Nassima Saghdani , Abdelmoula El Abbouchi , Nabil El Brahmi , Abderrazak Idir , Khadija Otmane Rachedi , Malika Berredjem , Rachid Haloui , Souad Elkhattabi , Hassan Ait Mouse , Taibi Ben Hadda , Mostapha Bousmina , Abdelmajid Zyad , Saïd El Kazzouli
{"title":"Design, synthesis, in-vitro, in-silico, DFT and POM studies of a novel family of sulfonamides as potent anti-triple-negative breast cancer agents","authors":"Nassima Saghdani , Abdelmoula El Abbouchi , Nabil El Brahmi , Abderrazak Idir , Khadija Otmane Rachedi , Malika Berredjem , Rachid Haloui , Souad Elkhattabi , Hassan Ait Mouse , Taibi Ben Hadda , Mostapha Bousmina , Abdelmajid Zyad , Saïd El Kazzouli","doi":"10.1016/j.compbiolchem.2024.108214","DOIUrl":null,"url":null,"abstract":"<div><p>In this study, a new family of ethacrynic acid-sulfonamides and indazole-sulfonamides was synthesized and tested <em>in vitro</em> against MDA-MB-468 triple-negative breast cancer cells and PBMCs human peripheral blood mononuclear cells, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The aim of this research is to discover novel compounds with potential therapeutic effects on breast cancer. The antiproliferative activity of these compounds showed a significant dose-dependent activity, with IC<sub>50</sub> values ranging between 2.83 and 7.52 µM. The lead compounds <strong>8</strong> and <strong>9</strong> displayed similar IC<sub>50</sub> values to paclitaxel with 2.83, 3.84 and 2.72 µM, respectively. This highlights the novelty and potential of these compounds as alternatives to current treatments. The binding properties of <strong>8</strong>, <strong>9,</strong> and paclitaxel with the active sites of the PARP1(Poly(ADP-ribose) polymérase 1) and EGFR (Epidermal growth factor receptor) proteins were analyzed by molecular docking methods showing, for PARP1 protein, binding affinities of −9.8 Kcal /mol, −10 Kcal /mol, and −9.4 Kcal /mol, respectively. While their binding affinities for EGFR protein are −7.5 Kcal/mol, −7.2 Kcal/mol and −6.9 Kcal/mol, respectively. Moreover, drug-likeness and ADMET (Absorption–distribution–metabolism–excretion–toxicity) analyses demonstrated that both molecules are orally bioavailable and have good pharmacokinetic and non-toxic profiles. DFT (Density functional theory) was also carried out on both compounds <strong>8</strong> and <strong>9</strong> additionally to POM (Petra/Osiris/Molinspiration) studies on all compounds. The outcomes of this study suggest that compounds <strong>8</strong> and <strong>9</strong> are promising candidates for further development as therapeutic agents against triple-negative breast cancer</p></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"113 ","pages":"Article 108214"},"PeriodicalIF":2.6000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Computational Biology and Chemistry","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1476927124002020","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
In this study, a new family of ethacrynic acid-sulfonamides and indazole-sulfonamides was synthesized and tested in vitro against MDA-MB-468 triple-negative breast cancer cells and PBMCs human peripheral blood mononuclear cells, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The aim of this research is to discover novel compounds with potential therapeutic effects on breast cancer. The antiproliferative activity of these compounds showed a significant dose-dependent activity, with IC50 values ranging between 2.83 and 7.52 µM. The lead compounds 8 and 9 displayed similar IC50 values to paclitaxel with 2.83, 3.84 and 2.72 µM, respectively. This highlights the novelty and potential of these compounds as alternatives to current treatments. The binding properties of 8, 9, and paclitaxel with the active sites of the PARP1(Poly(ADP-ribose) polymérase 1) and EGFR (Epidermal growth factor receptor) proteins were analyzed by molecular docking methods showing, for PARP1 protein, binding affinities of −9.8 Kcal /mol, −10 Kcal /mol, and −9.4 Kcal /mol, respectively. While their binding affinities for EGFR protein are −7.5 Kcal/mol, −7.2 Kcal/mol and −6.9 Kcal/mol, respectively. Moreover, drug-likeness and ADMET (Absorption–distribution–metabolism–excretion–toxicity) analyses demonstrated that both molecules are orally bioavailable and have good pharmacokinetic and non-toxic profiles. DFT (Density functional theory) was also carried out on both compounds 8 and 9 additionally to POM (Petra/Osiris/Molinspiration) studies on all compounds. The outcomes of this study suggest that compounds 8 and 9 are promising candidates for further development as therapeutic agents against triple-negative breast cancer
期刊介绍:
Computational Biology and Chemistry publishes original research papers and review articles in all areas of computational life sciences. High quality research contributions with a major computational component in the areas of nucleic acid and protein sequence research, molecular evolution, molecular genetics (functional genomics and proteomics), theory and practice of either biology-specific or chemical-biology-specific modeling, and structural biology of nucleic acids and proteins are particularly welcome. Exceptionally high quality research work in bioinformatics, systems biology, ecology, computational pharmacology, metabolism, biomedical engineering, epidemiology, and statistical genetics will also be considered.
Given their inherent uncertainty, protein modeling and molecular docking studies should be thoroughly validated. In the absence of experimental results for validation, the use of molecular dynamics simulations along with detailed free energy calculations, for example, should be used as complementary techniques to support the major conclusions. Submissions of premature modeling exercises without additional biological insights will not be considered.
Review articles will generally be commissioned by the editors and should not be submitted to the journal without explicit invitation. However prospective authors are welcome to send a brief (one to three pages) synopsis, which will be evaluated by the editors.