Research Article

New chalcone-type compounds and 2-pyrazoline derivatives: synthesis and caspase-dependent anticancer activity

Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université des frères Mentouri-Constantine, Constantine 25000, Algeria

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Houssem Boulebd

*Author for correspondence:

E-mail Address: boulebd.houssem@umc.edu.dz

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David M Pereira

**Author for correspondence:

E-mail Address: dpereira@ff.up.pt

REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal

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Patrícia Valentão

REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal

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Paula B Andrade

REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal

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Ali Belfaitah

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Artur MS Silva

***Author for correspondence:

E-mail Address: artur.silva@ua.pt

https://orcid.org/0000-0003-2861-8286

QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

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Published Online:26 Feb 2020https://doi.org/10.4155/fmc-2019-0342

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Abstract

Aim: There is a continuous and urgent need for new anticancer agents with novel structures and target selectivity. Methods & results: The anticancer activity of the prepared compounds was assessed against human lung (A549) and stomach (AGS) cancer cell lines and evaluated in the noncancer human lung fibroblast (MRC-5) cell line. 2-Pyrazolines were devoid of toxicity in all cell lines used, chalcones bearing a β-(benz)imidazole moiety being toxic toward AGS cell line. Mechanistic studies showed that these compounds trigger loss of cell viability and mitochondrial membrane potential, while eliciting morphological traits compatible with regulated cell death, which was ultimately shown to derive from caspase activation, specifically caspase-3. Conclusion: Chalcones 1–3 have been identified as new and promising anticancer agents toward the AGS cell line.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Weber FG, Brosche K, Seedorf C, Rinow A. 1,3,5-Triaryl-Δ2-pyrazoline. Monatsh. Chem. 100(6), 1924–1927 (1969).Crossref, CAS, Google Scholar
2. Bhatnagar I, George MV. Oxidation with metal oxides–II: oxidation of chalcone phenylhydrazones, pyrazolines, o-aminobenzylidine anils and o-hydroxy benzylidine anils with manganese dioxide. Tetrahedron 24(3), 1293–1298 (1968). • Highlights the biological interest of pyrazoline derivatives.Crossref, CAS, Google Scholar
3. Harikrishna N, Isloor AM, Ananda K, Obaid A, Fun H-K. Synthesis, and antitubercular and antimicrobial activity of 1′-(4-chlorophenyl) pyrazole containing 3,5-disubstituted pyrazoline derivatives. New J. Chem. 40(1), 73–76 (2016).Crossref, CAS, Google Scholar
4. Kitawat BS, Singh M. Synthesis, characterization, antibacterial, antioxidant, DNA binding and SAR study of a novel pyrazine moiety bearing 2-pyrazoline derivatives. New J. Chem. 38(9), 4290–4299 (2014).Crossref, CAS, Google Scholar
5. Bashir R, Ovais S, Yaseen S et al. Synthesis of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide as anticancer and anti-inflammatory agents. Bioorg. Med. Chem. Lett. 21(14), 4301–4305 (2011).Crossref, Medline, CAS, Google Scholar
