title: Amino and chlorambucil analogues of pentamidine--synthesis and biological examinations.
abstract: The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic effect on MCF-7 human breast cancer cell line (IC50 = 22 - 95 +/- 2 pM), mainly by the induction of apoptosis. The topoisomerase I/II inhibition assay and the ethidium displacement assay with the use of pBR322 plasmid DNA were used to the study of mechanism by which the obtained compounds could act. All the compounds are able to bind with DNA and interfere in vitro with the activity of topoisomerase (I and II). The determination of association constants with the use of calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 showed that the tested compounds bind within minor groove of B-DNA, but not selectively. The alkylating activity of chlorambucil derivatives determined in vitro using a Preussmann test was similar to the activity of chlorambucil. The influence of all the compounds on the amidolytic activity of plasmin and trypsin was also examined. The plasmin activity was inhibited by pentamidine, chlorambucil and aromatic bis-amines (IC50 = 0.1 - 8 mM), whereas the trypsin activity was influenced only by pentamidine.
authors.affiliation: Department of Organic Chemistry, Medical University, Mickiewicza 2A, 15-222 Białystok, Poland. anna.puckowska@umwb.edu.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Pućkowska
authors.forename: Danuta
authors.initials: D
authors.lastname: Drozdowska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Rusak
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bielawski
authors.forename: Irena
authors.initials: I
authors.lastname: Bruzgo
authors.forename: Krystyna
authors.initials: K
authors.lastname: Midura-Nowaczek
mesh_terms: D000933:Antifibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010419:Pentamidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000933:Antifibrinolytic Agents; D018906:Antineoplastic Agents, Alkylating; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014361:Trypsin Inhibitors; D002699:Chlorambucil; D010419:Pentamidine; D004247:DNA; C427203:calf thymus DNA