Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold

Deng, Xinxian; Guo, Lin; Xu, Lili; Zhen, Xuechu; Yu, Kunqian; Zhao, Weili; Fu, Wei

doi:10.1016/j.bmcl.2015.07.030

Cited by 14 publications

(11 citation statements)

References 24 publications

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“…Target compounds 10a – l were achieved in seven steps using 1 as starting materials, which were coupled with KCNO in acetic acid at ambient temperature. Cyclization of 2 was done at reflux in NaOH methanol solution (pH=10) [28] . 4 was achieved by regioselective nitration of 3 at −10 °C [29] .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Anti‐Proliferation Activity Evaluation of Novel 2‐Chloroquinazoline as Potential EGFR‐TK Inhibitors

Zheng

Jin

et al. 2021

Chemistry & Biodiversity

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A novel series of 2‐chloroquinazoline derivatives had been synthesized and their anti‐proliferation activities against the four EGFR high‐expressing cells A549, NCI‐H1975, AGS and HepG2 cell lines were evaluated. The preliminary SAR study of the scaffold of new compounds showed that the compounds with a chlorine substituent on R3 had a better anti‐proliferation activity than those substituted by hydrogen atom or vinyl group. Among them, 2‐chloro‐N‐[2‐chloro‐4‐(3‐chloro‐4‐fluoroanilino)quinazolin‐6‐yl]acetamide (10b) had the best activity, and the corresponding IC50 were 3.68, 10.06, 1.73 and 2.04 μM, respectively. And compound 10b had better or equivalent activity against four cell lines than Gefitinib. The activity of the compound 10b on the EGFR enzyme was subsequently tested. The Wound Healing of A549, AGS and HepG2 cells by this compound showed that the compound can inhibit the migration of cancer cells. Finally, the action channel of the compound 10b was supported by western blotting experiments. It provides useful information for the design of EGFR‐TK inhibitors.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Anti‐Proliferation Activity Evaluation of Novel 2‐Chloroquinazoline as Potential EGFR‐TK Inhibitors

Zheng

Jin

et al. 2021

Chemistry & Biodiversity

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“…By a combinatorial study using both the docking and MD analyses, as well as a detailed comparison between these results, it is demonstrated that the present docking model is reliable in reflecting the particular binding mechanism in the 5-HT 2A receptor active site. To further explore the interaction features of general 5-HT 2A antagonists and the binding model of arylpiperazine derivatives with the target protein, a comparison of previously-reported docking studies of known 5-HT 2A antagonists with the ones assessed in our current work was conducted [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Above Table 2 summarizes the important information obtained from these studies, for purpose to compare their similarities and differences, with their representative structures of the ligands summarized in Figure 10 .…”

Section: Resultsmentioning

confidence: 99%

“…Due to that an accurate 3D structure of the receptor is essential for docking analysis, and until now an X-ray structure of 5-HT 2A receptor is, yet, still unavailable, the homology modeling becomes a necessity in the present work. In addition, since, to our best knowledge, almost all (which is actually, 7 out of 9 as shown in Table 2 ) current crystal structures of 5-HT 2A receptor built by homology modeling for further docking analysis were based on the structure of β 2 -adrenergic receptor as a template [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], for purpose of a well comparison with previously-reported docking studies of known 5-HT 2A antagonists, the structure of 5-HT 2A receptor we used presently still adopted the structure of β 2 -adrenergic receptor as the homology modeling’s template. Actually, this structure was built by Ísberg et al, where the 5-HT 2A receptor model was constructed using the β 2 -adrenergic receptor (PDB entry 2RH1) as the main template, and then further modified to incorporate template features from the active G-protein-bound opsin crystal structure (PDB entry 3DQB) [ 47 ].…”

Section: Methodsmentioning

confidence: 99%

Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods

Feng

Wang

et al. 2017

Molecules

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As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) study by using both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches was carried out. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q2 = 0.587, non-cross-validated correlation coefficient R2ncv = 0.900 and predicted correlation coefficient for the test set of compounds R2pre = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT2A receptor. Meanwhile, as a docking supplementary tool to study the antagonists’ conformation in the binding cavity, molecular dynamics (MD) simulation was also performed, providing further elucidation about the changes in the ligand-receptor complex. Lastly, some new molecules were also newly-designed based on the above results that are potential arylpiperazine antagonists of 5-HT2A receptor. We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antagonists as antidepressant drugs as well as exploring the interaction mechanism of 5-HT2A antagonists.

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“…Scheme 2 outlines the synthesis route of compounds 19a-t. The key intermediate 2,4dichloroquinazoline (17) was synthesized according to the literature report [26] . The starting material 2-amino-1-methyl benzoate ( 14) was coupled with KCNO in acetic acid at ambient temperature.…”

Section: Chemistrymentioning

confidence: 99%

“…Intermediate 10 was synthesized according the procedures reported in the previous literature [26] . To a solution of 10 (3.62 g, 0.015 mol) and N-methyl-4-methoxyaniline (2.31g, 0.017 mol) in 25 mL of anhydrous isopropanol (IPA) was added 0.6 mL of concentrated HCl, and the mixture was stirred at room temperature overnight.…”

Section: Synthesis Of Intermediate 12mentioning

confidence: 99%

Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain

Yin

Wen

et al. 2019

Bioorganic Chemistry

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A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modelling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers.

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Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold

Cited by 14 publications

References 24 publications

Synthesis and Anti‐Proliferation Activity Evaluation of Novel 2‐Chloroquinazoline as Potential EGFR‐TK Inhibitors

Synthesis and Anti‐Proliferation Activity Evaluation of Novel 2‐Chloroquinazoline as Potential EGFR‐TK Inhibitors

Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods

Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain

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