6. Bhosle MR, Mali JR, Pal S, Srivastava AK, Mane RA. Synthesis and antihyperglycemic evaluation of new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids having pyrazolyl pharmacophores. Bioorg. Med. Chem. Lett. 24(12), 2651–2654 (2014).Crossref, Medline, CAS, Google Scholar
7. Bhosle MR, Deshmukh AR, Pal S, Srivastava AK, Mane RA. Synthesis of new thiazolylmethoxyphenyl pyrimidines and antihyperglycemic evaluation of the pyrimidines, analogues isoxazolines and pyrazolines. Bioorg. Med. Chem. Lett. 25(11), 2442–2446 (2015).Crossref, Medline, CAS, Google Scholar
8. Edrees M, Melha S, Saad A, Kheder N, Gomha S, Muhammad Z. Eco-friendly synthesis, characterization and biological evaluation of some novel pyrazolines containing thiazole moiety as potential anticancer and antimicrobial agents. Molecules 23(11), 2970 (2018).Crossref, Google Scholar
9. Moreno L, Quiroga J, Abonia R, Ramírez-Prada J, Insuasty B. Synthesis of new 1,3,5-triazine-based 2-pyrazolines as potential anticancer agents. Molecules 23(8), 1956 (2018).Crossref, Google Scholar
10. Chen K, Zhang Y-L, Fan J, Ma X, Qin Y-J, Zhu H-L. Novel nicotinoyl pyrazoline derivates bearing N-methyl indole moiety as antitumor agents: Design, synthesis and evaluation. Eur. J. Med. Chem. 156, 722–737 (2018).Crossref, Medline, CAS, Google Scholar
11. Ali I, Wani WA, Khan A et al. Synthesis and synergistic antifungal activities of a pyrazoline based ligand and its copper(II) and nickel(II) complexes with conventional antifungals. Microb. Pathog. 53(2), 66–73 (2012).Crossref, Medline, CAS, Google Scholar
12. Özdemir Z, Kandilci HB, Gümüşel B, Çalış Ü, Bilgin AA. Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur. J. Med. Chem. 42(3), 373–379 (2007).Crossref, Medline, Google Scholar
13. Abdel-Wahab BF, Abdel-Aziz HA, Ahmed EM. Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles. Eur. J. Med. Chem. 44(6), 2632–2635 (2009).Crossref, Medline, CAS, Google Scholar
14. Acharya BN, Saraswat D, Tiwari M et al. Synthesis and antimalarial evaluation of 1,3,5-trisubstituted pyrazolines. Eur. J. Med. Chem. 45(2), 430–438 (2010).Crossref, Medline, CAS, Google Scholar
15. Martins DM, Torres BG, Spohr PR et al. Antioxidant potential of new pyrazoline derivatives to prevent oxidative damage. Basic Clin. Pharmacol. Toxicol. 104(2), 107–112 (2009).Crossref, Medline, CAS, Google Scholar
16. El-Husseiny WM, El-Sayed MAA, Abdel-Aziz NI, El-Azab AS, Ahmed ER, Abdel-Aziz AAM. Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study. J. Enzyme Inhib. Med. Chem. 33(1), 507–518 (2018). • Highlights the biological interest of (benz)imidazole derivatives.Crossref, Medline, CAS, Google Scholar
17. Congiu C, Cocco MT, Onnis V. Design, synthesis, and in vitro antitumor activity of new 1,4-diarylimidazole-2-ones and their 2-thione analogues. Bioorg. Med. Chem. Lett. 18(3), 989–993 (2008).Crossref, Medline, CAS, Google Scholar
18. Zhao F, Lu W, Su F et al. Synthesis and potential antineoplastic activity of dehydroabietylamine imidazole derivatives. MedChemComm 9(12), 2091–2099 (2018).Crossref, Medline, CAS, Google Scholar
19. Uchida K, Nishiyama Y, Tanaka T, Yamaguchi H. In vitro activity of novel imidazole antifungal agent NND-502 against Malassezia species. Int. J. Antimicrob. 21(3), 234–238 (2003).Crossref, Medline, CAS, Google Scholar
20. Al-Mohammed NN, Alias Y, Abdullah Z, Shakir RM, Taha EM, Hamid AA. Synthesis and antibacterial evaluation of some novel imidazole and benzimidazole sulfonamides. Molecules 18(10), 11978–11995 (2013).Crossref, Medline, CAS, Google Scholar
