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

Ricardo C. Calhelha¹  Isabel C. F. R. Ferreira³  Daniela Peixoto¹  Rui M. V. Abreu³  Luís A. Vale-Silva²  Eugénia Pinto²  Raquel T. Lima⁵  M. Inês Alvelos⁴  M. Helena Vasconcelos² 

[1] Center of Chemistry, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal;Department of Biological Sciences, Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313 Porto, Portugal;CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta Apolónia, Apartado 1172, 5301-855 Bragança, Portugal;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;CEQUIMED-UP, Research Center of Medicinal Chemistry, University of Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313 Porto, Portugal

关键词: thieno[3;    2-b]pyridines;    aminodi(hetero)arylamines;    Buchwald-Hartwig C-N coupling;    antitumoral activity;    toxicity;    cell cycle;    apoptosis;   

DOI  :  10.3390/molecules17043834

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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