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Design, synthesis, and validation of novel nitrogen-based chalcone analogs against triple negative breast cancer

التفاصيل البيبلوغرافية
العنوان: Design, synthesis, and validation of novel nitrogen-based chalcone analogs against triple negative breast cancer
المؤلفون: Ala-Eddin Al Moustafa, Dana Elkhalifa, Mohammed H. Qusa, Feras Q. Alali, Farhan S. Cyprian, Abu Bakar Siddique, Ashraf A. Khalil, Khalid A. El Sayed
المصدر: European journal of medicinal chemistry. 187
سنة النشر: 2019
مصطلحات موضوعية: Models, Molecular, Chalcone, Cell cycle checkpoint, Cell Survival, Nitrogen, Mice, Nude, Cancer progression, Apoptosis, Triple Negative Breast Neoplasms, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Mice, Structure-Activity Relationship, 1 (3 chlorophenyl) 3 [4 (pyrrolidin 1 yl)phenyl]prop 2 en 1 one, 1 (3 methoxyphenyl) 3 [4 (piperidin 1 yl)phenyl]prop 2 en 1 one, 1 (3 methoxyphenyl) 3 [4 (pyrrolidin 1 yl)phenyl]prop 2 en 1 one, 1 (benzo[d][1,3]dioxol 5 yl) 3 [4 (pyrrolidin 1 yl)phenyl]prop 2 en 1 one, 1 [4 (methylsulfonyl)phenyl] 3 (4 morpholinophenyl)prop 2 en 1 one, 1 [4 (methylsulfonyl)phenyl] 3 [4 (piperidin 1 yl)phenyl]prop 2 en 1 one, 1 [4 (methylsulfonyl)phenyl] 3 [4 (pyrrolidin 1 yl)phenyl]prop 2 en 1 one, 1 [4 (methylthio)phenyl) 3 [4 (piperidin 1 yl)phenyl]prop 2 en 1 one, 1 [4 (methylthio)phenyl] 3 (4 morpholinophenyl)prop 2 en 1 one, 1 [4 (methylthio)phenyl] 3 [4 (pyrrolidin 1 yl)phenyl]prop 2 en 1 one, 3 (4 morpholinophenyl) 1 [4 (piperazin 1 yl) phenyl)prop 2 en 1 one, 3 [4 [bis(2 chloroethyl)amino]phenyl] 1 (2 methoxyphenyl)prop 2 en 1 one, 3 [4 [bis(2 chloroethyl)amino]phenyl] 1 [4 (methylsulfonyl)phenyl]prop 2 en 1 one, antineoplastic agent, chalcone derivative, chlormethine, colchicine, estrogen, morpholine, P cadherin, paclitaxel, piperidine derivative, protein Bax, protein bcl 2, pyrrolidine derivative, unclassified drug, uvomorulin, vasculotropin receptor 2, [3 [4 [bis(2 chloroethyl)amino]phenyl] 1 (3 methoxyphenyl)prop 2 en 1 one], chalcone, nitrogen, angiogenesis, animal cell, animal experiment, animal model, antineoplastic activity, antiproliferative activity, apoptosis, Article, cancer inhibition, cell invasion, cell migration, chorioallantois, clinical effectiveness, clinical evaluation, colony formation, comparative study, concentration response, controlled study, cytotoxicity, down regulation, drug design, drug efficacy, drug identification, drug synthesis, epithelial mesenchymal transition, G2 phase cell cycle checkpoint, human, human cell, IC50, in vivo study, MCF-7 cell line, MDA-MB-231 cell line, MDA-MB-468 cell line, mouse, nonhuman, triple negative breast cancer, tumor xenograft, upregulation, animal, cell cycle checkpoint, cell proliferation, cell survival, chemical structure, chemistry, dose response, drug effect, drug screening, experimental mammary neoplasm, female, molecular model, nude mouse, pathology, structure activity relation, synthesis, tumor cell culture, Animals, Cell Cycle Checkpoints, Cell Proliferation, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Female, Humans, Mammary Neoplasms, Experimental, Molecular Structure, Tumor Cells, Cultured, Nude mouse, Drug Discovery, Epithelial–mesenchymal transition, Triple-negative breast cancer, 030304 developmental biology, Pharmacology, E-cadherin/catenin complex and its signaling pathways, 0303 health sciences, biology, 010405 organic chemistry, Oral cancer, Organic Chemistry, Emt, General Medicine, biology.organism_classification, Nitrogen mustard, 0104 chemical sciences, Cell culture, Cancer research
الوصف: Great strides have been made in triple negative breast cancer (TNBC) treatment, which represents 20% of total predicted annual US breast cancer (BC) cases. Despite the development of several therapeutics, TNBC patients have poor overall survival rate, compared to other BC patients, justifying the urgent need to discover new entities for use to control TNBC. Chalcones are important natural products with diverse bioactivities including anticancer effects. This study aimed to design, synthesize and validate novel chalcone leads as potential therapies for TNBC. Fourteen novel chalcone analogs were designed and synthesized comprising alicyclic amines (pyrrolidine, morpholine and piperidine) or nitrogen mustard (Bis-(2-chloroethyl) amine) substituents. Among them, compound 14 ((E)-3-(4-(Bis(2-chloroethyl) amino) phenyl)-1-(3-methoxyphenyl) prop-2-en-1-one) was identified as the most effective against TNBC and other BC phenotypes, with anti-proliferative IC50 values ranging between 3.94 and 9.22 μM against the TNBC cell lines MDA-MB-231 and MDA-MB-468, as well as against the estrogen positive MCF-7 cell line. Chalcone 14 effectively suppressed the colony formation capacity of MDA-MB-231, MDA-MB-468, and MCF-7 cell lines at 5 and 10 μM treatment concentrations. Furthermore, compound 14 has significantly inhibited cell invasion and migration of MDA-MB-231 and MCF-7 BC cell lines. Additionally, compound 14 had significantly promoted apoptosis by upregulating BAX and downregulating Bcl-2 proteins. Compound 14 induced significant cell cycle arrest of TNBC cells at the G2/M phase. It also induced a reversal of Epithelial Mesenchymal Transition (EMT) by upregulating the epithelial markers E-cadherin and Pan-cadherin and downregulating FAK. Furthermore, it had dramatically diminished new vessel formation (vasculogenesis) in chick chorioallantoic membrane (CAM) model by 60.20 ± 8.47%. Chalcone 14 inhibited 46.41 ± 0.71% of the TNBC MAD-MB-231 cells growth in a nude mouse orthotopic xenograft model in comparison with vehicle control treated animals. Collectively, this study results propose chalcone 14 as a promising lead molecule for the control of TNBC as well as other breast cancer phenotypes. This research work was supported by Grants# GCC-2017-2 and QUST-1-CPH-2018-18 from Qatar University ; and GSRA award# GSRA4-2-0418-17024 from Qatar National Research Fund (a member of Qatar Foundation). Scopus
تدمد: 1768-3254
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::877db4dbb7ab790d9a59c4c276405d6d
https://pubmed.ncbi.nlm.nih.gov/31838326
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....877db4dbb7ab790d9a59c4c276405d6d
قاعدة البيانات: OpenAIRE
الوصف
تدمد:17683254