Novel Quinoline Nitrate Derivatives: Synthesis, Characterization, and Evaluation of their Anticancer Activity with a Focus on Molecular Docking and NO Release


Дәйексөз келтіру

Толық мәтін

Аннотация

Background:Nitric Oxide (NO) has recently gained recognition as a promising approach in the field of cancer therapy. The quinoline scaffold is pivotal in cancer drug research and is known for its versatility and diverse mechanisms of action.

Objective:This study presents the synthesis, characterization, and evaluation of novel quinoline nitrate derivatives as potential anticancer agents.

Methods:The compounds were synthesized through a multi-step process involving the preparation of substituted 1-(2-aminophenyl) ethan-1-one, followed by the synthesis of substituted 2- (chloromethyl)-3,4-dimethylquinolines, and finally, the formation of substituted (3,4- dimethylquinolin-2-yl) methyl nitrate derivatives. The synthesized compounds were characterized using various spectroscopic techniques. Molecular docking studies were conducted to assess the binding affinity of the compounds to the EGFR tyrosine kinase domain.

Results:The docking scores revealed varying degrees of binding affinity, with compound 6k exhibiting the highest score. The results suggested a correlation between molecular docking scores and anticancer activity. Further evaluations included MTT assays to determine the cytotoxicity of the compounds against Non-Small Cell Lung Cancer (A-549) and pancreatic cancer (PANC-1) cell lines. Compounds with electron-donating groups displayed notable anticancer potential, and there was a correlation between NO release and anticancer activity. The study also investigated nitric oxide release from the compounds, revealing compound 6g as the highest NO releaser.

Conclusion:The synthesized quinoline nitrate derivatives showed promising anticancer activity, with compound 6g standing out as a potential lead compound. The correlation between molecular docking, NO release, and anticancer activity suggests the importance of specific structural features in the design of effective anticancer agents.

