New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells

Farghaly, A. M.; Aboulwafa, Omaima M.; Baghdadi, Hoda H.; Razik, Heba A. Abd El; Sedra, Samir M.Y.; Shamaa, Marium M.

doi:10.1016/j.bioorg.2021.105208

Cited by 19 publications

(7 citation statements)

References 74 publications

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“…Furthermore, a π–cation interaction between the aniline phenyl ring with Lys 721 amino acid was identified. In the same way, recently thienopyrimidine derivatives were synthesized and the active compounds showed similar binding interactions with EGFR active site as erlotinib, whereas the synthesized derivatives created the essential interactions with Met 769 and Thr 766 (Farghaly et al, 2021; Mghwary et al, 2019). From this point, the findings of the docking investigation indicated that the tested compounds achieved positive outcomes (Table 6).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, a suitable inhibitor of EGFR should include a hydrophobic head, such as a phenyl ring, residing in the hydrophobic region I of the enzyme and attached to the aromatic heterocyclic fused system through an NH spacer. Finally, a second hydrophobic moiety (hydrophobic tail) occupies the hydrophobic region II and is fused or connected to the aromatic heterocyclic system (Farghaly et al, 2021; Gaber et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3‐d]pyrimidine derivatives as EGFR inhibitors

Sayed

Halim

El‐Ansary

et al. 2023

Drug Development Research

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New series of 20 thieno[2,3‐d]pyrimidine derivatives have been synthesized. The National Cancer Institute evaluated all the newly synthesized compounds for their antiproliferative activity against a panel of 60 cancer cell lines. Compound 7b exhibited a remarkable antineoplastic activity at 10 µM dose and was therefore tested at five dose concentrations. The significant and broad‐spectrum antineoplastic action of compound 7b was observed against 37 of the tested cancer cell lines with a dose that inhibits 50% of the growth compared to control values in the micromolar range of 1.95–9.6 µM. The dose which inhibits the growth completely in the cytostatic range of 3.99–100 µM was also observed. Compound 7b effectively inhibited epidermal growth factor receptor (EGFR) with 50% inhibition concentration value (IC50) = 0.096 ± 0.004 compared to erlotinib with IC50 = 0.037 ± 0.002. Moreover, compound 7b revealed a powerful downregulation effect on total EGFR concentration and its phosphorylation. In addition, compound 7b inhibited phosphatidylinositol 3‐kinase, protein kinase B, and the mammalian target of rapamycin pathway phosphorylation. Furthermore, compound 7b raised total apoptosis by 21.93‐fold in the ovarian cancer cell line (OVCAR‐4) and caused an arrest in the cell cycle in the G1/S phase. It also raised the level of caspase‐3 by 4.72‐fold. Furthermore, to determine the binding manner of the most effective derivatives and validate their capacity to comply with the pharmacophoric properties necessary for EGFR inhibition, they were docked into the active site of the EGFR.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3‐d]pyrimidine derivatives as EGFR inhibitors

Sayed

Halim

El‐Ansary

et al. 2023

Drug Development Research

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“…The activity of the compound reduced dramatically when substituted with F at both the R 1 and R 2 positions. These In the series of thieno[3,2-d]-pyrimidine derivatives, compound 42 [72] has significant aromatase inhibitory activity with an IC 50 value of 131.7 ± 2.12 nM as well as against MCF-7 cell lines with IC 50 Compound 42 was permitted to acclimate within the active site in such a manner that the heme group was implicated in a supplemental hydrophobic-stacking engagement with the 6-membered pyrimidine ring of the thienopyrimidine skeleton with a distance of 3.83 Å, comparable to the engagement that exists among heme, ASD, and letrozole, reported in Figure 13.…”

Section: Aromatase Inhibitorsmentioning

confidence: 99%

Current progress in the targeted therapy of breast cancer: Structure–activity correlation and docking studies (2015–2021)

Pandey

Mondal

Kajal

et al. 2023

Archiv der Pharmazie

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Despite cancer research and therapy, breast cancer remains a complicated health crisis in women and represents a top biomedical research priority. Nowadays, breast cancer is an extremely heterogeneous disease and is known as the leading cause of death among women worldwide. The incidence and mortality rates of breast cancer have been increasing gradually for the past decades. Nowadays, common treatments for breast cancer are chemotherapy, endocrine therapy, immunotherapy, radiotherapy, and surgery. The most common targets in breast cancer treatment are human epidermal growth factor receptor 2 (HER2) and estrogen receptors.The literature suggests that several targets/pathways are also involved in the development of breast cancer, that is, poly(ADP-ribose) polymerase (PARP), bromodomain-containing protein 4 (BRD4), cyclin-dependent kinase 4/6 (CDK4/ 6), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), polo-like kinase 1 (PLK1), phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), histone deacetylase (HDAC), nuclear factor kappa B (NF-κB), PD-L1, and aromatase inhibitors.Meanwhile, the study of breast cancer is a hot topic in the current scenario of basic/clinical research. This review article provides information on different targets associated with breast cancer and summarizes the progress of current research on synthesized inhibitors as anti-breast cancer agents from 2015 to 2021. The review aims to provide structure-activity relationship and docking studies for designing novel compounds for breast cancer therapy.

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“…Recently, thienopyrimidine has proved to be an attractive heterocyclic scaffold for cancer treatment through dual enzyme inhibition, such as EGFR and HER‐2, compound VI (Elmetwally et al, 2019), EGFR and ErbB‐2 enzymes, compound VII (Rheault et al, 2009), EGFR and VEGFR, compound VIII (Mghwary et al, 2019) or EGFR and ARO, compounds IX , X , and XI (AboulWafa et al, 2020; Farghaly et al, 2021; Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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

Sobh

Khalil

Faggal

et al. 2022

Drug Development Research

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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.

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New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells

Cited by 19 publications

References 74 publications

Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3‐d]pyrimidine derivatives as EGFR inhibitors

Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3‐d]pyrimidine derivatives as EGFR inhibitors

Current progress in the targeted therapy of breast cancer: Structure–activity correlation and docking studies (2015–2021)

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

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