Novel Thieno [2,3-b]pyridine Anticancer Compound Lowers Cancer Stem Cell Fraction Inducing Shift of Lipid to Glucose Metabolism

Abstract

Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC–MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.

Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines

“…It has also been shown that treatment of breast cancer cells (MDA-MB-231) with a previous thieno [2,3-b]pyridine lead morphology changes and membrane blebbing that mimics PI-PLC knockdown cells [4]. It has also been shown that treatment of breast cancer cells (MDA-MB-231) with a previous thieno [2,3-b]pyridine lead compound induced growth reduction in addition to causing cells to shift from lipid to glucose metabolism, providing further evidence that these compounds act through inferring with lipid metabolism [2]. Additional studies into thienopyridine-containing compounds have identified a range of other potential cellular targets, including TDP-1 [5], P2Y12 receptors [6], Adenosine A2A receptors [7], as well as potentially inhibiting microtubule assembly [8,9].…”

“…The 3-amino-2-arylcarboxamido-thieno [2,3-b]pyridines are a family of drug-like molecules that are well established in the literature for inducing potent anti-proliferative effects in triple-negative breast cancer (MDA-MB-231) and colorectal cancer (HCT116) pcell lines [1][2][3][4]. It is postulated that thieno [2,3-b]pyridines induce anti-neoplastic action through disrupting phospholipid metabolism by the inhibition of phosphoinositide phospholipase C (PI-PLC).…”

Utility of 2-Chloro-N-arylacetamide and 1,1′-(Piperazine-1,4-diyl)bis(2-chloroethanone) as Versatile Precursors for Novel Mono- and Bis[thienopyridines]

“…Thieno­[2,3- b ]­pyridine derivatives occupy a unique position and have received considerable attention due to their diverse pharmacological activities, which include anticancer, , antiviral, , anti-inflammatory, , antimicrobial, , antidiabetic, , and osteogenic antiproliferative activity. Furthermore, they can be used as adenosine A1 receptor ligands for the potential treatment of epilepsy and as antiplatelet drugs .…”

Study of the Biological Activity of Microwave Synthesized of some new Pyridine derivatives fused with Sulfonamide Moiety

“…Pyridine derivatives a heterocyclic compound that have a wide range of biological activities [1][2][3][4], including antimicrobial [5,6], antitumor [7,8], antiviral [9], anticancer [10], antituberculosis, anti-inflammatory [11] [12], and heart treatment properties [13,14]. Sulfonamides have also shown strong pharmacological effects [14].…”