title: Novel pentamidine derivatives: synthesis, anti-tumor properties and polynucleotide-binding activities.
abstract: Novel amidino-substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determined. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino-substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso-propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series. Amongst all tested compounds the compound 10 is the only one that possesses antiproliferative activity against SW 620 cell line (4 μM). Spectroscopic studies of the interactions of prepared diamidines with double-stranded DNA and RNA polynucleotides show that all compounds preferentially bind into the minor groove of DNA, while most of them intercalate into RNA. The structure-dependant biological activity and the lack of DNA/RNA selective binding suggest that the mechanism of action of the here-presented compounds is controlled not only by the interactions with cellular nucleic acids, but also with other more specific protein targets.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Jarak
authors.forename: Marko
authors.initials: M
authors.lastname: Marjanović
authors.forename: Ivo
authors.initials: I
authors.lastname: Piantanida
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
mesh_terms: D000578:Amidines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010419:Pentamidine / Q000138:chemical synthesis* / Q000494:pharmacology; D011119:Polynucleotides / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011119:Polynucleotides; D010419:Pentamidine