Авторлар туралы

Venkata Thanneeru

Department of Pharmaceutical Chemistry, GITAM Deemed to be University

Email: info@benthamscience.net

Naresh Panigrahi

Department of Pharmaceutical Chemistry, GITAM Deemed to be University

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Әдебиет тізімі

  1. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin., 2023, 73(1), 17-48. doi: 10.3322/caac.21763 PMID: 36633525
  2. Tilsed, C.M.; Fisher, S.A.; Nowak, A.K.; Lake, R.A.; Lesterhuis, W. J. Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action. Front. Oncol., 2022, 12, 960317. doi: 10.3389/fonc.2022.960317 PMID: 35965519
  3. Mintz, J.; Vedenko, A.; Rosete, O.; Shah, K.; Goldstein, G.; Hare, J.M.; Ramasamy, R.; Arora, H. Current advances of nitric oxide in cancer and anticancer therapeutics. Vaccines (Basel), 2021, 9(2), 94. doi: 10.3390/vaccines9020094 PMID: 33513777
  4. Sinha, B.K. Can nitric oxide-based therapy be improved for the treatment of cancers? A perspective. Int. J. Mol. Sci., 2023, 24(17), 13611. doi: 10.3390/ijms241713611 PMID: 37686417
  5. Pieretti, J.C.; Pelegrino, M.T.; Nascimento, M.H.M.; Tortella, G.R.; Rubilar, O.; Seabra, A.B. Small molecules for great solutions: Can nitric oxide-releasing nanomaterials overcome drug resistance in chemotherapy? Biochem. Pharmacol., 2020, 176, 113740. doi: 10.1016/j.bcp.2019.113740 PMID: 31786262
  6. Hidmi, A.; Alzahayqa, M.; Erikat, S.; Bahar, R.; Hindi, L.; Al-Maharik, N.; Salah, Z. Nitric oxide-releasing NO–curcumin hybrid inhibits colon cancer cell proliferation and induces cell death in vitro. Processes (Basel), 2022, 10(5), 800. doi: 10.3390/pr10050800
  7. Morbidelli, L.; Donnini, S.; Ziche, M. Role of Nitric Oxide in Tumor Angiogenesis. Angiogenesis in Brain Tumors; Kirsch, M.; Black, P.McL., Eds.; Springer US, 2004, Vol. 117, pp. 155-167. doi: 10.1007/978-1-4419-8871-3_11
  8. Wink, D.A.; Hines, H.B.; Cheng, R.Y.S.; Switzer, C.H.; Flores-Santana, W.; Vitek, M.P.; Ridnour, L.A.; Colton, C.A. Nitric oxide and redox mechanisms in the immune response. J. Leukoc. Biol., 2011, 89(6), 873-891. doi: 10.1189/jlb.1010550 PMID: 21233414
  9. Li, C.Y.; Anuraga, G.; Chang, C.P.; Weng, T.Y.; Hsu, H.P.; Ta, H.D.K.; Su, P.F.; Chiu, P.H.; Yang, S.J.; Chen, F.W.; Ye, P.H.; Wang, C.Y.; Lai, M.D. Repurposing nitric oxide donating drugs in cancer therapy through immune modulation. J. Exp. Clin. Cancer Res., 2023, 42(1), 22. doi: 10.1186/s13046-022-02590-0 PMID: 36639681
  10. Huang, Z.; Fu, J.; Zhang, Y. Nitric oxide donor-based cancer therapy: Advances and prospects. J. Med. Chem., 2017, 60(18), 7617-7635. doi: 10.1021/acs.jmedchem.6b01672 PMID: 28505442
  11. Li, H.T.; Zhu, X. Quinoline-based compounds with potential activity against drugresistant cancers. Curr. Top. Med. Chem., 2021, 21(5), 426-437. doi: 10.2174/18734294MTA3pNDMx4 PMID: 32552650
  12. Ayala-Aguilera, C.C.; Valero, T.; Lorente-Macías, Á.; Baillache, D.J.; Croke, S.; Unciti-Broceta, A. Small molecule kinase inhibitor drugs (1995–2021): medical indication, pharmacology, and synthesis. J. Med. Chem., 2022, 65(2), 1047-1131. doi: 10.1021/acs.jmedchem.1c00963 PMID: 34624192
  13. Martorana, A.; La Monica, G.; Lauria, A. Quinoline-based molecules targeting c-Met, EGF, and VEGF receptors and the proteins involved in related carcinogenic pathways. Molecules, 2020, 25(18), 4279. doi: 10.3390/molecules25184279 PMID: 32961977
  14. El-Fakharany, Z.S.; Nissan, Y.M.; Sedky, N.K.; Arafa, R.K.; Abou-Seri, S.M. New proapoptotic chemotherapeutic agents based on the quinolone-3-carboxamide scaffold acting by VEGFR-2 inhibition. Sci. Rep., 2023, 13(1), 11346. doi: 10.1038/s41598-023-38264-w PMID: 37443185
  15. Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L.; Mardis, E.; Kupfer, D.; Wilson, R.; Kris, M.; Varmus, H. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. USA, 2004, 101(36), 13306-13311. doi: 10.1073/pnas.0405220101 PMID: 15329413
  16. Vincent, A.; Herman, J.; Schulick, R.; Hruban, R.H.; Goggins, M. Pancreatic cancer. Lancet, 2011, 378(9791), 607-620. doi: 10.1016/S0140-6736(10)62307-0 PMID: 21620466
  17. Zong, Y.; Pegram, M.D. Anti–epidermal growth factor receptor monoclonal antibodies in triple-negative breast cancer. Cancer J., 2013, 19(1), 56-62.
  18. Mendelsohn, J.; Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene, 2000, 19(56), 6550-6565. doi: 10.1038/sj.onc.1204082 PMID: 11426640
  19. Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. Aminohaloborane in organic synthesis. 1. Specific ortho substitution reaction of anilines. J. Am. Chem. Soc., 1978, 100(15), 4842-4852. doi: 10.1021/ja00483a034
  20. Tverdokhlebov, A.; Degtyarenko, A.; Tolmachev, A.; Volovenko, Y. Chlorotrimethylsilane-mediated friedländer synthesis of 2-(α-chloroalkyl)quinoline derivatives. Synthesis, 2007, 2007(24), 3891-3895. doi: 10.1055/s-2007-990869
  21. Fotopoulou, T.; Iliodromitis, E.K.; Koufaki, M.; Tsotinis, A.; Zoga, A.; Gizas, V.; Pyriochou, A.; Papapetropoulos, A.; Andreadou, I.; Kremastinos, D.T. Design and synthesis of nitrate esters of aromatic heterocyclic compounds as pharmacological preconditioning agents. Bioorg. Med. Chem., 2008, 16(8), 4523-4531. doi: 10.1016/j.bmc.2008.02.051 PMID: 18328715
  22. Park, J.H.; Liu, Y.; Lemmon, M.A.; Radhakrishnan, R. Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem. J., 2012, 448(3), 417-423. doi: 10.1042/BJ20121513 PMID: 23101586
  23. Pattar, S.V.; Adhoni, S.A.; Kamanavalli, C.M.; Kumbar, S.S. In silico molecular docking studies and MM/GBSA analysis of coumarin-carbonodithioate hybrid derivatives divulge the anticancer potential against breast cancer. Beni. Suef Univ. J. Basic Appl. Sci., 2020, 9(1), 36. doi: 10.1186/s43088-020-00059-7
  24. Tolosa, L.; Donato, M.T.; Gómez-Lechón, M.J. General cytotoxicity assessment by means of the MTT assay. Methods Mol. Biol., 2015, 1250, 333-348.
  25. Ling, Y.; Ye, X.; Ji, H.; Zhang, Y.; Lai, Y.; Peng, S.; Tian, J. Synthesis and evaluation of nitric oxide-releasing derivatives of farnesylthiosalicylic acid as anti-tumor agents. Bioorg. Med. Chem., 2010, 18(10), 3448-3456. doi: 10.1016/j.bmc.2010.03.077 PMID: 20435479
  26. Iglesias, E.; Casado, J. Mechanisms of hydrolysis and nitrosation reactions of alkyl nitrites in various media. Int. Rev. Phys. Chem., 2002, 21(1), 37-74. doi: 10.1080/01442350110092693
  27. Oae, S.; Asai, N.; Fujimori, K. Alkaline hydrolyses of alkyl nitrites and related carboxylic esters. J. Chem. Soc., Perkin Trans., 1978, 2, 571-577. doi: 10.1039/p29780000571
  28. Durchschein, K.; Hall, M.; Faber, K. Unusual reactions mediated by FMN-dependent ene- and nitro-reductases. Green Chem., 2013, 15(7), 1764. doi: 10.1039/c3gc40588e

Қосымша файлдар

Қосымша файлдар
Әрекет
1. JATS XML
Жүктеу

© Bentham Science Publishers, 2025