder

Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Calcutta 700 032, India (S.R., B.M., A.D., H.K.M.), and Department of Pharmacy, Jadavpur University, Calcutta 700 032, India (B.H.)

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.