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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Novel 2-pyridone Analogs with Anti-cancer Activity: Synthesis, In silico, and In vitro Evaluation

Author(s): Prem Shankar Mishra*, Velayutham Ravichandiran* and Rakhi Mishra

Volume 21, Issue 7, 2024

Published on: 20 March, 2023

Page: [1195 - 1207] Pages: 13

DOI: 10.2174/1570180820666230223113234

Price: $65

Abstract

Background: 2-pyridone is frequently used to synthesize and develop new bioactive molecules approved for treating many diseases. The produced compounds play a significant role in inhibiting cancer growth.

Objective: Through a molecular docking investigation, we determined the binding affinity of 2-pyridone compounds with the Matrix Metalloproteinase receptor, which allowed us to develop, produce, and test the in vitro anticancer efficacy of those compounds.

Methods: 2-pyridones (A1-A12) were synthesized in a multistep process, followed by spectrum analysis to confirm the structure. In silico screening of the synthesized compounds was carried out with the assistance of AutoDock software. Flow cytometry was used on the HT-29 colon cancer cell line to measure A1-A12’s anticancer effect in a lab setting.

Results: The enzyme matrix metalloproteinase receptor and A1-A12 interacted unexpectedly during a docking study (MMP3, MMP9 & MMP13). Research has shown a strong affinity for MMP3 receptors for A9, A10, A11, A12, and A4, respectively. Further flow cytometric testing revealed compound A9 (R1) to be highly cytotoxic, with an IC50 value of 20.77 M. The anticancer activity of A9 (R1) against HT-29 colon cancer cell lines was also confirmed by in vitro results.

Conclusion: These findings suggested that 2-pyridone compounds have promising therapeutic potential for cancer treatment, and more research on these lead moieties would be advantageous to discovering an effective anticancer drug.

Keywords: 2-pyridones, molecular modelling, matrix metalloproteinase, HT-29 cell line, flow cytometric assay, CRC.

