journal article
Open Access
Dec 01, 2022
Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids
Abstract
Designed Chalcone-Dihydropyrimidinone hybrid compounds were synthesized expeditiously. The hybridization was performed through the Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) from the propargyloxy chalcones and azido-dihydropyrimidinones. The hybrid products were prepared in five steps with a 30–48% overall yield. Most of the compounds showed selective cytotoxicity and lower IC50 values (<10 µM) against MCF-7 (breast adenocarcinoma) cancer. Cytotoxicity was also observed against OVCAR-3 (ovary, adenocarcinoma), NCI/ADR-RES (ovary, multidrug-resistant adenocarcinoma), and U-251 (brain, glioblastoma) cell lines. The potency of the most active hybrids 9d, 9g, and 9h was greater than the individual parental compounds, suggesting the effectiveness of molecular hybridization on the cytotoxicity. Compounds 9d, 9g, and especially 9h showed high selectivity for breast cancer cells (MCF-7) regarding human keratinocytes (HaCaT). Molecular docking calculations for the 9d, 9g, and 9h hybrids in the active site of estrogen supported the hypothesis that the compounds act as ER-α antagonists, disrupting the cell proliferation process of MCF-7, corroborating the potency and selectivity observed for this tumoral cell line.
Topics
No keywords indexed for this article. Browse by subject →
References
63
[1]
"An Overview of Molecular Hybrids in Drug Discovery" Expert Opin. Drug Discov. (2016) 10.1517/17460441.2016.1135125
[2]
Talevi "Multi-target pharmacology: Possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective" Front. Pharmacol. (2015) 10.3389/fphar.2015.00205
[3]
Morphy "Designed Multiple Ligands. An Emerging Drug Discovery Paradigm" J. Med. Chem. (2005) 10.1021/jm058225d
[4]
Nepali "Rational Approaches, Design Strategies, Structure Activity Relationship and Mechanistic Insights for Anticancer Hybrids" Eur. J. Med. Chem. (2014) 10.1016/j.ejmech.2014.03.018
[5]
Decker, M. (2017). Design of Hybrid Molecules for Drug Development, Elsevier.
[6]
Bansal "Multifunctional compounds: Smart molecules for multifactorial diseases" Eur. J. Med. Chem. (2014) 10.1016/j.ejmech.2014.01.060
[7]
Tsogoeva "Recent Progress in the Development of Synthetic Hybrids of Natural or Unnatural Bioactive Compounds for Medicinal Chemistry" Mini Rev. Med. Chem. (2010) 10.2174/138955710791608280
[8]
Tietze "Natural Product Hybrids as New Leads for Drug Discovery" Angew. Chem. Int. Ed. (2003) 10.1002/anie.200200553
[9]
Vendrusculo "Synthesis of Novel Perillyl-Dihydropyrimidinone Hybrids Designed for Antiproliferative Activity" Med. Chem. Commun. (2018) 10.1039/c8md00270c
[10]
Sharma "Discovery of a New Class of Natural Product-Inspired Quinazolinone Hybrid as Potent Antileishmanial agents" J. Med. Chem. (2013) 10.1021/jm400053v
[11]
Camps "New Tacrine-Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer’s Disease" J. Med. Chem. (2000) 10.1021/jm000980y
[12]
Singh "Recent developments in biological activities of chalcones: A mini review" Eur. J. Med. Chem. (2014) 10.1016/j.ejmech.2014.08.033
[13]
Zhuang "Chalcone: A Privileged Structure in Medicinal Chemistry" Chem. Rev. (2017) 10.1021/acs.chemrev.7b00020
[14]
Rani "Recent developments in biological aspects of chalcones: The odyssey continues" Expert Opin. Drug Discov. (2019) 10.1080/17460441.2019.1573812
[15]
Salum "Cytotoxic 3,4,5-Trimethoxychalcones as Mitotic Arresters and Cell Migration Inhibitors" Eur. J. Med. Chem. (2013) 10.1016/j.ejmech.2013.02.037
[16]