21. Peng X-M, Cai G-X, Zhou C-H. Recent developments in azole compounds as antibacterial and antifungal agents. Curr. Top. Med. Chem. 13(16), 1963–2010 (2013).Crossref, Medline, CAS, Google Scholar
22. Achar KC, Hosamani KM, Seetharamareddy HR. In vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives. Eur. J. Med. Chem. 45(5), 2048–2054 (2010).Crossref, Medline, CAS, Google Scholar
23. Abdel-Wahab BF, Awad GE, Badria FA. Synthesis, antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation of new imidazole-based heterocycles. Eur. J. Med. Chem. 46(5), 1505–1511 (2011).Crossref, Medline, CAS, Google Scholar
24. Bettencourt A, Castro M, Silva J et al. New nitrogen compounds coupled to phenolic units with antioxidant and antifungal activities: synthesis and structure–activity relationship. Molecules 23(10), 2530 (2018). • Highlights the synthesis of chalcone-type compounds.Crossref, Google Scholar
25. Rozmer Z, Perjési P. Naturally occurring chalcones and their biological activities. Phytochem. Rev. 15(1), 87–120 (2016).Crossref, CAS, Google Scholar
26. Nasir Abbas Bukhari S, Jasamai M, Jantan I, Ahmad W. Review of methods and various catalysts used for chalcone synthesis. Mini-Rev. Org. Chem. 10(1), 73–83 (2013).Crossref, Google Scholar
27. Nasir Abbas Bukhari S, Jasamai M, Jantan I. Synthesis and biological evaluation of chalcone derivatives (mini review). Mini-Rev. Org. Chem. 12(13), 1394–1403 (2012). • Highlights the biological interest of chalcone-type compounds.Google Scholar
28. Fathi MAA, El-Hafeez AAA, Abdelhamid D, Abbas SH, Montano MM, Abdel-Aziz M. 1,3,4-oxadiazole/chalcone hybrids: design, synthesis, and inhibition of leukemia cell growth and EGFR, Src, IL-6 and STAT3 activities. Bioorg. Chem. 84, 150–163 (2019).Crossref, Medline, CAS, Google Scholar
29. Go M, Wu X, Liu X. Chalcones: an update on cytotoxic and chemoprotective properties. Curr. Med. Chem. 12(4), 483–499 (2005).Crossref, CAS, Google Scholar
30. Lin Y-M, Zhou Y, Flavin MT, Zhou L-M, Nie W, Chen F-C. Chalcones and flavonoids as anti-tuberculosis agents. Bioorg. Med. Chem. 10(8), 2795–2802 (2002).Crossref, Medline, CAS, Google Scholar
31. Mahapatra DK, Asati V, Bharti SK. Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives. Eur. J. Med. Chem. 92, 839–865 (2015).Crossref, Medline, CAS, Google Scholar
32. Bandgar BP, Patil SA, Gacche RN et al. Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents. Bioorg. Med. Chem. Lett. 20(2), 730–733 (2010).Crossref, Medline, CAS, Google Scholar
33. Nowakowska Z. A review of anti-infective and anti-inflammatory chalcones. Eur. J. Med. Chem. 42(2), 125–137 (2007).Crossref, Medline, CAS, Google Scholar
34. Yin B-T, Yan C-Y, Peng X-M et al. Synthesis and biological evaluation of α-triazolyl chalcones as a new type of potential antimicrobial agents and their interaction with calf thymus DNA and human serum albumin. Eur. J. Med. Chem 71, 148–159 (2014).Crossref, Medline, CAS, Google Scholar
35. Domínguez JN, León C, Rodrigues J, Gamboa De Domínguez N, Gut J, Rosenthal PJ. Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives. J. Med. Chem. 48(10), 3654–3658 (2005).Crossref, Medline, CAS, Google Scholar
36. Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev. 117(12), 7762–7810 (2017).Crossref, Medline, CAS, Google Scholar
37. Gomes M, Muratov E, Pereira M et al. Chalcone derivatives: promising starting points for drug design. Molecules 22(8), 1210 (2017). •• Shows the anticancer potential of chalcone-type compounds.Crossref, Google Scholar