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[1]
Dekker, E.; Tanis, P.J.; Vleugels, J.L.A.; Kasi, P.M.; Wallace, M.B. Colorectal cancer. Lancet, 2019, 394(10207), 1467-1480.
[http://dx.doi.org/10.1016/S0140-6736(19)32319-0] [PMID: 31631858]
[2]
Kuipers, E.J.; Grady, W.M.; Lieberman, D.; Seufferlein, T.; Sung, J.J.; Boelens, P.G.; van de Velde, C.J.H.; Watanabe, T. Colorectal cancer. Nat. Rev. Dis. Primers, 2015, 1(1), 15065.
[http://dx.doi.org/10.1038/nrdp.2015.65] [PMID: 27189416]
[3]
Mármol, I.; Sánchez-de-Diego, C.; Pradilla Dieste, A.; Cerrada, E.; Rodriguez Yoldi, M. Colorectal Carcinoma: A general overview and future perspectives in colorectal cancer. Int. J. Mol. Sci., 2017, 18(1), 197.
[http://dx.doi.org/10.3390/ijms18010197] [PMID: 28106826]
[4]
Schmitt, M.; Greten, F.R. The inflammatory pathogenesis of colorectal cancer. Nat. Rev. Immunol., 2021, 21(10), 653-667.
[http://dx.doi.org/10.1038/s41577-021-00534-x] [PMID: 33911231]
[5]
Cagan, R.; Meyer, P. Rethinking cancer: current challenges and opportunities in cancer research. Dis. Model. Mech., 2017, 10(4), 349-352.
[http://dx.doi.org/10.1242/dmm.030007] [PMID: 28381596]
[6]
Shelley, M.G. World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer. Adv. Nutr., 2016, 7(2), 418-419.
[http://dx.doi.org/10.3945/an.116.012211] [PMID: 26980827]
[7]
Lv, Z.; Zhang, Y.; Zhang, M.; Chen, H.; Sun, Z.; Geng, D.; Niu, C.; Li, K. Design and synthesis of novel 2′-hydroxy group substituted 2-pyridone derivatives as anticancer agents. Eur. J. Med. Chem., 2013, 67, 447-453.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.046] [PMID: 23920246]
[8]
Cocco, M.T.; Congiu, C.; Onnis, V. Synthesis and antitumour activity of 4-hydroxy-2-pyridone derivatives. Eur. J. Med. Chem., 2000, 35(5), 545-552.
[http://dx.doi.org/10.1016/S0223-5234(00)00149-5] [PMID: 10889333]
[9]
Guo, L.; Luo, X.; Yang, P.; Zhang, Y.; Huang, J.; Wang, H.; Guo, Y.; Huang, W.; Chen, Z.; Wang, S.; Wang, J.; Lei, J.; Xiang, S.; Liu, Y. Ilicicolin A exerts antitumor effect in castration-resistant prostate cancer via suppressing EZH2 signaling pathway. Front. Pharmacol., 2021, 12723729
[http://dx.doi.org/10.3389/fphar.2021.723729] [PMID: 34776951]
[10]
Williams, D.R.; Bremmer, M.L.; Brown, D.L.; D’Antuono, J. Total synthesis of (.+-.)-ilicicolin H. J. Org. Chem., 1985, 50(15), 2807-2809.
[http://dx.doi.org/10.1021/jo00215a053]
[11]
Lin, X.; Yuan, S.; Chen, S.; Chen, B.; Xu, H.; Liu, L.; Li, H.; Gao, Z. Heterologous expression of Ilicicolin H biosynthetic gene cluster and production of a new potent antifungal reagent. Ilicicolin J. Molecules, 2019, 24(12), 2267.
[http://dx.doi.org/10.3390/molecules24122267] [PMID: 31216742]
[12]
Ward, A.; Brogden, R.N.; Heel, R.C.; Speight, T.M.; Avery, G.S. Amrinone. A preliminary review of its pharmacological properties and therapeutic use. Drugs, 1983, 26(6), 468-502.
[http://dx.doi.org/10.2165/00003495-198326060-00002] [PMID: 6360634]
[13]
Endoh, M. Amrinone, forerunner of novel cardiotonic agents, caused paradigm shift of heart failure pharmacotherapy. Circ. Res., 2013, 113(4), 358-361.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.301689] [PMID: 23908328]
[14]
Young, R.A.; Ward, A. Milrinone. Drugs, 1988, 36(2), 158-192.
[http://dx.doi.org/10.2165/00003495-198836020-00003] [PMID: 3053125]
[15]
Colucci, W.S. Cardiovascular effects of milrinone. Am. Heart J., 1991, 121(6), 1945-1947.
[http://dx.doi.org/10.1016/0002-8703(91)90829-7] [PMID: 2035424]
[16]
Tang, X.; Liu, P.; Li, R.; Jing, Q.; Lv, J.; Liu, L.; Liu, Y. Milrinone for the treatment of acute heart failure after acute myocardial infarction: A systematic review and meta-analysis. Basic Clin. Pharmacol. Toxicol., 2015, 117(3), 186-194.
