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Orientador(es)
Resumo(s)
Hepatocellular 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.
Descrição
Palavras-chave
Thieno[3,2-b]pyridines Anti-hepatocellular carcinoma activity Hepatotoxicity Cell cycle QSAR studies
Contexto Educativo
Citação
Abreu, 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. 5800-5086
Editora
Elsevier