DESIGN, SYNTHESIS, ANTI-CANCER ACTIVITY, AND MOLECULAR DOCKING STUDIES OF LIGNIN-PYRROLE DERIVATIVES AS A JAK3 INHIBITOR
DOI:
https://doi.org/10.22159/ajpcr.2024v17i12.52831Keywords:
Regioselective, Pyrrole, Anti-cancer, HeLa, Molecular docking.Abstract
Objectives: The aim of the study was to predict the interaction patterns between poly (ADP-ribose) polymerase (PARP), vascular endothelial growth factor receptor (VEGFR1), and Janus kinase 3 (JAK3) with lignin-pyrrole derivatives using molecular docking studies. In vitro anti-cancer activity of lignin-pyrrole derivatives on HeLa cells.
Methods: The key proteins such as PARP, Rad18, VEGFR1, JAK3, alpha-beta tubulin, SarA, Rad6, VEGFR2, leukocyte type core 2 beta 1, 6-N-acetylglucosaminyltransferase,and epidermal growth factor receptor kinase domain were retrieved from the protein data bank. The effect of compounds on cell proliferation of HeLa cells was determined by MTT assay. The cell was treated with or without compound and was incubated for 48 h.
Results: The cytotoxicity assay was performed for the initial screening of lignin-pyrrole derivatives. Among the tested molecules, compound 4b emerged to be potent against HeLa cells at lower concentrations.
Conclusion: Molecular docking studies revealed that the screened compounds are found to be good PARP, VEGFR1, and JAK3 inhibitors. In vitro screening proved that the compounds can be good antiproliferative agents.
Downloads
References
Vartak SV, Swarup HA, Gopalakrishnan V, Gopinatha VK, Ropars V, Nambiar M, et al. Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner. FEBS J. 2018;285(21):3959-76. doi: 10.1111/febs.14661, PMID 30230716
Ashrafizadeh M, Aghamiri S, Tan SC, Zarrabi A, Sharifi E, Rabiee N, et al. Nanotechnological approaches in prostate cancer therapy: Integration of engineering and biology. Nano Today. 2022;45:101532. doi: 10.1016/j.nantod.2022.101532
Sharath Kumar KS, Hanumappa A, Vetrivel M, Hegde M, Girish YR, Byregowda TR, et al. Antiproliferative and tumor inhibitory studies of 2,3 disubstituted 4-thiazolidinone derivatives. Bioorg Med Chem Lett. 2015;25(17):3616-20. doi: 10.1016/j.bmcl.2015.06.069, PMID 26152430
Sharath Kumar KS, Hanumappa A, Hegde M, Narasimhamurthy KH, Raghavan SC, Rangappa KS. Synthesis and antiproliferative effect of novel 4-thiazolidinone-, pyridine- and piperazine-based conjugates on human leukemic cells. Eur J Med Chem. 2014;81:341- 9. doi: 10.1016/j.ejmech.2014.05.009, PMID 24852281
Hegde M, Sharath Kumar KS, Thomas E, Ananda H, Raghavan SC, Rangappa KS. A novel benzimidazole derivative binds to the DNA minor groove and induces apoptosis in leukemic cells. RSC Adv. 2015;5(113):93194-208. doi: 10.1039/C5RA16605E
Mirzaei S, Gholami MH, Hashemi F, Zabolian A, Hushmandi K, Rahmanian V, et al. Employing siRNA tool and its delivery platforms in suppressing cisplatin resistance: approaching to a new era of cancer chemotherapy. Life Sci. 2021;277:119430. doi: 10.1016/j.lfs.2021.119430, PMID 33789144
Puneeth HR, Ananda H, Kumar KS, Rangappa KS, Sharada AC. Synthesis and antiproliferative studies of curcumin pyrazole derivatives. Med Chem Res. 2016;25(9):1842-51. doi: 10.1007/s00044-016-1628-5
Ananda H, Sharath Kumar KS, Nishana M, Hegde M, Srivastava M, Byregowda R, et al. Regioselective synthesis and biological studies of novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives as potential antiproliferative agents. Mol Cell Biochem. 2017;426(1-2):149-60. doi: 10.1007/s11010-016-2887-7, PMID 27882441
Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, et al. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005;167(4):969- 80. doi: 10.1016/S0002-9440(10)61187-X, PMID 16192633
Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2(12):1097-105. doi: 10.1177/1947601911423031, PMID 22866201
Chen A. PARP inhibitors: Its role in treatment of cancer. Chin J Cancer. 2011;30(7):463-71. doi: 10.5732/cjc.011.10111, PMID 21718592
Jagadish S, Hemshekhar M, NaveenKumar SK, Sharath KumarKS, Sundaram MS, Basappa GK, et al. Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress. Toxicol Appl Pharmacol. 2017;334:167-79. doi: 10.1016/j.taap.2017.09.008, PMID 28911973
Ananda H, Sharath Kumar KS, Sudhanva MS, Rangappa S, Rangappa KS. A trisubstituted pyrazole derivative reduces DMBA-induced mammary tumor growth in rats by inhibiting estrogen receptor-α expression. Mol Cell Biochem. 2018;449(1-2):137-44. doi: 10.1007/s11010-018-3350-8, PMID 29777335
Ananda H, Kumar KS, Hegde M, Rangappa KS. Induction of apoptosis and downregulation of ERα in DMBA-induced mammary gland tumors in Sprague-Dawley rats by synthetic 3,5-disubstituted isoxazole derivatives. Mol Cell Biochem. 2016;420(1-2):141-50. doi: 10.1007/s11010-016-2777-z, PMID 27473146
Jagadish S, Rajeev N, NaveenKumar SK, Sharath Kumar KS, Paul M, Hegde M, et al. Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation. Mol Cell Biochem. 2016;414(1-2):137-51. doi: 10.1007/ s11010-016-2667-4, PMID 26899710
Nirgude S, Mahadeva R, Koroth J, Kumar S, Kumar KS, Gopalakrishnan V, et al. ST09, A novel curcumin derivative, blocks cell migration by inhibiting matrix metalloproteases in breast cancer cells and inhibits tumor progression in EAC mouse tumor models. Molecules. 2020;25(19):4499. doi: 10.3390/molecules25194499, PMID 33008036
Kumari S, Kotyan S, Sugunan S, Rajanikant GK, Kumar KS, Adiga SK, et al. The synthesis of a novel pentoxifylline derivative with superior human sperm motility enhancement properties. New J Chem. 2021;45(2):1072-81. doi: 10.1039/D0NJ03522J
O’Hagan D. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nat Prod Rep. 2000;17(5):435-46. doi: 10.1039/A707613D, PMID 11072891
Fan H, Peng J, Hamann MT, Hu JF. Lamellarins and related pyrrole-derived alkaloids from marine organisms. Chem Rev. 2008;108(1):264- 87. doi: 10.1021/cr078199m, PMID 18095718
Ivan BC, Barbuceanu SF, Hotnog CM, Anghel AI, Ancuceanu RV, Mihaila MA, et al. New pyrrole derivatives as promising biological agents: Design, synthesis, characterization, in silico, and cytotoxicity evaluation. Int J Mol Sci. 2022;23(16):8854. doi: 10.3390/ijms23168854, PMID 36012121
Estévez V, Villacampa M, Menéndez JC. Multicomponent reactions for the synthesis of pyrroles. Chem Soc Rev. 2010;39(11):4402-21. doi: 10.1039/B917644F, PMID 20601998
Sharath Kumar KS, Ananda H, Rangappa S, Raghavan SC, Rangappa KS. Regioselective competitive synthesis of 3,5-bis(het) aryl pyrrole-2-carboxylates/carbonitriles vs. β-enaminones from β-thioxoketones. Tetrahedron Lett. 2021;82:153373. doi: 10.1016/j. tetlet.2021.153373
Lingaraju GS, Swaroop TR, Vinayaka AC, Sharath Kumar KS, Sadashiva MP, Rangappa KS. An easy access to 4,5-disubstituted thiazoles via base-induced click reaction of active methylene isocyanides with methyl dithiocarboxylates. Synthesis. 2012;44(9):1373-9. doi: 10.1055/s-0031-1290762
Sharath Kumar KS, Swaroop TR, Harsha KB, Narasimhamurthy KH, Rangappa KS. T3P®-DMSO mediated one pot cascade protocol for the synthesis of 4-thiazolidinones from alcohols. Tetrahedron Lett. 2012;53(42):5619-23. doi: 10.1016/j.tetlet.2012.08.020