38. Yadav P, Lal K, Kumar A, Guru SK, Jaglan S, Bhushan S. Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles. Eur. J. Med. Chem. 126, 944–953 (2017).Crossref, Medline, CAS, Google Scholar
39. Park S, Kim EH, Kim J, Kim SH, Kim I. Biological evaluation of indolizine–chalcone hybrids as new anticancer agents. Eur. J. Med. Chem. 144, 435–443 (2018).Crossref, Medline, CAS, Google Scholar
40. Romagnoli R, Prencipe F, Lopez-Cara LC et al. Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells. J. Enzyme Inhib. Med. Chem. 33(1), 727–742 (2018).Crossref, Medline, CAS, Google Scholar
41. Zhu M, Wang J, Xie J et al. Design, synthesis, and evaluation of chalcone analogues incorporate α,β-unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis. Eur. J. Med. Chem. 157, 1395–1405 (2018).Crossref, Medline, CAS, Google Scholar
42. Jin H, Kim HS, Seo GS, Lee SH. A new chalcone derivative, 3-phenyl-1-(2,4,6-tris(methoxymethoxy)phenyl)prop-2-yn-1-one), inhibits phorbol ester-induced metastatic activity of colorectal cancer cells through upregulation of heme oxygenase-1. Eur. J. Med. Chem. 841, 1–9 (2018).CAS, Google Scholar
43. Break MKB, Hossan MS, Khoo Y et al. Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway. Fitoterapia 125, 161–173 (2018). • Our previous study on (benz)imidazole derivatives.Crossref, Medline, Google Scholar
44. Boulebd H, Ismaili L, Martin H et al. New (benz)imidazolopyridino tacrines as nonhepatotoxic, cholinesterase inhibitors for Alzheimer disease. Future Med. Chem. 9(8), 723–729 (2017). •• References used in the experimental part.Link, CAS, Google Scholar
45. Pereira DM, Correia-Da-Silva G, Valentao P, Teixeira N, Andrade P. GC-MS lipidomic profiling of the echinoderm Marthasterias glacialis and screening for activity against human cancer and noncancer cell lines. Comb. Chem. High T. Scr. 17(5), 450–457 (2014).Medline, CAS, Google Scholar
46. Da Silva DC, Andrade PB, Valentão P, Pereira DM. Neurotoxicity of the steroidal alkaloids tomatine and tomatidine is RIP1 kinase-and caspase-independent and involves the eIF2α branch of the endoplasmic reticulum. J. Steroid Biochem. Mol. Biol. 171, 178–186 (2017).Crossref, Medline, Google Scholar
47. Pereira DM, Silva TC, Losada-Barreiro S, Valentão P, Paiva-Martins F, Andrade PB. Toxicity of phenolipids: protocatechuic acid alkyl esters trigger disruption of mitochondrial membrane potential and caspase activation in macrophages. Chem. Phys. Lipids 206, 16–27 (2017).Crossref, Medline, CAS, Google Scholar
48. Silva TC, De Andrade PB, Paiva-Martins F, Valentão P, Pereira DM. In vitro anti-inflammatory and cytotoxic effects of aqueous extracts from the edible sea anemones Anemonia sulcata and Actinia equina. Int. J. Mol. Sci. 18(3), 653 (2017).Crossref, Google Scholar
49. Boulebd H, Zama S, Insaf B et al. Synthesis and biological evaluation of heterocyclic privileged medicinal structures containing (benz)imidazole unit. Monatsh. Chem. 147(12), 2209–2220 (2016).Crossref, CAS, Google Scholar
50. Huwá Davies D. Non-oxidative conversion of ketone carbonyls into carboxy carbonyls. Comparison of 2-acylthiazoles and 2-acylimidazoles in the aldol condensation and the stereospecific cleavage of an example of the latter to a β-hydroxy ester via the azolium salt. J. Chem. Soc., Perkin Trans. 1 (11), 2691–2698 (1991).Google Scholar
51. Mathew B, Suresh J, Anbazhagan S. Development of novel (1-H) benzimidazole bearing pyrimidine-trione based MAO-A inhibitors: Synthesis, docking studies and antidepressant activity. J. Saudi Chem. Soc. 20, S132–S139 (2016).Crossref, CAS, Google Scholar
