Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors
-
Begüm Nurpelin Sağlık
,
Ahmet Mücahit Şen
Abstract
Inhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.
Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
1. Health N.I.o. NIH Curriculum Supplement Series. Bethesda, MD: National Institutes of Health. Biological Sciences Curriculum Study; 2007.Search in Google Scholar
2. McGuire, A, Brown, JA, Malone, C, McLaughlin, R, Kerin, MJ. Effects of age on the detection and management of breast cancer. Cancers (Basel) 2015;7:908–29. https://doi.org/10.3390/cancers7020815.Search in Google Scholar
3. Bach, DH, Lee, SK. Long noncoding RNAs in cancer cells. Cancer Lett 2018;419:152–66. https://doi.org/10.1016/j.canlet.2018.01.053.Search in Google Scholar
4. She, EX, Hao, Z. A novel piperazine derivative potently induces caspase-dependent apoptosis of cancer cells via inhibition of multiple cancer signaling pathways. Am J Transl Res 2013;5:622–633. Accession Number: WOS:000325391000006 24093059.Search in Google Scholar
5. Hanahan, D, Weinberg, RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. https://doi.org/10.1016/j.cell.2011.02.013.Search in Google Scholar
6. van Mulken, TJM, Schols, RM, Scharmga, AMJ, Winkens, B, Cau, R, Schoenmakers, FBF, et al. First-in-human robotic supermicrosurgery using a dedicated microsurgical robot for treating breast cancer-related lymphedema: a randomized pilot trial. Nat Commun 2020;11:757. https://doi.org/10.1038/s41467-019-14188-w.Search in Google Scholar
7. Lee, HH, Chen, CH, Luo, KH, Chuang, HY, Huang, CJ, Cheng, YK, et al. Five-year survival outcomes of intensity-modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) using forward IMRT or Tomotherapy for breast cancer. Sci Rep 2020;10:4342. https://doi.org/10.1038/s41598-020-61403-6.Search in Google Scholar
8. Wang, Z, Huo, B, Wu, Q, Dong, L, Fu, H, Wang, S, et al. The role of procalcitonin in differential diagnosis between acute radiation pneumonitis and bacterial pneumonia in lung cancer patients receiving thoracic radiotherapy. Sci Rep 2020;10:2941. https://doi.org/10.1038/s41598-020-60063-w.Search in Google Scholar
9. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–1467. https://doi.org/10.1016/S0140-6736(97)11423-4.Search in Google Scholar
10. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717. https://doi.org/10.1016/S0140-6736(05)66544-0.Search in Google Scholar
11. Osmaniye, D, Levent, S, Ardıç, CM, Atlı, Ö, Özkay, Y, Kaplancıklı, ZA. Synthesis and anticancer activity of some novel benzothiazole-thiazolidine derivatives. Phosphorus Sulfur 2017;193:249–56. https://doi.org/10.1080/10426507.2017.1395878.Search in Google Scholar
12. Cutinho, PF, Roy, J, Anand, A, Cheluvaraj, R, Murahari, M, Chimatapu, HSV. Design of metronidazole derivatives and flavonoids as potential non-nucleoside reverse transcriptase inhibitors using combined ligand- and structure-based approaches. J Biomol Struct Dyn 2020;38:1626–48. https://doi.org/10.1080/07391102.2019.1614094.Search in Google Scholar PubMed
13. Daoud, S, Taha, MO. Pharmacophore modeling of JAK1: a target infested with activity-cliffs. J Mol Graph Model 2020;99:107615. https://doi.org/10.1016/j.jmgm.2020.107615.Search in Google Scholar
14. Asati, V, Mahapatra, DK, Bharti, SK. Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: potential anticancer agents. Eur J Med Chem 2014;87:814–33. https://doi.org/10.1016/j.ejmech.2014.10.025.Search in Google Scholar
15. Creelan, BC, Antonia, SJ. Immunotherapy in lung cancer: "b7-bombers" and other new developments. Semin Respir Crit Care Med 2013;34:810–21. https://doi.org/10.1055/s-0033-1358551.Search in Google Scholar
