Synthesis of Novel Methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates and Antitumor Activity Evaluation: Studies In Vitro and In Ovo Grafts of Chick Chorioallantoic Membrane (CAM) with a Triple Negative Breast Cancer Cell Line.

Bruna R Silva,Rita Rebelo,Juliana M Rodrigues,Maria-João R P Queiroz,Cristina P R Xavier,M Helena Vasconcelos

doi:10.3390/molecules26061594

Abstract

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 μM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.

Highlights

These results suggested that compound 2e interferes with the cell cycle profile of triple negative breast cancer (TNBC) MDA-MB-231 cells
Eight novel methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were prepared in moderate to high yields by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with different boronated compounds. These were tested against TNBC cell lines and the potential of three novel thieno[3,2b]pyridine derivatives 2e, 2f, 2h as anticancer agents in TNBC cell lines was demonstrated
No toxicity was observed in non-tumorigenic breast cells

Summary

Introduction

Regardless the great number of research studies worldwide to improve our understanding and effort to develop new therapies, breast cancer is still the most frequent diagnosed cancer and the main cause of cancer death in women [1]. Due to a recent histopathologic classification, breast cancer is divided into different subtypes depending on the expression of key proteins such as human epidermal growth factor receptor. 2 (HER-2) estrogen and progesterone receptors; Ki67; claudins; epidermal growth factor receptor (EGFR) and others. The subtypes of breast cancer are designated as luminal. A, luminal B, HER2-enriched (+), basal-like and claudin-low [2]. The most aggressive, invasive and with poor prognosis type of breast cancer is the triple negative breast cancer (TNBC), which is immunohistochemically characterized by the lack of estrogen receptor, progesterone receptor and absence of HER2 amplification [1].

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Conclusion