Mohamed M Hawwas, Ahmed S Mancy, Mohamed Ramadan, Tarek S Ibrahim, Ashraf H Bayoumi, Mohamed Alswah
{"title":"一种新型吡唑啉喹啉-2- 1杂合体作为EGFR和BRAFV600E双抑制剂的创新方法。","authors":"Mohamed M Hawwas, Ahmed S Mancy, Mohamed Ramadan, Tarek S Ibrahim, Ashraf H Bayoumi, Mohamed Alswah","doi":"10.1007/s11030-025-11127-4","DOIUrl":null,"url":null,"abstract":"<p><p>Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC<sub>50</sub> values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF<sup>V600E</sup>. Compound 4e exhibited the highest inhibitory activities, with IC<sub>50</sub> values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF<sup>V600E</sup>, compared to the reference drugs erlotinib (IC<sub>50</sub> 0.06 ± 0.002 μM) and vemurafenib (IC<sub>50</sub> 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF<sup>V600E</sup>. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF<sup>V600E</sup> compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAF<sup>V600E</sup> inhibitors.\",\"authors\":\"Mohamed M Hawwas, Ahmed S Mancy, Mohamed Ramadan, Tarek S Ibrahim, Ashraf H Bayoumi, Mohamed Alswah\",\"doi\":\"10.1007/s11030-025-11127-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC<sub>50</sub> values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF<sup>V600E</sup>. Compound 4e exhibited the highest inhibitory activities, with IC<sub>50</sub> values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF<sup>V600E</sup>, compared to the reference drugs erlotinib (IC<sub>50</sub> 0.06 ± 0.002 μM) and vemurafenib (IC<sub>50</sub> 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF<sup>V600E</sup>. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF<sup>V600E</sup> compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.</p>\",\"PeriodicalId\":708,\"journal\":{\"name\":\"Molecular Diversity\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-03-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Diversity\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1007/s11030-025-11127-4\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11127-4","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAFV600E inhibitors.
Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC50 values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAFV600E. Compound 4e exhibited the highest inhibitory activities, with IC50 values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAFV600E, compared to the reference drugs erlotinib (IC50 0.06 ± 0.002 μM) and vemurafenib (IC50 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAFV600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAFV600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.
期刊介绍：
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;
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