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,M Helena Vasconcelos,Maria-João R P Queiroz,Daniela Peixoto,Luís A Vale-Silva,Rui M V Abreu,Raquel T Lima,Isabel C F R Ferreira,M Inês Alvelos,Eugénia Pinto

doi:10.3390/molecules17043834

Ricardo C Calhelha, M Helena Vasconcelos + Show 8 more

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https://doi.org/10.3390/molecules17043834

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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.

Highlights

Despite the great amount of research and rapid development of new therapies seen during the past decade, cancer continues to be a leading cause of death worldwide
Reacting methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate (1) [8] with different bromo-nitrobenzenes under Pd-catalyzed Buchwald-Hartwig C-N coupling conditions (i) using xantphos as the ligand and Cs2CO3 as the base, the di(hetero)arylnitro compounds 2a–c were obtained in high yields
The nitro compounds 2a–c were reduced in almost quantitative yield to the corresponding aminodi(hetero)arylamines 3a–c using conditions; (ii) [11]

Summary

Introduction

Despite the great amount of research and rapid development of new therapies seen during the past decade, cancer continues to be a leading cause of death worldwide. Conventional anti-cancer therapies in current clinical use (such as anti-hormonal therapy, radiotherapy and chemotherapy) improve patient survival, the resulting drug toxicity and severe side effects are still causing high failure rates of cure. When organ-confined tumors advance to locally invasive or metastatic stages, this usually associates to resistance to conventional therapies, disease relapse, and to patient death within a short period of time [2]. Our research group has synthesized various methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives functionalized at the pyridine ring by Pd-catalyzed C-N (Buchwald-Hartwig) and C-C (Suzuki and Sonogashira) couplings and some of them presented cell growth inhibitory activity in tumor cell lines [5,6,7]. Among the 6-(hetero)arylaminothieno[3,2-b]pyridine derivatives obtained by C-N coupling the most promising compounds bear a benzothiazole (GI50 3.5–6.4 μM) or an indole (GI50 15.8–18.1 μM) moiety [5]

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