Discovery of a novel class anti-proliferative agents and potential inhibitors of EGFR tyrosine kinases based on 4-anilinotetrahydropyrido[4,3-d]pyrimidine scaffold: Design, synthesis and biological evaluations

Zhang, Yong; Zhang, Kai; Zhao, Meng; Zhang, Lixia; Qin, Mingze; Guo, Shuchun; Zhao, Yanfang; Gong, Ping

doi:10.1016/j.bmc.2015.05.059

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…16 We selected oxo ester 1 17 as a starting reactant, since both the amino and carboxyl group are orthogonally protected, permitting specific deprotection at various steps (Scheme 2). Typically, the N-benzyl moiety is removed by chloroformates such as 1-chloroethyl chloroformate, 18 oxidatively by using ceric ammonium nitrate, 19 through hydrogenolysis, 20 and by using other procedures, 21 whereas the tert-butyloxycarbonyl function is cleaved by acid catalysis, in the presence of anhydrous trifluoroacetic acid (TFA) or hydrogen chloride in ether. 21 Condensation of 1 with aniline, according to our earlier published procedure, 9a provided stable enamine 2 in high yields.…”

Section: Paper Syn Thesismentioning

confidence: 99%

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

et al. 2017

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The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (±)-cis and (±)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.

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Section: Paper Syn Thesismentioning

confidence: 99%

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

et al. 2017

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“…Among the series compounds, compounds 5–10 were found to be the most potent in EGFR inhibition with an IC 50 range of 8–18 nM. Also, this study found that compounds 7–10 were found to inhibit HER2, which is more potent, giving rise to the dual inhibition activity ( Zhang Y. et al, 2015 ). These heterocycles have shown good cytotoxicity in this study.…”

Section: Fused Pyrimidine Derivativesmentioning

confidence: 80%

“…Changing the phenyl ring to indole or indazole gave compounds that were less effective as EGFR inhibitors ( Smaill et al, 2016 ). The presence of benzyloxy and phenoxy increases the selectivity to EGFR rather than to HER2 ( Zhang Y. et al, 2015 ). 4) Substitution at R 2 : the presence of nitrogen (N) is essential for its activity, whereas replacing it with carbon (C) showed a significant loss in its activity ( Hou et al, 2016 ).…”

Section: Fused Pyrimidine Derivativesmentioning

confidence: 99%

“…The presence of tertiary N makes the molecules selective to EGFR ( Cockerill et al, 2001 ), whereas substituting it with C=O retains activity ( Zhang D. et al, 2018 ). The addition of acrylamide ( Smaill et al, 2001 ), benzyloxy ( Zhang Y. et al, 2015 ), phenoxy ( Zhang D. et al, 2018 ), piperidine ( Klutchko et al, 2006 ), and alkene enabled the molecules to exhibit selective inhibition against EGFR, whereas substituting with morpholine and imidazole imbibes a dual inhibitory activity ( Smaill et al, 2001 ).…”

Section: Fused Pyrimidine Derivativesmentioning

confidence: 99%

Section: Fused Pyrimidine Derivativesmentioning

confidence: 99%

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A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

et al. 2022

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Epidermal growth factor receptor (EGFR) belongs to the family of tyrosine kinase that is activated when a specific ligand binds to it. The EGFR plays a vital role in the cellular proliferation process, differentiation, and apoptosis. In the case of cancer, EGFR undergoes uncontrolled auto-phosphorylation that results in increased cellular proliferation and decreased apoptosis, causing cancer promotion. From the literature, it shows that pyrimidine is one of the most commonly studied heterocycles for its antiproliferative activity against EGFR inhibition. The authors have collated some interesting results in the heterocycle-fused pyrimidines that have been studied using different cell lines (sensitive and mutational) and in animal models to determine their activity and potency. It is quite clear that the fused systems are highly effective in inhibiting EGFR activity in cancer cells. Therefore, the structure–activity relationship (SAR) comes into play in determining the nature of the heterocycle and the substituents that are responsible for the increased activity and toxicity. Understanding the SAR of heterocycle-fused pyrimidines will help in getting a better overview of the molecules concerning their activity and potency profile as future EGFR inhibitors.

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Current Approaches in the Development of Covalent Irreversible EGFR Inhibitors

Patel¹,

Pawara²,

Surana³

2019

Third Generation EGFR Inhibitors

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Discovery of a novel class anti-proliferative agents and potential inhibitors of EGFR tyrosine kinases based on 4-anilinotetrahydropyrido[4,3-d]pyrimidine scaffold: Design, synthesis and biological evaluations

Cited by 10 publications

References 36 publications

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

Current Approaches in the Development of Covalent Irreversible EGFR Inhibitors

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