Design, synthesis, in-vitro, in-silico, DFT and POM studies of a novel family of sulfonamides as potent anti-triple-negative breast cancer agents

IF 2.6 4区 生物学 Q2 BIOLOGY Computational Biology and Chemistry Pub Date : 2024-09-19 DOI:10.1016/j.compbiolchem.2024.108214
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
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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

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作为强效抗三阴性乳腺癌药物的新型磺酰胺家族的设计、合成、体外、实验室、DFT 和 POM 研究
本研究合成了一系列新的乙酰丙酸磺酰胺类化合物和吲唑磺酰胺类化合物,并利用 MTT(3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴化物)测定法对 MDA-MB-468 三阴性乳腺癌细胞和 PBMCs 人类外周血单核细胞进行了体外测试。这项研究的目的是发现对乳腺癌有潜在治疗作用的新型化合物。这些化合物的抗增殖活性表现出明显的剂量依赖性,IC50 值介于 2.83 和 7.52 µM 之间。先导化合物 8 和 9 的 IC50 值与紫杉醇相似,分别为 2.83、3.84 和 2.72 µM。这凸显了这些化合物的新颖性和替代现有疗法的潜力。分子对接法分析了 8、9 和紫杉醇与 PARP1(Poly(ADP-ribose) polymérase 1)和 EGFR(表皮生长因子受体)蛋白活性位点的结合特性,结果显示,它们与 PARP1 蛋白的结合亲和力分别为 -9.8 Kcal /mol、-10 Kcal /mol 和 -9.4 Kcal /mol。而它们与表皮生长因子受体蛋白的结合亲和力分别为-7.5 Kcal/mol、-7.2 Kcal/mol和-6.9 Kcal/mol。此外,药物相似性和 ADMET(吸收-分布-代谢-排泄-毒性)分析表明,这两种分子都具有良好的口服生物利用度、药代动力学特征和无毒性特征。除了对所有化合物进行 POM(Petra/Osiris/Molinspiration)研究外,还对化合物 8 和 9 进行了 DFT(密度泛函理论)研究。研究结果表明,化合物 8 和 9 有希望进一步发展成为治疗三阴性乳腺癌的药物。
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来源期刊
Computational Biology and Chemistry
Computational Biology and Chemistry 生物-计算机:跨学科应用
CiteScore
6.10
自引率
3.20%
发文量
142
审稿时长
24 days
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.
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