title: New anticancer active and selective phenylene-bisbenzothiazoles: synthesis, antiproliferative evaluation and DNA binding.
abstract: Novel amidino-derivatives of phenylene-bisbenzothiazoles were synthesized and tested for their antiproliferative activity against several human cancer cell lines, as well as DNA-binding properties. The synthetic approach used for preparation of isomeric amidino substituted-phenylene-bis-benzothyazoles 3a-3f was achieved by condensation reaction of isophthaloyl dichloride 1a and terephthaloyl dichloride 1b or with phthalic acid 1c with 5-amidinium-2-aminobenzothiolate 2a and 5-(imidazolinium-2-yl)-2-aminobenzothiolate 2b in good yields. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid. All tested compounds (3a-3f) showed antiproliferative effects on tumour cells in a concentration-dependant manner. The strongest activity and cytotoxicity was observed for diimidazolinyl substituted phenylene-bisbenzothiazole compound 3b. These effects were shown to be related to DNA-binding properties, topoisomerase I and II poisoning effects and apoptosis induction. The highest tested selectivity towards tumour cells was observed for the imidazolyl substituted phenylene-benzothiazole 3d that showed no cytotoxic effects on normal fibroblasts making it an excellent candidate for further chemical optimization and preclinical evaluation.
authors.affiliation: Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, baruna Filipovića 28a, 10000 Zagreb, Croatia.
authors.forename: Livio
authors.initials: L
authors.lastname: Racané
authors.forename: Sandra Kraljević
authors.initials: SK
authors.lastname: Pavelić
authors.forename: Raja
authors.initials: R
authors.lastname: Nhili
authors.forename: Sabine
authors.initials: S
authors.lastname: Depauw
authors.forename: Charles
authors.initials: C
authors.lastname: Paul-Constant
authors.forename: Ivana
authors.initials: I
authors.lastname: Ratkaj
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Krešimir
authors.initials: K
authors.lastname: Pavelić
authors.forename: Vesna
authors.initials: V
authors.lastname: Tralić-Kulenović
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008956:Models, Chemical; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004247:DNA; C005465:benzothiazole