Girish YR, Sharath Kumar KS, Thimmaiah KN, Rangappa KS, Shashikanth S. ZrO2-β-cyclodextrin catalyzed synthesis of2,4,5-trisubstituted imidazoles and 1,2-disubstituted benzimidazoles under solvent free conditions and evaluation of their antibacterial study. RSC Adv. 2015;5(92):75533-46. doi: 10.1039/C5RA13891D
Girish YR, Kumar KS, Manasa HS, Shashikanth S. ZnO: An ecofriendly, green nano-catalyst for the synthesis of pyrazole derivatives under aqueous media. J Chin Chem Soc. 2014;61(11):1175-9. doi: 10.1002/jccs.201400170
Narasimhamurthy KH, Chandrappa S, Sharath Kumar KS, Harsha KB, Ananda H, Rangappa KS. Easy access for the synthesis of 2-aryl 2,3-dihydroquinazolin-4(1H)-ones using gem-dibromomethylarenes as synthetic aldehyde equivalent. RSC Adv. 2014;4(65):34479-86. doi: 10.1039/C4RA02312A
Girish YR, Sharath Kumar KS, Muddegowda U, Lokanath NK, Rangappa KS, Shashikanth S. ZrO2-supported Cu(ii)-β-cyclodextrin complex: construction of 2,4,5-trisubstituted-1,2,3-triazoles via azide-chalcone oxidative cycloaddition and post-triazole alkylation. RSC Adv. 2014;4(99):55800-6. doi: 10.1039/C4RA09970B
Swaroop TR, Sharath Kumar KS, Palanivelu M, Chaitanya S, Rangappa KS. A catalyst-free green protocol for the synthesis of pyranopyrazoles using room temperature ionic liquid choline chloride-urea. J Heterocycl Chem. 2014;51(6):1866-70. doi: 10.1002/jhet.1864
Narasimhamurthy KH, Chandrappa S, Kumar KS, Swaroop TR, Rangappa KS. Synthetic utility of propylphosphonic anhydride-DMSO media: An efficient one-pot three-component synthesis of 2-Arylquinolines. Chem Lett. 2013;42(9):1073-5. doi: 10.1246/cl.130432
Rajeev N, Sharath Kumar KS, Bommegowda YK, Rangappa KS, Sadashiva MP. Catalyst free sequential one-pot reaction for the synthesis of 3-indole propanoates/propanoic acid/propanamides as antituberculosis agents. J Chin Chem Soc. 2021;68(1):39-44. doi: 10.1002/jccs.202000386
Verma SK, Verma R, Girish YR, Verma S, Pramoda K, Vaishnav Y, et al. Two-dimensional Ti3C2Tx MXenes as a catalyst support for the synthesis of 1,4-disubstituted-1,2,3-triazoles via azide-nitroalkene oxidative cycloaddition. J Mol Struct. 2023;1281:135145. doi: 10.1016/j.molstruc.2023.135145
Preetham HD, Muddegowda U, Sharath Kumar KS, Rangappa S, Rangappa KS. Identification of β-aminopyrrolidine containing peptides as β-amyloid aggregation inhibitors for Alzheimer’s disease. J Pept Sci. 2022;28(6):e3386. doi: 10.1002/psc.3386, PMID 34981876
Verma SK, Verma R, Girish YR, Xue F, Yan L, Verma S, et al. Heterogeneous graphitic carbon nitrides in visible-light-initiated organic transformations. Green Chem. 2022;24(2):438-79. doi: 10.1039/ D1GC03490A
Preetham HD, Umashankara M, Kumar KS, Rangappa S, Rangappa KS. Pyrrolidine-based cationic γ-peptide: a DNA-binding molecule works as a potent anti-gene agent. Med Chem Res. 2022;31(3):507-16. doi: 10.1007/s00044-021-02833-3
Zha GF, Preetham HD, Rangappa S, Sharath Kumar KS, Girish YR, Rakesh KP, et al. Benzimidazole analogues as efficient arsenals in war against methicillin-resistance Staphylococcus aureus (MRSA) and its SAR studies. Bioorg Chem 2021;115:105175. doi: 10.1016/j. bioorg.2021.105175, PMID 34298242
Verma SK, Verma R, Kumar KS, Banjare L, Shaik AB, Bhandare RR, et al. A key review on oxadiazole analogs as potential methicillin-resistant Staphylococcus aureus (MRSA) activity: Structure-activity relationship studies. Eur J Med Chem 2021;219:113442. doi: 10.1016/j. ejmech.2021.113442, PMID 33878562
