title: Antiproliferative Effect of Novel Aminoacridine-based Compounds.
abstract: We tested the antiproliferative activity and mechanism of the action of several novel aminoacridine derivatives. Six different cancer cell lines were used to evaluate the potential cytotoxic effect of eleven aminoacridine-based molecules. A standard MTT assay was used for cell bioavailability analysis. Additionally, the potential cytotoxic effect of the tested compounds on non-cancer cells was investigated in rat skeletal muscle myotubes (L6) and in bovine aortic smooth muscle cells. In order to investigate whether the DNA binding activity of tested compounds correlated with their cytotoxic effect, circular dichroism (CD) measurement and DNA T4 ligase assay were performed. Finally, the potential mutagenic activity of the lead compound 5 was investigated. The cytotoxic effect of compound 5 in cancer cells was obtained in lower concentrations than the well-known: 9- aminoacridine based drug, amsacrine. The lead compound binds to DNA, but in a different mode than the parent molecules. Additionally, compound 5 was not cytotoxic in the effective range of concentrations in non-cancer cells. In identical concentrations, the parent compound (9-aminoacridine) and amsacrine were extremely toxic for both types of these normal cells. Finally, based on CD measurement and T4 ligase assay, it was confirmed that 5 binds to DNA but in different from the parent compounds manner. Important to mention, that compound 5 might have increased mutagenic activity which must be verified in vivo. Based on these in vitro results, we conclude that 5 is a more potent and more selective antiprolifirative compound than amsacrine. Compound 5 was also more effective in HepG2 and P-12 cells. Thus, 5 is suitable for future in vivo biological evaluation and its structure might be used as a basis for developing novel anticancer drugs.
authors.forename: Anna
authors.initials: A
authors.lastname: Munder
authors.forename: Yoni
authors.initials: Y
authors.lastname: Moskovitz
authors.forename: Boris
authors.initials: B
authors.lastname: Redko
authors.forename: Ariel Rachel
authors.initials: AR
authors.lastname: Levy
authors.forename: Sharon
authors.initials: S
authors.lastname: Ruthstein
authors.forename: Gary
authors.initials: G
authors.lastname: Gellerman
authors.affiliation: Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat Gan 52900, Israel. gruzmaa@biu.ac.il.
authors.forename: Arie
authors.initials: A
authors.lastname: Gruzman
mesh_terms: D000609:Aminoacridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000677:Amsacrine / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000037:antagonists & inhibitors / Q000737:chemistry; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000737:chemistry; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009928:Organ Specificity; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D000677:Amsacrine; D004247:DNA; D011088:DNA Ligases; D000072481:DNA Ligase ATP