[http://dx.doi.org/10.1111/bcpt.12385] [PMID: 25625413]
[17]
Bishop, J.R.; Pavuluri, M.N. Review of risperidone for the treatment of pediatric and adolescent bipolar disorder and schizophrenia. Neuropsychiatr. Dis. Treat., 2008, 4(1), 55-68.
[PMID: 18728804]
[18]
Forrestall, K.L.; Burley, D.E.; Cash, M.K.; Pottie, I.R.; Darvesh, S. 2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease. Chem. Biol. Interact., 2021, 335109348
[http://dx.doi.org/10.1016/j.cbi.2020.109348] [PMID: 33278462]
[19]
Davis, S.; Rafia, R.; Carroll, C.; Hamilton, J.; Essat, M. Pirfenidone for treating idiopathic pulmonary fibrosis: An evidence review group perspective of a nice single technology appraisal. PharmacoEconomics, 2019, 37(6), 763-775.
[http://dx.doi.org/10.1007/s40273-018-0727-1] [PMID: 30345464]
[20]
Kim, E.S.; Keating, G.M. Pirfenidone: a review of its use in idiopathic pulmonary fibrosis. Drugs, 2015, 75(2), 219-230.
[http://dx.doi.org/10.1007/s40265-015-0350-9] [PMID: 25604027]
[21]
Finnerty, J.P.; Ponnuswamy, A.; Dutta, P.; Abdelaziz, A.; Kamil, H. Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis. BMC Pulm. Med., 2021, 21(1), 411.
[http://dx.doi.org/10.1186/s12890-021-01783-1] [PMID: 34895203]
[22]
Kim, E.S.; Scott, L.J. Palbociclib: A review in HR-positive, her2-negative, advanced or metastatic breast cancer. Target. Oncol., 2017, 12(3), 373-383.
[http://dx.doi.org/10.1007/s11523-017-0492-7] [PMID: 28488183]
[23]
Singh, S.B.; Liu, W.; Li, X.; Chen, T.; Shafiee, A.; Card, D.; Abruzzo, G.; Flattery, A.; Gill, C.; Thompson, J.R.; Rosenbach, M.; Dreikorn, S.; Hornak, V.; Meinz, M.; Kurtz, M.; Kelly, R.; Onishi, J.C. Antifungal spectrum, in vivo efficacy, and structure-activity relationship of ilicicolin h. ACS Med. Chem. Lett., 2012, 3(10), 814-817.
[http://dx.doi.org/10.1021/ml300173e] [PMID: 24900384]
[24]
Darden, C.; Mitra, D.; McSorley, D.; Davis, K.; Band, J.; Iyer, S. Treatment satisfaction in women receiving palbociclib combination therapies for advanced/metastatic breast cancer. Future Oncol., 2019, 15(2), 141-150.
[http://dx.doi.org/10.2217/fon-2018-0531] [PMID: 30207163]
[25]
Garnock-Jones, K.P. Brexpiprazole: A Review in Schizophrenia. CNS Drugs, 2016, 30(4), 335-342.
[http://dx.doi.org/10.1007/s40263-016-0325-8] [PMID: 27023789]
[26]
Frampton, J.E. Brexpiprazole: A Review in Schizophrenia. Drugs, 2019, 79(2), 189-200.
[http://dx.doi.org/10.1007/s40265-019-1052-5] [PMID: 30671869]
[27]
McEvoy, J.; Citrome, L. Brexpiprazole for the Treatment of Schizophrenia: A review of this novel serotonin-dopamine activity modulator. Clin. Schizophr. Relat. Psychoses, 2016, 9(4), 177-186.
[http://dx.doi.org/10.3371/CSRP.MCCI.010316] [PMID: 26757416]
[28]
Ming, T.L.; Meizhen, F.; Min, X.; Winnie, N.; Tracy, L.; Diamond, J.A.; Grobler, D.J. Doravirine and Islatravir have complementary resistance profiles and create a combination with a high barrier to resistance. Antimicrob. Agents Chemother., 2016, 60(4), 02650-15.
[29]
Bleasby, K.; Fillgrove, K.L.; Houle, R.; Lu, B.; Palamanda, J.; Newton, D.J.; Lin, M.; Chan, G.H.; Sanchez, R.I. In vitro evaluation of the drug interaction potential of Doravirine. Antimicrob. Agents Chemother., 2019, 63(4), e02492-e18.
[http://dx.doi.org/10.1128/AAC.02492-18] [PMID: 30745395]
[30]
Hagimori, M.; Nishimura, Y.; Mizuyama, N.; Shigemitsu, Y. Synthesis, photophysical evaluation, and computational study of 2-methoxy- and 2-morpholino pyridine compounds as highly emissive fluorophores in solution and the solid state. Dyes Pigments, 2019, 171107705
[http://dx.doi.org/10.1016/j.dyepig.2019.107705]
[31]
Tokito, A.; Jougasaki, M. Matrix metalloproteinases in non-neoplastic disorders. Int. J. Mol. Sci., 2016, 17(7), 1178.
[http://dx.doi.org/10.3390/ijms17071178] [PMID: 27455234]