Wilson Lucas S, Zijian Qin R, Rakesh KP, Sharath Kumar KS, Qin HL. Chemical and biology of sulfur fluoride exchange (SuFEx) click chemistry for drug discovery. Bioorg Chem. 2023;130:106227. doi: 10.1016/j.bioorg.2022.106227, PMID 36368173
Sharath Kumar KS, Girish YR, Ashrafizadeh M, Mirzaei S, Rakesh KP, Hossein Gholami M, et al. AIE-featured tetraphenylethylene nanoarchitectures in biomedical application: Bioimaging, drug delivery and disease treatment. Coord Chem Rev. 2021;447:214135. doi: 10.1016/j.ccr.2021.214135
Verma R, Verma SK, Rakesh KP, Girish YR, Ashrafizadeh M, Sharath Kumar KS, et al. Pyrazole-based analogs as potential antibacterial agents against methicillin-resistance Staphylococcus aureus (MRSA) and its SAR elucidation. Eur J Med Chem. 2021;212:113134. doi: 10.1016/j.ejmech.2020.113134, PMID 33395624
Mary YS, Mary YS, Armaković S, Armaković SJ, Krátký M, Vinsova J, et al. Concentration and solvent dependent SERS, DFT, MD simulations and molecular docking studies of a thioxothiazolidine derivative with antimicrobial properties. J Mol Liq. 2021;329:115582. doi: 10.1016/j. molliq.2021.115582
Kumar AD, Vivek HK, Srinivasan B, Naveen S, Kumara K, Lokanath NK, et al. Design, synthesis, characterization, crystal structure, Hirshfeld surface analysis, DFT calculations, anticancer, angiogenic properties of new pyrazole carboxamide derivatives. J Mol Struct. 2021;1235:130271. doi: 10.1016/j.molstruc.2021.130271
Shwetha B, Sudhanva MS, Jagadeesha GS, Thimmegowda NR, Hamse VK, Sridhar BT, et al. Furan-2-carboxamide derivative, a novel microtubule stabilizing agent induces mitotic arrest and potentiates apoptosis in cancer cells. Bioorg Chem. 2021;108:104586. doi: 10.1016/j.bioorg.2020.104586, PMID 33607574
Al-Ostoot FH, Sherapura A, Vigneshwaran V, Basappa G, Vivek HK, Prabhakar BT, et al. Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression. Pharmacol Rep. 2021;73(5):1328- 43. doi: 10.1007/s43440-021-00266-8, PMID 33904146
Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theor Comput. 2010;6(5):1509-19. doi: 10.1021/ct900587b, PMID 26615687
Channa Basappa V, Hamse Kameshwar V, Kumara K, Achutha DK, Neratur Krishnappagowda L, Kariyappa AK. Design and synthesis of coumarin-triazole hybrids: Biocompatible anti-diabetic agents, in silico molecular docking and ADME screening. Heliyon. 2020;6(10):e05290. doi: 10.1016/j.heliyon.2020.e05290, PMID 33102875
Pattar SV, Adhoni SA, Kamanavalli CM, Kumbar SS. 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
Swamy SG, Kameshwar VH, Shubha PB, Looi CY, Shanmugam MK, Arfuso F, et al. Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target Oncol. 2017;12(1):1-10. doi: 10.1007/s11523-016-0452-7, PMID 27510230
Girish YR, Kumar BA, Kumar KS, Hamse VK, Prashantha K, Sudhanva M, et al. Identification of novel benzimidazole-based small molecule targeting dual targets tankyrase and Bcl2 to induce apoptosis in Colon cancer. J Mol Struct. 2022;1269:133813. doi: 10.1016/j. molstruc.2022.133813
Chowdary N, Preetham HD, Verma SK, Hamse VK, Umashankara M, Raj N, et al. A short hydrophobic peptide conjugated 3,5- disubstituted pyrazoles as antibacterial agents with DNA gyrase inhibition. J Mol Struct. 2023;1276:134661. doi: 10.1016/j.molstruc.2022.134661
Published
How to Cite
Issue
Section
Copyright (c) 2024 Devaraju, Nisha Chiriapanda Lohith, Ranjini P
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.
