title: Antiproliferative activity of amino substituted benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles explored by 2D and 3D cell culture system.
abstract: Benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with amino chains on the different positions have been evaluated by 2D and 3D assays on the human breast cancer cells. Pentacyclic derivatives were synthesized by microwave assisted amination to study the influence of the thiophene substructure on antitumor activity in comparison to tetracyclic analogues. The results obtained from 2D assay reveals that the antitumor activity is strongly dependent on the nature and position of amino chains. Tetracyclic derivatives displayed selective activity on SK-BR-3 with the 2-amino substituted derivatives as the most active ones while pentacyclic derivatives 6-16 and 21-25 showed more pronounced activity on T-47D. The evaluation of antitumor activity in the 3D assay pointed out that some of the tetracyclic and pentacyclic amino substituted derivatives showed selective activity on the MDA-MB-231 cell line. Influence of physico-chemical properties of the compounds on antiproliferative activity have been investigated by multivariate statistical methods. As a measure of lipophilicity, experimental Chrom LogD values have been determined and number of structural parameters have been calculated for investigated compounds. Main factors contributing to the antiproliferative effect for both 2D and 3D cell cultures are found to be basicity, lipophilicity, molecular weight and number of H-bond donors.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, P. O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Perin
authors.affiliation: Department of General and Inorganic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, P. O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Bobanović
authors.affiliation: Department of in vitro Pharmacology, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Zlatar
authors.affiliation: Department of in vitro Pharmacology, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.affiliation: Chemistry Department, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Vanja
authors.initials: V
authors.lastname: Kelava
authors.affiliation: Chemistry Department, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Koštrun
authors.affiliation: Chemistry Department, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Vesna Gabelica
authors.initials: VG
authors.lastname: Marković
authors.affiliation: Department of in vitro Pharmacology, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. Electronic address: karmen.brajsa@glpg.com.
authors.forename: Karmen
authors.initials: K
authors.lastname: Brajša
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, P. O. Box 177, HR-10000 Zagreb, Croatia. Electronic address: mhranjec@fkit.hr.
authors.forename: Marijana
authors.initials: M
authors.lastname: Hranjec
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D015999:Multivariate Analysis; D011728:Pyridones / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D002264:Carboxylic Acids; D011728:Pyridones; C492469:benzothieno(3,2-b)-4-pyridone-2-carboxylic acid; D004317:Doxorubicin
keywords: 2D and 3D in vitro cytotoxicity assay; Antiproliferative activity; Lipophilicity; Physico-chemical properties; benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles