Synthesis and cytotoxicity evaluation of novel cyclic/non-cyclic N-aryl enamino amides against human cancer cell lines

Shahab Bohlooli , Negin Nejatkhah, Saghi Sepehri, Donya Doostkamel, Nima Razzaghi-Asl

Abstract


Background and purpose: Considering the undesirable consequences of prevalent cancer diseases, design and development of potent and selective anticancer chemotherapeutics is a major concern. Several studies have unraveled the potential of dihydropyrimidinone (DHPM) scaffold toward generating anticancer agents.

Experimental approach: In the present work, a series of new dihydropyrimidinethiones (DHPMTs) along with a few acyclic enamino amides were synthesized and evaluated for their cytotoxic activity against human gastric (AGS), liver (Hep-G2), and breast (MCF-7) cancer cell lines.

Findings/Results: Among the assessed compounds, one of the DHPMT derivatives (compound 5: 4-(3-fluorophenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-ttrahydropyrimidine-5-carboxamide) exhibited superior cytotoxicity in all of the target cell lines (AGS, IC50 9.9 µM; MCF-7, IC50 15.2 µM; and Hep-G2, IC50 40.5 µM). Cytotoxicity assessments showed that non-cyclic enamino amides exhibited weaker activities when compared to cyclic analogues (DHPMs).

Conclusion and implications: DHPMTs were better cytotoxic agents than non-cyclic enamino amides. Structure activity relationship studies guided us toward the design of DHPMT derivatives with OH and NH groups particularly on meta position of 4-phenyl ring and hydrophobic bulky substituents on carboxamide side chain within the structure. Possible interaction with the hydrophobic site(s) of the cellular target was supposed. The results of this study emphasized the potential role of DHPMTs and their optimized derivatives as privileged medicinal scaffolds to inhibit the growth of gastric, breast, and liver cancer cells.

 


Keywords


Keywords: Cancer; Cytotoxicity; Dihydropyrimidinethione; Enamino amide; MTT.

Full Text:

PDF

References


Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.

DOI: 10.1016/j.cell.2011.02.013.

You W, Henneberg M. Cancer incidence increasing globally: the role of relaxed natural selection. Evol Appl. 2017;11(2):140-152.

DOI: 10.1111/eva.12523.

Danaei G, Hoom SV, Lopez AD, Murray CJL, Ezzati M. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366(9499):1784-1793.

DOI: 10.1016/S0140-6736(05)67725-2.

Wainberg ZA, Anghel A, Desai AJ, Ayala R, Luo T, Safran B, et al. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res. 2010;16(5):1509-1519.

DOI: 10.1158/1078-0432.CCR-09-1112.

Matos LHS, Masson FT, Simeoni LA, Homem-de-Mello M. Biological activity of dihydropyrimidinone (DHPM) derivatives: a systematic review. Eur J Med Chem. 2018;143:1779-1789.

DOI: 10.1016/j.ejmech.2017.10.073.

Rawoof AN, Muzzaffar AM, Samiullah B, Radha T, Rayees AB, Manzoor AM. Biological activities and synthetic approaches of dihydropyrimidinones and thiones-an updated review. Curr Bioact Compd. 2016;12(4):236-250.

DOI: 10.2174/15734072126661605171500.

Soumyanarayanan U, Bhat VG, Kar SS, Mathew JA. Monastrol mimic Biginelli dihydropyrimidinone derivatives: synthesis, cytotoxicity screening against HepG2 and HeLa cell lines and molecular modeling study. Org Med Chem Lett. 2012;2(1):23-33.

DOI: 10.1186/2191-2858-2-23.

Prashantha Kumar BR, Masih P, Karthikeyan E, Bansal A, Vijayan S, Vijayan P. Synthesis of novel Hantzsch dihydropyridines and Biginelli dihydropyrimidines of biological interest: a 3D-QSAR study on their cytotoxicity. Med Chem Res. 2010;19:344-363.

DOI: 10.1007/s00044-009-9195-7.

Manos-Turvey A, Al-Ashtal HA, Needham PG, Hartline CB, Prichard MN, Wipf P, et al. Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members. Bioorg Med Chem Lett. 2016;26(20):5087-5091.

DOI: 10.1016/j.bmcl.2016.08.080.

Udayakumar V, GowsikaJ, Pandurangan A. A novel synthesis and preliminary in vitro cytotoxic evaluation of dihydropyrimidine-2,4(1H,3H)-dione derivatives. J Chem Sci. 2017;129(2):249-258.

DOI: 10.1007/s12039-017-1223-4.

Lal J, Gupta SK, Thavaselvam D, Agarwal DD. Design, synthesis, synergistic antimicrobial activity and cytotoxicity of 4-aryl substituted 3,4-dihydropyrimidinones of curcumin. Bioorg Med Chem Lett. 2012;22(8):2872-2876.

DOI: 10.1016/j.bmcl.2012.02.056.

Razzaghi-Asl N, Kamrani-Moghadam M, Farhangi B, Vahabpour R, Zabihollahi R, Sepehri S. Design, synthesis and evaluation of cytotoxic, antimicrobial, and anti-HIV-1 activities of new 1,2,3,4-tetrahydropyrimidine derivatives. Res Pharm Sci. 2019;14(2):155-166.

DOI: 10.4103/1735-5362.253363.

Miri R, Firuzi O, Razzaghi-Asl N, Javidnia K, Edraki N. Inhibitors of Alzheimer's BACE-1 with 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structure. Arch Pharm Res. 2015;38(4):456-469.

DOI:10.1007/s12272-014-0401-x.

Tavangar S, Bohlooli S, Razzaghi-Asl N, Synthesis and cytotoxic effect of a few N-heteroaryl enamino amides and dihydropyrimidinethiones on AGS and MCF-7 human cancer cell lines. Res Pharm Sci. 2020;15(2):154-163.

DOI: 10.4103/1735-5362.283815

Razzaghi-Asl N, Miri R, Firuzi O. Assessment of the cytotoxic effect of a series of 1,4-dihydropyridine derivatives against human cancer cells. Iran J Pharm Res. 2016;15(3):413-420.

Russowsky D, Canto RMF, Sanches SA, D’Oca MG, de Fátima Â, Pilli RA, et al. Synthesis and differential antiproliferative activity of Biginelli compounds against cancer cell lines: monastrol, oxo-monastrol and oxygenated analogues. Bioorg Chem. 2006;34(4):173-182.

DOI: 10.1016/j.bioorg.2006.04.003.

Kaan HY, Ulaganathan V, Rath O, Prokopcova H, Dallinger D, Kappe CO, et al. Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol. J Med Chem. 2010;53(15):5676-5683.

DOI: 10.1021/jm100421n.

Bidram Z, Sirous H, Khodarahmi GA, Hassanzadeh F, Dana N, Hariri AA, et al. Monastrol derivatives: in silico and in vitro cytotoxicity assessments. Res Pharm Sci. 2020;15(3):249-262.

DOI: 10.4103/1735-5362.288427

Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuery P, et al. Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. J Biol Chem. 2007;282(13):9740-9747.

DOI: 10.1074/jbc.M608883200.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.