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Selective Antimicrotubule Activity of N1-Phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5) against Kinetoplastid Parasites

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, the Ohio State University, Columbus, Ohio (K.A.W., D.D., G.B., M.S.); Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (D.L.S., T.O.,); Haskins Laboratories and Department of Biology, Pace University, New York, New York (D.R., C.B.)

Analogs of the antimitotic herbicide oryzalin (3,5-dinitro-N4,N4-di-n-propylsulfanilamide) were recently prepared that were more potent in vitro than the parent compound against the kinetoplastid parasite Leishmania donovani (Bioorg Med Chem Lett 12:2395-2398, 2002). In the present work, we show that the most active molecule in the group, N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5), is a potent, selective antimitotic agent against kinetoplastid parasites. GB-II-5 possesses IC₅₀ values of 0.41 and 0.73 µM in vitro against two strains of the related parasite Trypanosoma brucei but is much less toxic to J774 murine macrophages and PC3 prostate cancer cells, exhibiting IC₅₀ values of 29 and 35 µM against these lines, respectively. Selectivity is also observed for GB-II-5 with purified leishmanial and mammalian tubulin. The assembly of 15 µM leishmanial tubulin is completely inhibited by 10 µM GB-II-5, whereas 40 µM GB-II-5 inhibits the assembly of 15 µM porcine brain tubulin by only 17%. In cultured L. donovani and T. brucei, treatment with 5 and 0.5 µM GB-II-5, respectively, causes a striking increase in the fraction of G₂M cells compared with control. Given the potency and selectivity of this agent against kinetoplastid tubulin, GB-II-5 emerges as an exciting new antitrypanosomal and antileishmanial lead compound.

Address correspondence to: Dr. Karl Werbovetz, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210. E-mail: werbovetz.1{at}osu.edu

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