16. Hong, S, Didwania, A, Olopade, O, Ganschow, P. The expanding use of third-generation aromatase inhibitors: what the general internist needs to know. J Gen Intern Med 2009;24 (Suppl 2):S383–8. https://doi.org/10.1007/s11606-009-1037-2.Search in Google Scholar
17. Santen, RJ. Inhibition of aromatase: insights from recent studies. Steroids 2003;68:559–67. https://doi.org/10.1016/s0039-128x(03)00096-5.Search in Google Scholar
18. El-masry, A, Fahmy, H, Ali Abdelwahed, S. Synthesis and antimicrobial activity of some new benzimidazole derivatives. Molecules 2000;5:1429–38. https://doi.org/10.3390/51201429.Search in Google Scholar
19. Sondhi, SM, Singh, N, Kumar, A, Lozach, O, Meijer, L. Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff’s bases. Bioorg Med Chem 2006;14:3758–65. https://doi.org/10.1016/j.bmc.2006.01.054.Search in Google Scholar PubMed
20. Zhu, J, Wu, CF, Li, X, Wu, GS, Xie, S, Hu, QN, et al. Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg Med Chem 2013;21:4218–24. https://doi.org/10.1016/j.bmc.2013.05.001.Search in Google Scholar PubMed
21. Aslam, S, Zaib, S, Ahmad, M, Gardiner, JM, Ahmad, A, Hameed, A, et al. Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors. Eur J Med Chem 2014;78:106–17. https://doi.org/10.1016/j.ejmech.2014.03.035.Search in Google Scholar PubMed
22. Can, OD, Osmaniye, D, Demir Ozkay, U, Saglik, BN, Levent, S, Ilgin, S, et al. MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains. Eur J Med Chem 2017;131:92–106. https://doi.org/10.1016/j.ejmech.2017.03.009.Search in Google Scholar PubMed
23. Zhu, W, Da, Y, Wu, D, Zheng, H, Zhu, L, Wang, L, et al. Design, synthesis and biological evaluation of new 5-nitro benzimidazole derivatives as AT1 antagonists with anti-hypertension activities. Bioorg Med Chem 2014;22:2294–302. https://doi.org/10.1016/j.bmc.2014.02.008.Search in Google Scholar PubMed
24. Narasimhan, B, Sharma, D, Kumar, P. Benzimidazole: a medicinally important heterocyclic moiety. Med Chem Res 2010;21:269–83. https://doi.org/10.1007/s00044-010-9533-9.Search in Google Scholar
25. Bansal, Y, Silakari, O. The therapeutic journey of benzimidazoles: a review. Bioorg Med Chem 2012;20:6208–36. https://doi.org/10.1016/j.bmc.2012.09.013.Search in Google Scholar PubMed
26. Acar Cevik, U, Kaya Cavusoglu, B, Saglik, BN, Osmaniye, D, Levent, S, Ilgin, S, et al. Synthesis, docking studies and biological activity of new benzimidazole- triazolothiadiazine derivatives as aromatase inhibitor. Molecules 2020;25:1642. https://doi.org/10.3390/molecules25071642.Search in Google Scholar PubMed PubMed Central
27. Evren, AE, Yurttas, L, Ekselli, B, Akalin-Ciftci, G. Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents. Phosphorus Sulfur 2019;194:820–8. https://doi.org/10.1080/10426507.2018.1550642.Search in Google Scholar
28. Acar Çevik, U, Osmaniye, D, Kaya Çavuşoğlu, B, Sağlik, BN, Levent, S, Ilgin, S, et al. Synthesis of novel benzimidazole–oxadiazole derivatives as potent anticancer activity. Med Chem Res 2019;28:2252–61. https://doi.org/10.1007/s00044-019-02451-0.Search in Google Scholar
29. Evren, AE, Yurttas, L, Yılmaz-Cankilic, M. Synthesis of novel N-(naphthalen-1-yl)propanamide derivatives and evaluation their antimicrobial activity. Phosphorus Sulfur 2019;195:158–64. https://doi.org/10.1080/10426507.2019.1657428.Search in Google Scholar
