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dc.contributor.authorVarvaresou, Aen_US
dc.contributor.authorIakovou, Ken_US
dc.contributor.authorGikas, Een_US
dc.contributor.authorFichtner, Ien_US
dc.contributor.authorFiebig, HHen_US
dc.contributor.authorKelland, LRen_US
dc.contributor.authorDouble, JAen_US
dc.contributor.authorBibby, MCen_US
dc.contributor.authorHendriks, HRen_US
dc.identifier.citationANTICANCER RESEARCH, 24 pp. 907 - 919en_US
dc.description.abstractBackground: A new series of imidazothioxanthones has recently been synthesized as potential anticancer agents with the aim of overcoming drug resistance. The route of synthesis and DNA-binding properties of the compounds were reported previously. This paper describes the general structure-activity relationships for the class of imidazothioxanthones in panels of human and murine tumor cell lines in vitro, and the in vivo activity against human and murine solid tumors of the most potent compound, N-[3-(Dimethylamino)propylo]-11-oxo-11H-benzothiopyrano (3;2’: 2, 3)pyrido(1,2-a) imidazo-2carboxamide (10a). In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. Materials and Methods: The cytotoxicity of compounds 10a, 11-oxo-N-(2(pyrrolidino)ethylo)-11H-benzothiopyrano (3;2’:2,3)pyrido[1,2a] imidazo-2-carboxamide, 11-oxo-N-(2-(piperidino)ethylo)-11H-benzothiopyrano [3;2’:2,3]pyrido(1,2-a) imidazo-2-carboxamide and N-(2-(morpholino)ethylo)-11-oxo-11H-benzothiopyrano [3;2’: 2, 3]pyrido(1,2-a)imidazo-2-carboxamide (10c-10e) was assessed in human tumor cell lines and xenografts using the sulforhodamine B assay, MTT assay and the clonogenic assay. The human ovarian xenograft, PXN/109TC, two human breast carcinomas. MT-1 and MCF-7, and the murine colon adenocarcinoma, MAC 15A were used for the in vivo testing of compound 10a. In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. Results: Two compounds, 10a and 10c, showed cytotoxic activity below 10 mM in the NCI in vitro screen of 60 human tumor cell lines. The IC50 value of compound 10a was 6.8 mM and that of 10c, 8.3 mM. In addition, both compounds possessed differential activity against leukemia, colon and mammary cancer. The activity pattern was confirmed in two further screens using monolayer and clonogenic assays. In vivo antitumor studies showed that 10a was active against the human mammary carcinoma MT-1 and murine colon cancer MAC15A. Marginal activity was observed in human ovarian cancer model PXN/109T/C and the compound was inactive in human mammary cancer MCF-7. Conclusion: The results warrant further in vivo testing of 10a in additional human solid tumor models. The molecular modeling showed that the planarity of the chromophore and the side-chain conformation could assist the insertion of compound 10a between the base pairs of the double helix. On the other hand docking to the nucleotide sequence GGAATTGCCTCA suggested that the molecule could also act as a minor groove binder.en_US
dc.format.extent907 - 919en_US
dc.titleAntitumor activity of imidazothioxanthones in murine and human tumor models in vitro and in vivoen_US
dc.typeJournal Article
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfANTICANCER RESEARCHen_US
pubs.notesaffiliation: Varvaresou, A (Reprint Author), Sch Hlth & Caring Profess, Dept Aesthet, Inst Educ Technol, Ag Spryidonos Str, GR-12210 Athens, Greece. EORTC New Drug Dev Off, Amsterdam, Netherlands. Univ Athens, Sch Pharm, Dept Pharmaceut Chem, Athens, Greece. Max Delbruck Ctr Mol Med, Berlin, Germany. Oncotest GmbH, Inst Expt Oncol, Freiburg, Germany. Inst Canc Res, CRC, Ctr Canc Therapeut, Sutton, Surrey, England. Univ Bradford, Canc Res Unit, Bradford BD7 1DP, W Yorkshire, England. keywords: imidazothioxanthones; cytotoxicity; antitumor activity; human tumor xenografts; murine tumors; molecular modeling-docking keywords-plus: DNA-INTERCALATING AGENTS; CELL-LINES; ANTICANCER AGENTS; BINDING; SCREEN; ASSAY; N-<2-(DIMETHYLAMINO)ETHYL>ACRIDINE-4-CARBOXAMIDE; ESTABLISHMENT; FEASIBILITY; XENOGRAFTS research-areas: Oncology web-of-science-categories: Oncology author-email: [email protected] orcid-numbers: Gikas, Evagelos/0000-0002-0107-9991 Hendriks, Hans/0000-0003-1109-4615 number-of-cited-references: 24 times-cited: 4 usage-count-last-180-days: 0 usage-count-since-2013: 0 journal-iso: Anticancer Res. doc-delivery-number: 820JM unique-id: ISI:000221385000054 da: 2018-09-11en_US
pubs.notesNot knownen_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorKelland, Lloyden_US

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