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Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2- carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies

2011Journal article Open access
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dc.contributor.authorAbreu, Rui M.V.
dc.contributor.authorFerreira, Isabel C.F.R.
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorLima, Raquel T.
dc.contributor.authorVasconcelos, M. Helena
dc.contributor.authorAdega, Filomena
dc.contributor.authorChaves, Raquel
dc.contributor.authorQueiroz, Maria João R.P.
dc.date.accessioned2011-12-20T16:27:35Z
dc.date.available2011-12-20T16:27:35Z
dc.date.issued2011
dc.description.abstractHepatocellular carcinoma (HCC) is a highly complex cancer, resistant to commonly used treatments and new therapeutic agents are urgently needed. A total of thirty-two thieno[3,2-b]pyridine derivatives of two series: methyl 3-amino- -(hetero)arylthieno[3,2-b]pyridine-2-carboxylates (1ae1t) and methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates (2ae2n), previously prepared by some of us, were evaluated as new potential anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety emerges as the key element for the anti-HCC activity. The methyl 3-amino-6-[(3-aminophenyl)ethynyl]thieno[3,2-b]pyridine-2-carboxylate (2f) is the most potent compound presenting GI50 values on HepG2 cells of 1.2 mM compared to 2.9 mM of the positive control ellipticine, with no observed hepatotoxicity (PLP1 GI50 > 125 mM against 3.3 mM of ellipticine). Moreover this compound changes the cell cycle profile of the HepG2 cells, causing a decrease in the % of cells in the S phase and a cell cycle arrest in the G2/M phase. QSAR studies were also performed and the correlations obtained using molecular and 1D descriptors revealed the importance of the presence of amino groups and hydrogen bond donors for anti-HCC activity, and hydrogen bond acceptors for hepatotoxicity. The best correlations were obtained with 3D descriptors belonging to different subcategories for anti-HCC activity and hepatotoxicity, respectively. These results point to different molecular mechanisms of action of the compounds in anti-HCC activity and hepatotoxicity. This work presents some promising thieno[3,2-b]pyridine derivatives for potential use in the therapy of HCC. These compounds can also be used as scaffolds for further synthesis of more potent analogs.por
dc.description.sponsorshipThe authors are grateful to Foundation for Science and Technology (FCT, Portugal) through the financial support of the research centres and through the research project PTDC/QUIeQUI/111060/ 2009 also financed by FEDER/COMPETE/QREN/EU. R.M.V. Abreu, R.C. Calhelha, and Filomena Adega thank to FCT, POPH-QREN and FSE for their SFRH/PROTEC/49450/2009 and SFRH/BPD/68344/2010 grants and researcher contract under “Programa Compromisso com Ciência-2007”, respectively.
dc.identifier.citationAbreu, Rui M.V.; Ferreira, Isabel C. F. R.; Calhelha, Ricardo C.; Lima, Raquel T.; Vasconcelos, M. Helena; Adega, Filomenna; Chaves, Raquel; Queiroz, Maria-João R. P. (2011). Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2- carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies. European Journal of Medicinal Chemistry. ISSN 1768-3254. 46:12, p. 5800-5086por
dc.identifier.doi10.1016/j.ejmech.2011.09.029
dc.identifier.issn1768-3254
dc.identifier.urihttp://hdl.handle.net/10198/6469
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherElsevierpor
dc.relationSFRH/PROTEC/49450/2009
dc.subjectThieno[3,2-b]pyridinespor
dc.subjectAnti-hepatocellular carcinoma activitypor
dc.subjectHepatotoxicitypor
dc.subjectCell cyclepor
dc.subjectQSAR studiespor
dc.titleAnti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2- carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studiespor
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FQUI-QUI%2F111060%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F68344%2F2010/PT
oaire.citation.endPage5806por
oaire.citation.startPage5800por
oaire.citation.titleEuropean Journal of Medicinal Chemistrypor
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamSFRH
person.familyNameAbreu
person.familyNameFerreira
person.familyNameCalhelha
person.givenNameRui M.V.
person.givenNameIsabel C.F.R.
person.givenNameRicardo C.
person.identifier144781
person.identifier.ciencia-id0F19-0DE2-12A2
person.identifier.ciencia-id9418-CF95-9919
person.identifier.ciencia-idF313-E3CE-554E
person.identifier.orcid0000-0002-7745-8015
person.identifier.orcid0000-0003-4910-4882
person.identifier.orcid0000-0002-6801-4578
person.identifier.ridE-8500-2013
person.identifier.ridJ-2172-2014
person.identifier.scopus-author-id7003290613
person.identifier.scopus-author-id36868826600
person.identifier.scopus-author-id6507978333
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspor
rcaap.typearticlepor
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