Shankaraiah "Synthesis of Different Heterocycles-Linked Chalcone Conjugates as Cytotoxic Agents and Tubulin Polymerization Inhibitors" Bioorgan. Med. Chem. (2017) 10.1016/j.bmc.2017.07.031
[17]
Wei "Coumarin-chalcone hybrids: Promising agents with diverse pharmacological properties" RSC Adv. (2016) 10.1039/c5ra26294a
[18]
Mao "Synthesis and biological evaluation of novel hybrid compounds between chalcone and piperazine as potential antitumor agents" RSC Adv. (2016) 10.1039/c5ra20197g
[19]
"Highly selective anthraquinone-chalcone hybrids as potential antileukemia agents" Bioorgan. Med. Chem. Lett. (2018) 10.1016/j.bmcl.2018.06.048
[20]
Park "Biological evaluation of indolizine-chalcone hybrids as new anticancer agents" Eur. J. Med. Chem. (2018) 10.1016/j.ejmech.2017.12.056
[21]
Thiriveedhi "Novel Hybrid Molecules of Quinazoline Chalcone Derivatives: Synthesis and Study of In Vitro Cytotoxic Activities" Lett. Drug Des. Discov. (2018) 10.2174/1570180814666171013162148
[22]
Mass "The Quinazoline-Chalcone and Quinazolinone-Chalcone Hybrids: A Promising Combination for Biological Activity" Mini Rev. Med. Chem. (2021) 10.2174/1389557520666200730160325
[23]
Jernei, T., Duró, C., Dembo, A., Lajkó, E., Takács, A., Kohidai, L., Schlosser, G., and Csámpai, A. (2019). Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona-Chalcone Hybrids with 1,4-Disubstituted and 1,5-Disubstituted 1,2,3-Triazole Linkers. Molecules, 24.
10.3390/molecules24224077
[24]
New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity
Samar H. Abbas, Amer Ali Abd El-Hafeez, Mai E. Shoman et al.
Bioorganic Chemistry
2019
10.1016/j.bioorg.2018.10.064
[25]
Chouiter "New chalcone-type compounds and 2-pyrazoline derivatives: Synthesis and caspase-dependent anticancer activity" Future Med. Chem. (2020) 10.4155/fmc-2019-0342
[26]
Djemoui "A step-by-step synthesis of triazole-benzimidazole-chalcone hybrids: Anticancer activity in human cells" J. Mol. Struct. (2020) 10.1016/j.molstruc.2019.127487
[27]
Bukhari "Review of Methods and Various Catalysts Used for Chalcone Synthesis" Mini Rev. Org. Chem. (2013) 10.2174/1570193x11310010006
[28]
Qin "Chalcone hybrids as privileged scaffolds in antimalarial drug discovery: A key review" Eur. J. Med. Chem. (2020) 10.1016/j.ejmech.2020.112215
[29]
Gao "Chalcone hybrids as potential anticancer agents: Current development, mechanism of action, and structure-activity relationship" Med. Res. Rev. (2020) 10.1002/med.21698
[30]
Hein "Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: New reactivity of copper(I) acetylides" Chem. Soc. Rev. (2010) 10.1039/b904091a
[31]
Neumann "The CuAAC: Principles, homogeneous and heterogeneous catalysts, and novel developments and applications" Macromol. Rapid Commun. (2019) 10.1002/marc.201900359
[32]
Lal "Design, synthesis, characterization, antimicrobial evaluation and molecular modeling studies of some dehydroacetic acid-chalcone-1,2,3-triazole hybrids" Bioorgan. Chem. (2018) 10.1016/j.bioorg.2018.01.016
[33]
Singh "1,2,3-Triazole tethered β-lactam-chalcone bifunctional hybrids: Synthesis and anticancer evaluation" Eur. J. Med. Chem. (2012) 10.1016/j.ejmech.2011.10.033
[34]
Guantai "Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds" Bioorgan. Med. Chem. (2010) 10.1016/j.bmc.2010.10.009
[35]
Mayer "Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen" Science (1999) 10.1126/science.286.5441.971
[36]
Cochran "Monastrol inhibition of the mitotic kinesin Eg5" J. Biol. Chem. (2005) 10.1074/jbc.m413140200
[37]
