New benzothienopyrimidine derivatives as dual EGFR/ARO inhibitors: Design, synthesis, and their cytotoxic effect on MCF‐7 breast cancer cell line

Abstract

New cytotoxic agents based on benzothienopyrimidine scaffold were designed, synthesized, and evaluated against the MCF‐7 breast cancer line in comparison to erlotinib and letrozole as reference drugs. Eight compounds demonstrated up to 20‐fold higher anticancer activity than erlotinib, and five of these compounds were up to 11‐fold more potent than letrozole in MTT assay. The most promising compounds were evaluated for their inhibitory activity against EGFR and ARO enzymes. Compound 12, which demonstrated potent dual EGFR and ARO inhibitory activity with IC50 of 0.045 and 0.146 µM, respectively, was further evaluated for caspase‐9 activation, cell cycle analysis, and apoptosis. The results revealed that the tested compound 12 remarkably induced caspase‐9 activation (IC50 = 16.29 ng/ml) caused cell cycle arrest at the pre‐G1/G1 phase and significantly increased the concentration of cells at both early and late stage of apoptosis. In addition, it showed a higher safety profile on normal MCF‐10A cells, and higher antiproliferative activity on cancer cells (IC50 = 8.15 µM) in comparison to normal cells (IC50 = 41.20 µM). It also revealed a fivefold higher selectivity index than erlotinib towards MCF‐7 cancer cells. Docking studies were performed to rationalize the dual inhibitory activity of compound 12.

A novel thieno[2,3‐d]pyrimidine derivative inhibiting vascular endothelial growth factor receptor‐2: A story of computer‐aided drug discovery

“…The nucleophilic substitution reaction of the key intermediate 4 with hydrazine hydrate in absolute ethanol resulted in the formation of compound 5 (Abdelhaleem et al, 2018). The reaction of hydrazinyl derivative 5 with 2,4‐dichlorobenzoyl chloride in pyridine afforded the hydrazide derivative (the designed thieno[2,3‐ d ]pyrimidine derivative, compound 6 ; Sobh et al, 2022).…”

Synthesis of novel nicotinic acid derivatives of potential antioxidant and anticancer activity

“…The phases of a cell cycle include the first growth period (G 1 ), synthesis (S), second growth period (G 2 ), and mitosis (M). [ 47 ] Cancer‐targeting agents act by terminating cell growth at any of these checkpoints. [ 41,47 ] DNA flow cytometry analysis was used to investigate the stage at which cell cycle arrest occurs in the HCT‐15 cell line.…”

“…[ 47 ] Cancer‐targeting agents act by terminating cell growth at any of these checkpoints. [ 41,47 ] DNA flow cytometry analysis was used to investigate the stage at which cell cycle arrest occurs in the HCT‐15 cell line. This was accessed by incubating HCT‐15 cells for 24 h with compound 5c at its IC 50 concentration (1.57 M).…”

“…[ 48 ] Labeling with both Annexin V and PI enables the differentiation of viable, early apoptotic, late apoptotic, and necrotic cells. [ 47 ] Staining with Annexin V‐FITC cellular protein and counterstaining with PI were performed on HCT‐15 cancer cells 24 h following the treatment with 5c at its IC 50 concentration (1.57 M). The tested compound significantly increased the favorable apoptotic impact of Annexin V‐FITC.…”

Dihydroazolopyrimidines: Past, Present and Perspectives in Synthesis, Green Chemistry and Drug Discovery

“…In addition to all the necessary spectral data for compounds 76 a-i and 77 a-g,j, the structure of representative 76 a was undoubtedly confirmed by the single crystal X-ray crystallography. In a recent work Ergan et al [272] described similar reaction (Scheme 70) using the same idea and its formulation as well as the same reaction conditions, but without referring to the original work by Wang et al [269] Application of 2-hydrazineylpyrimidine derivative in reaction with nitrous acid can also lead to anellation with the tetrazole ring, [273][274][275][276] but these reactions are described mainly for the derivatives that are out of the focus of this review.…”