[32]
Benjamin, M.M.; Khalil, R.A. Matrix metalloproteinase inhibitors as investigative tools in the pathogenesis and management of vascular disease. EXS, 2012, 103, 209-279.
[http://dx.doi.org/10.1007/978-3-0348-0364-9_7] [PMID: 22642194]
[33]
Lausch, E.; Keppler, R.; Hilbert, K.; Cormier-Daire, V.; Nikkel, S.; Nishimura, G.; Unger, S.; Spranger, J.; Superti-Furga, A.; Zabel, B. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am. J. Hum. Genet., 2009, 85(2), 168-178.
[http://dx.doi.org/10.1016/j.ajhg.2009.06.014] [PMID: 19615667]
[34]
Pezeshkian, Z.; Nobili, S.; Peyravian, N.; Shojaee, B.; Nazari, H.; Soleimani, H.; Asadzadeh-Aghdaei, H.; Ashrafian Bonab, M.; Nazemalhosseini-Mojarad, E.; Mini, E. Insights into the role of matrix metalloproteinases in precancerous conditions and in colorectal cancer. Cancers (Basel), 2021, 13(24), 6226.
[http://dx.doi.org/10.3390/cancers13246226] [PMID: 34944846]
[35]
Neha, M.; Gayathri, C.; Ganji, P.N. Role of matrix metalloproteinases in colorectal cancer; theragnostic approaches to gastric and colon cancer. Cancer, 2020, 4, 49-59.
[36]
Liu, J.; Khalil, R.A. Matrix metalloproteinase inhibitors as investigational and therapeutic tools in unrestrained tissue remodeling and pathological disorders. Prog. Mol. Biol. Transl. Sci., 2017, 148, 355-420.
[http://dx.doi.org/10.1016/bs.pmbts.2017.04.003] [PMID: 28662828]
[37]
Mottaghi, S.; Abbaszadeh, H. Natural lignans honokiol and magnolol as potential anticarcinogenic and anticancer agents. A comprehensive mechanistic review. Nutr. Cancer, 2022, 74(3), 761-778.
[http://dx.doi.org/10.1080/01635581.2021.1931364] [PMID: 34047218]
[38]
Young, K.K.; Seung, C.L.; Dong, W.K.; Mankil, J.; Dae, W. Kim. A new and facile synthesis of 2-pyridones. Bull. Korean Chem. Soc., 2001, 22(2), 234-236.
[39]
Ekins, S.; Mestres, J.; Testa, B. In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling. Br. J. Pharmacol., 2007, 152(1), 9-20.
[http://dx.doi.org/10.1038/sj.bjp.0707305] [PMID: 17549047]
[40]
van Meerloo, J.; Kaspers, G.J.L.; Cloos, J. Cell sensitivity assays: the MTT assay. Methods Mol. Biol., 2011, 731(31), 237-245.
[http://dx.doi.org/10.1007/978-1-61779-080-5_20] [PMID: 21516412]
[41]
Dikalov, S.I.; Harrison, D.G. Methods for detection of mitochondrial and cellular reactive oxygen species. Antioxid. Redox Signal., 2014, 20(2), 372-382.
[http://dx.doi.org/10.1089/ars.2012.4886] [PMID: 22978713]
[42]
Zhu, H.; Tang, L.; Zhang, C.; Wei, B.; Yang, P.; He, D.; Zheng, L.; Zhang, Y. Synthesis of Chalcone derivatives: Inducing apoptosis of hepg2 cells via regulating reactive oxygen species and mitochondrial pathway. Front. Pharmacol., 2019, 10, 1341.
[http://dx.doi.org/10.3389/fphar.2019.01341]
[43]
Farzane, S.; Aditya, B.; Luca, C. Analysis of the mitochondrial membrane potential using the cationic jc-1 dye as a sensitive fluorescent probe. Bio Protoc., 2019, 9(1)e3128
[44]
Rieger, A.M.; Nelson, K.L.; Konowalchuk, J.D.; Barreda, D.R. Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. J. Vis. Exp., 2011, 24(50), 2597.
[http://dx.doi.org/10.3791/2597] [PMID: 21540825]
[45]
Zhang, Y.; Zhang, Q.; Bao, J.; Huang, J.; Zhang, H. Apiosporamide, A., 4-hydroxy-2-pyridone alkaloid, induces apoptosis via PI3k/AKT signaling pathway in osteosarcoma cells. OncoTargets Ther., 2019, 12, 8611-8620.
[http://dx.doi.org/10.2147/OTT.S218692] [PMID: 31695421]
[46]
Otto, T.; Sicinski, P. Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer, 2017, 17(2), 93-115.
[http://dx.doi.org/10.1038/nrc.2016.138] [PMID: 28127048]
[47]
Darzynkiewicz, Z. Critical aspects in analysis of cellular DNA content. Curr. Protoc. Cytom., 2011, 56(7)
[http://dx.doi.org/10.1002/0471142956.cy0702s56]

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