Matos "Biological Activity of Dihydropyrimidinone (DHPM) Derivatives: A Systematic Review" Eur. J. Med. Chem. (2018) 10.1016/j.ejmech.2017.10.073
[38]
Kaur "Recent synthetic and medicinal perspectives of dihydropyrimidinones: A Review" Eur. J. Med. Chem. (2017) 10.1016/j.ejmech.2017.03.025
[39]
Braga "A Mini-Review on Biginelli adducts with notable pharmacological properties" J. Adv. Res. (2015) 10.1016/j.jare.2014.10.006
[40]
Oliveira "Synthesis and antitumoral activity of novel hybrid monastrol-fatty acids against glioma cells" Med. Chem. Commun. (2018) 10.1039/c8md00169c
[41]
Souza "Hybrid 3,4-dihydropyrimidin-2-(thi)ones as dual-functional bioactive molecules: Fluorescent probes and cytotoxic agents to cancer cells" New J. Chem. (2020) 10.1039/d0nj01368d
[42]
Malik "Application of triazoles as bioisosteres and linkers in the development of microtubule targeting agents" RSC Med. Chem. (2020) 10.1039/c9md00458k
[43]
Hau "Assembly of organosilver (I) frameworks with terminal ethynide and ethenyl groups on separate pendent arms attached to an aromatic ring" Polyhedron (2013) 10.1016/j.poly.2012.06.082
[44]
Chang "Synthesis of 1,3-Diaryl-1H-Benzo[g]Indazoles" Tetrahedron (2012) 10.1016/j.tet.2012.07.011
[45]
Lebed "Synthesis of new polyfunctional 5,6,7,8-tetrahydroimidazo-[1,5-c]pyrimidin-5-ones by the aza-Wittig reaction followed by intramolecular cyclization and 1,3-prototropic Shift" Russ. J. Org. Chem. (2009) 10.1134/s1070428009060207
[46]
Chen "A convergent route for the total synthesis of Malyngamides O, P, Q and R" J. Org. Chem. (2009) 10.1021/jo9003103
[47]
Moro "Synthesis and photophysical properties of fluorescent 2,1,3-benzothiadiazole-triazole-linked glycoconjugates: Selective chemosensors for Ni (II)" Tetrahedron (2013) 10.1016/j.tet.2012.10.043
[48]
Priti "Analysis of Cell Viability by the MTT Assay" Cold Spring Harb. Protoc. (2018)
[49]
Afonso de Lima, C., de Souza Bueno, I.L., Nunes Siqueira Vasconcelos, S., Sciani, J.M., Ruiz, A.L.T.G., Foglio, M.A., Carvalho, J.E.D., and Barbarini Longato, G. (2020). Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies. Pharmaceuticals, 13.
10.3390/ph13100327
[50]
Hostettmann, K. (1990). Methods in Plant Biochemistry: Assays for Bioactivity, Academic Press.
Showing 50 of 63 references
Metrics
14
Citations
63
References
Details
- Published
- Dec 01, 2022
- Vol/Issue
- 1(1)
- Pages
- 3-21
- License
- View
Authors
Funding
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
Award: 19/2551-0001767-7
Fundação de Apoio à Pesquisa do Estado de São Paulo
Award: 19/2551-0001767-7
Fundação de Apoio à Pesquisa do Estado do Rio Grande do Sul
Award: 19/2551-0001767-7
Cite This Article
Eduardo B. Mass, Carolina A. de Lima, Marcelo G. M. D’Oca, et al. (2022). Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids. Drugs and Drug Candidates, 1(1), 3-21. https://doi.org/10.3390/ddc1010002
Related
You May Also Like
Plant-Derived Natural Products: A Source for Drug Discovery and Development
Noureddine Chaachouay, Lahcen Zidane · 2024
778 citations
Virtual Screening Algorithms in Drug Discovery: A Review Focused on Machine and Deep Learning Methods
Tiago Oliveira, Michel Silva · 2023
115 citations
Revolutionizing Drug Discovery: A Comprehensive Review of AI Applications
Rushikesh Dhudum, Ankit Ganeshpurkar · 2024
83 citations
Synergy, Additive Effects, and Antagonism of Drugs with Plant Bioactive Compounds
Noureddine Chaachouay · 2025
76 citations
Algal Nanoparticles and Their Antibacterial Activity: Current Research Status and Future Prospectives
Maheswari Behera, Prateek Ranjan Behera · 2023
37 citations