30. Acar Cevik, U, Saglik, BN, Osmaniye, D, Levent, S, Kaya Cavusoglu, B, Karaduman, AB, et al. Synthesis and docking study of benzimidazole-triazolothiadiazine hybrids as aromatase inhibitors. Arch Pharm (Weinheim) 2020;353:2000008. https://doi.org/10.1002/ardp.202000008.Search in Google Scholar PubMed
31. Saeed, S, Rashid, N, Jones, PG, Ali, M, Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur J Med Chem 2020;45:1323–31. https://doi.org/10.1016/j.ejmech.2009.12.016.Search in Google Scholar PubMed
32. Duan, YC, Ma, YC, Zhang, E, Shi, XJ, Wang, MM, Ye, XW, et al. Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents. Eur J Med Chem 2013;62:11–9. https://doi.org/10.1016/j.ejmech.2012.12.046.Search in Google Scholar PubMed
33. Kraljevic, TG, Harej, A, Sedic, M, Pavelic, SK, Stepanic, V, Drenjancevic, D, et al. Synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole-coumarin hybrids. Eur J Med Chem 2016;124:794–808. https://doi.org/10.1016/j.ejmech.2016.08.062.Search in Google Scholar
34. Foote, KM, Blades, K, Cronin, A, Fillery, S, Guichard, SS, Hassall, L, et al. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-y l}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem 2013;56:2125–38. https://doi.org/10.1021/jm301859s.Search in Google Scholar
35. Al-Said, MS, Bashandy, MS, Al-Qasoumi, SI, Ghorab, MM. Anti-breast cancer activity of some novel 1,2-dihydropyridine, thiophene and thiazole derivatives. Eur J Med Chem 2011;46:137–41. https://doi.org/10.1016/j.ejmech.2010.10.024.Search in Google Scholar
36. QikProp, version 4.8. New York, NY: Schrödinger, LLC; 2016.Search in Google Scholar
37. Ghosh, D, Griswold, J, Erman, M, Pangborn, W. Structural basis for androgen specificity and oestrogen synthesis in human aromatase. Nature 2009;457:219. https://doi.org/10.1038/nature07614.Search in Google Scholar
38. Maestro, version 10.6. New York, NY: Schrödinger, LLC; 2016.Search in Google Scholar
39. Schrödinger, LLC. New York, NY: Schrödinger, LLC, 2016.Search in Google Scholar
40. LigPrep, version 3.8. New York, NY: Schrödinger, LLC; 2016.Search in Google Scholar
41. Glide, version 7.1. New York, NY: Schrödinger, LLC; 2016.Search in Google Scholar
42. Daina, A, Michielin, O, Zoete, V. iLOGP: a simple, robust and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach, J Chem Inf Model 2014;54:3284–301. https://doi.org/10.1021/ci500467k.Search in Google Scholar
43. Lipinski, CA, Franco, L, Dominy Beryl, W, Feeney Paul, J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3–26. https://doi.org/10.1016/s0169-409x(00)00129-0.Search in Google Scholar
44. Jorgensen, WL, Duffy, EM. Prediction of drug solubility from structure. Adv Drug Deliv Rev 2002;54:355–66. https://doi.org/10.1016/s0169-409x(02)00008-x.Search in Google Scholar
45 Daina, A, Michielin, O, Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci Rep 2017;7:1–13. https://doi.org/10.1038/srep42717.Search in Google Scholar PubMed PubMed Central
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/znc-2020-0104).
© 2020 Walter de Gruyter GmbH, Berlin/Boston
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- Frontmatter
- Historical Research Article
- A tutorial translation of the description of the historically first polymer drug conjugate and its in vivo evaluation
- Research Articles
- The expression and purification of LpxA of Chlamydia trachomatis and preparation of its polyclonal antibody
- Natural antioxidants in emulsions O/W
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- Synthetic cell-permeable caveolin-1 scaffolding domain peptide activates phagocytosis of Escherichia coli by regulating Rab5 activity
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