Molecules 2012, 17(4), 3834-3843; doi:10.3390/molecules17043834
Article

Aminodi(hetero)arylamines in the Thieno[3,2-b]pyridine Series: Synthesis, Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Evaluation of Toxicity Using Non-Tumor Cells

Ricardo C. Calhelha 1,2 , Isabel C. F. R. Ferreira 2,* email, Daniela Peixoto 1 , Rui M. V. Abreu 2 , Luís A. Vale-Silva 3,4 , Eugénia Pinto 3,4 , Raquel T. Lima 4,5 , M. Inês Alvelos 5 , M. Helena Vasconcelos 3,5  and Maria-João R. P. Queiroz 1,* email
1 Center of Chemistry, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal 2 CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta Apolónia, Apartado 1172, 5301-855 Bragança, Portugal 3 Department of Biological Sciences, Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313 Porto, Portugal 4 CEQUIMED-UP, Research Center of Medicinal Chemistry, University of Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313 Porto, Portugal 5 Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
* Authors to whom correspondence should be addressed.
Received: 12 March 2012; in revised form: 24 March 2012 / Accepted: 26 March 2012 / Published: 28 March 2012
(This article belongs to the Special Issue Bioactive Compounds)
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Abstract: Three aminodi(hetero)arylamines were prepared via a palladium-catalyzed C-N Buchwald-Hartwig coupling of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate with different bromonitrobenzenes, followed by reduction of the nitro groups of the coupling products to the corresponding amino compounds. The aminodi(hetero)arylamines thus obtained were evaluated for their growth inhibitory effect on four human tumor cell lines MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), NCI-H460 (non-small cell lung cancer) and HepG2 (hepatocellular carcinoma). The toxicity to non-tumor cells was also evaluated using a porcine liver primary cell culture (PLP1), established by us. The aminodi(hetero)arylamine with the NH2 group in the ortho position and an OMe group in the para position to the NH of the di(hetero)arylamine, is the most promising compound giving the lowest GI50 values (1.30–1.63 µM) in all the tested human tumor cell lines, presenting no toxicity to PLP1 at those concentrations. The effect of this compound on the cell cycle and induction of apoptosis was analyzed in the NCI-H460 cell line. It was observed that it altered the cell cycle profile causing a decrease in the percentage of cells in the G0/G1 phase and an increase of the apoptosis levels.
Keywords: thieno[3,2-b]pyridines; aminodi(hetero)arylamines; Buchwald-Hartwig C-N coupling; antitumoral activity; toxicity; cell cycle; apoptosis

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MDPI and ACS Style

Calhelha, R.C.; Ferreira, I.C.F.R.; Peixoto, D.; Abreu, R.M.V.; Vale-Silva, L.A.; Pinto, E.; Lima, R.T.; Alvelos, M.I.; Vasconcelos, M.H.; Queiroz, M.-J. Aminodi(hetero)arylamines in the Thieno[3,2-b]pyridine Series: Synthesis, Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Evaluation of Toxicity Using Non-Tumor Cells. Molecules 2012, 17, 3834-3843.

AMA Style

Calhelha RC, Ferreira ICFR, Peixoto D, Abreu RMV, Vale-Silva LA, Pinto E, Lima RT, Alvelos MI, Vasconcelos MH, Queiroz M-J. Aminodi(hetero)arylamines in the Thieno[3,2-b]pyridine Series: Synthesis, Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Evaluation of Toxicity Using Non-Tumor Cells. Molecules. 2012; 17(4):3834-3843.

Chicago/Turabian Style

Calhelha, Ricardo C.; Ferreira, Isabel C. F. R.; Peixoto, Daniela; Abreu, Rui M. V.; Vale-Silva, Luís A.; Pinto, Eugénia; Lima, Raquel T.; Alvelos, M. Inês; Vasconcelos, M. Helena; Queiroz, Maria-João R. P. 2012. "Aminodi(hetero)arylamines in the Thieno[3,2-b]pyridine Series: Synthesis, Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Evaluation of Toxicity Using Non-Tumor Cells." Molecules 17, no. 4: 3834-3843.

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