title: Selective antimicrotubule activity of N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5) against kinetoplastid parasites.
abstract: 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 microM 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 microM against these lines, respectively. Selectivity is also observed for GB-II-5 with purified leishmanial and mammalian tubulin. The assembly of 15 microM leishmanial tubulin is completely inhibited by 10 microM GB-II-5, whereas 40 microM GB-II-5 inhibits the assembly of 15 microM porcine brain tubulin by only 17%. In cultured L. donovani and T. brucei, treatment with 5 and 0.5 microM 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.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. werbovetz.1@osu.edu
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Dan L
authors.initials: DL
authors.lastname: Sackett
authors.forename: Dawn
authors.initials: D
authors.lastname: Delfín
authors.forename: Gautam
authors.initials: G
authors.lastname: Bhattacharya
authors.forename: Manar
authors.initials: M
authors.lastname: Salem
authors.forename: Tomasz
authors.initials: T
authors.lastname: Obrzut
authors.forename: Donna
authors.initials: D
authors.lastname: Rattendi
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bacchi
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D004136:Dinitrobenzenes / Q000737:chemistry / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006540:Herbicides / Q000737:chemistry / Q000494:pharmacology; D016830:Kinetoplastida / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D051381:Rats; D013424:Sulfanilamides / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D004136:Dinitrobenzenes; D006131:Growth Inhibitors; D006540:Herbicides; C480520:N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide; D013424:Sulfanilamides; C012465:oryzalin