Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity

Adly, Mina E.; Gedawy, Ehab M.; El‐Malah, Afaf; El-Telbany, F. A.

doi:10.2174/1871520618666180124121441

Cited by 10 publications

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“…Observed agreement between kinase inhibition and antiproliferative activity can be further assessed to identify the potential inhibitors of oncogenic receptors including FLT3 receptor. However, similar to our findings, previous studies reported that compounds bearing the thieno[2,3- d ]pyrimidines scaffold exhibited inhibitory activity against kinases [ 31 , 37 ].…”

Section: Resultssupporting

confidence: 92%

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Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

et al. 2021

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This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

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Section: Resultssupporting

confidence: 92%

“…Thus, the ability to target kinase activity represents an attractive therapeutic strategy for cancer treatment [ 30 ]. However, similar thieno[2,3- d ]pyrimidine derivatives were reported remarkable selectivity toward cancer cells as compared to normal cells [ 31 , 32 ].…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

et al. 2021

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“…Motivated by these facts, herein, we designed and synthesized novel cyclohepta[4,5]thieno[2,3- d ]pyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors (Figure 2). The structural modifications involved replacement of 4-anilinoquinazoline scaffold with is their bioisostere thieno[2,3- d ]pyrimidine core fused to large lipophilic cycloalkyl group guided by their reported potent anticancer activity 31 , 32 . In addition, we explored the substitution of the phenyl ring of 4-anilino or 4-aryloxy moieties with, halogen, hydrogen bond donor (such as amino group), hydrogen bond acceptor (nitro, methoxy groups) or hydrogen bond donor/acceptor (sulphonylamino group) to substantiate the effect of such variations on the dual EGFR and VEGFR-2 inhibitory activity as well as their anticancer activity against MCF-7 breast cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile

Mghwary

Gedawy

Kamal

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Aim: Design and synthesis of thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors. Material and methods: A series of novel 6,7,8,9-tetrahydro-5 H -cyclohepta[4,5]thieno[2,3- d ]pyrimidine derivatives with different substituents on C-4 position was synthesized and evaluated for their anticancer activity against MCF-7 cell line. EGFR, VEGFR-2 inhibitory assay, the cell cycle analysis and apoptosis induction ability of the most potent compound 5f were evaluated. Results: Most of the compounds showed moderate to significant anticancer activity. Compound 5f exhibited the most potent anticancer activity being 1.73- and 4.64-folds more potent than erlotinib and doxorubicin, respectively. Compound 5f showed potent EGFR inhibitory activity being 1.18-folds more potent than reference standard erlotinib and it also showed good VEGFR-2 inhibitory activity at the micromolar level with IC 50 value 1.23 µM. Compound 5f caused induction of cell cycle arrest at G2/M phase and accumulation of cells in pre-G1 phase. Compound 5f induced cellular apoptosis.

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“…In detail, Ethyl 2‐amino‐6‐methyl‐4,5,6,7‐tetrahydro[1]benzothiophene‐3‐carboxylate 2 was synthesized through the reaction of 4‐methylcyclohexanone 1 with 2‐cyanoacetamide adopting Gewald method (Shearouse et al, 2014). Cyclization of the latter with formamide formed tricyclic tetrahydro[1]benzothienopyrimidine derivative 3 (Adly et al, 2018). Then, the chlorination of pyrimidinone 3 with phosphorus oxychloride using a pyridine catalyst resulted in the formation of chloropyrimidine 4 (Khalil et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

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

Sobh

Dahab

Alsfouk

et al. 2023

Drug Development Research

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Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR‐2) inhibitors, a novel thieno[2,3‐d]pyrimidine derivative has been designed and its activity against VEGFR‐2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer‐induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug‐like nature of the designed candidate. According to the previous results, the thieno[2,3‐d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR‐2 (IC50 = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC50 values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI‐38). Finally, the thieno[2,3‐d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3‐d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase‐3, caspase‐9, Bcl‐2 associated X‐protein, and B‐cell lymphoma 2.

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Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity

Abstract: 4-Substitutedaminothieno[2,3-d]pyrimidine is a promising backbone for the design and synthesis of potent cytotoxic leads.

Cited by 10 publications

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Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile

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

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