52. Özdemir Z, Kandilci HB, Gümüşel B, Çalış Ü, Bilgin AA. Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur. J. Med. Chem. 42(3), 373–379 (2007).Crossref, Medline, Google Scholar
53. Jagrat M, Behera J, Yabanoglu S et al. Pyrazoline based MAO inhibitors: synthesis, biological evaluation and SAR studies. Bioorg. Med. Chem. Lett. 21(14), 4296–4300 (2011).Crossref, Medline, CAS, Google Scholar
54. Alex JM, Singh S, Kumar R. 1‐Acetyl‐3, 5‐diaryl‐4, 5‐dihydro (1H) pyrazoles: exhibiting anticancer activity through intracellular ROS scavenging and the mitochondria‐dependent death pathway. Arch. Pharm. 347(10), 717–727 (2014).Crossref, Medline, CAS, Google Scholar
55. Altintop MD, Özdemir A, Kaplancikli ZA, Turan‐Zitouni G, Temel HE, Çiftçi GA. Synthesis and biological evaluation of some pyrazoline derivatives bearing a dithiocarbamate moiety as new cholinesterase inhibitors. Arch. Pharm. 346(3), 189–199 (2013). •• Shows the anticancer potential of chalcone-type compounds.Crossref, Medline, CAS, Google Scholar
56. Bandgar BP, Gawande SS, Bodade RG, Totre JV, Khobragade CN. Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents. Bioorg. Med. Chem. 18(3), 1364–1370 (2010).Crossref, Medline, CAS, Google Scholar
57. Syam S, Abdelwahab SI, Al-Mamary MA, Mohan S. Synthesis of chalcones with anticancer activities. Molecules 17(6), 6179–6195 (2012).Crossref, Medline, CAS, Google Scholar
58. Fitzmaurice C, Allen C, Barber RM et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 3(4), 524–548 (2017).Crossref, Medline, Google Scholar
59. Galluzzi L, Vitale I, Aaronson SA et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25(3), 486–541 (2018).Crossref, Medline, Google Scholar
60. Pereira DM, Valentao P, Correia-Da-Silva G, Teixeira N, Andrade PB. Plant secondary metabolites in cancer chemotherapy: where are we? Curr. Pharm. Biotechnol. 13(5), 632–650 (2012).Crossref, Medline, CAS, Google Scholar
61. Ramirez-Tagle R, Escobar C, Romero V et al. Chalcone-induced apoptosis through caspase-dependent intrinsic pathways in human hepatocellular carcinoma cells. Int. J. Mol. Sci. 17(2), 260 (2016).Crossref, Medline, Google Scholar
62. Ahmed FF, El-Hafeez AAA, Abbas SH, Abdelhamid D, Abdel-Aziz M. New 1,2,4-triazole-chalcone hybrids induce caspase-3 dependent apoptosis in A549 human lung adenocarcinoma cells. Eur. J. Med. Chem. 151, 705–722 (2018).Crossref, Medline, CAS, Google Scholar

Vol. 12, No. 6

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Received 1 December 2019

Accepted 7 January 2020

Published online 26 February 2020

Published in print March 2020

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To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/doi/suppl/10.4155/fmc-2019-0342

Financial & competing interests disclosure

This work received financial support from National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência) through the projects UID/QUI/50006/2013, UID/Multi/04423/2013, UID/QUI/00062/2019 (QOPNA research unit), Portuguese NMR Network, co-financed by European Union (FEDER under the Partnership Agreement PT2020), and the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (project NORTE-01-0145-FEDER-000024). BH thanks M.E.S.R.S. (Ministère de l’Enseignement Supérieur et de la Recherche Scientifique) and DGRST (Direction Générale de la Recherche Scientifique et Technologique), Algeria for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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