Efficient synthesis of 6-(hetero)arylthieno[3,2-b]pyridines by Suzuki–Miyaura coupling. Evaluation of growth inhibition on human tumor cell lines, SARs and effects on the cell cycle

A wide variety of new bi(hetero)aryl derivatives of the thieno[3,2-b]pyridine skeleton was obtained in high to excellent yields (65–91%) by Suzuki–Miyaura cross-coupling of the methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate, recently reported by us, with aryl or heteroaryl pinacolboranes or potassium trifluoroborates.The coupling products obtained were evaluated for their growth inhibitory effect on three human tumor cell lines, representing different tumor models, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma) and NCI-H460 (non-small cell lung cancer). Some of the compounds showed an interesting activity against the tested cell lines, with GI50 values in the μM range, and it was possible to establish some structure–activity relationships (SARs). Several compounds presented GI50 values below 15 μM, particularly a bithiophene and an o-aniline thienopyridine derivative. The first presented selectivity for MCF-7 and NCI-H460 cell lines, with very low GI50 values (0.7–1.0 μM), while the latter was active against the three cell lines tested in this study, also presenting very low GI50 values (2.5–4.2 μM). The effect of these two compounds on cell cycle progression was analyzed in the NCI-H460 cell line. Results showed that both compounds interfered with the normal cell cycle distribution.

Bi(hetero)aryl derivatives of the thieno[3,2-b]pyridine were obtained by Suzuki–Miyaura cross-coupling of the methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate with aryl or heteroaryl pinacolborane esters or potassium trifluoroborates, in good to excellent yields. The coupling products were evaluated for their growth inhibitory effect on three representative human tumor cell lines. For the two most promising compounds, cell cycle analysis was performed in one of the cell lines in study.Figure optionsDownload as PowerPoint slide