STUDY OF THE INHIBITORY EFFECTS OF VITAMIN E DERIVATIVES ON MITOCHONDRIAL COMPLEX II SUBUNIT USING MOLECULAR DOCKING

IRMA RATNA KARTIKA; TENI ERNAWATI; Sri WIDIA A. JUSMAN; MOHAMAD SADIKIN

doi:10.22159/ijap.2024v16i3.50040

Authors

IRMA RATNA KARTIKA Doctoral Program of Biomedical Science, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. Program Study of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Negeri Jakarta, Jakarta, Indonesia https://orcid.org/0000-0002-7010-4783
TENI ERNAWATI Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency of Indonesia (BRIN), KST BJ Habibie, Kawasan Puspiptek, 452 Building, Tangerang Selatan 15314, Indonesia. https://orcid.org/0000-0003-2235-8591
Sri WIDIA A. JUSMAN Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia https://orcid.org/0000-0002-8169-6825
MOHAMAD SADIKIN Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

DOI:

https://doi.org/10.22159/ijap.2024v16i3.50040

Keywords:

Vitamin E, Pentanoic acid, Heptanoic acid, octanoic Acid, SDH

Abstract

Objective: The goal of this study was to create vitamin E derivatives and explore their potential anticancer properties using a computational approach.

Methods: The Steglich method was used for the synthesis of the vitamin E-fatty acid (pentanoic acid, heptanoic acid, and octanoic acid) derivatives, with N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) as the catalysts. The structure of the synthesized products was determined by ultraviolet-visible (UV-Vis) spectroscopy, fourier transform infrared (FTIR) spectroscopy, and liquid chromatography-mass spectrometry (LC-MS). Molecular docking was carried out on the succinate dehydrogenase (SDH) enzyme using AutoDockTools.

Results: α–Tocopherol pentanoate (α–TP), α–tocopherol heptanoate (α–TH), and α–tocopherol octanoate (α–TO) were the three vitamin E derivatives synthesized in this study. Based on the results of molecular docking, the novel compounds (α–TP, α–TH, and α–TO) generated bond energies of-10.57,-9.61, and-9.20 kcal/mol, respectively.

Conclusion: All newly synthesized compounds exhibited lower binding affinity values than α–tocopherol (α–T). This confirms that these compounds might not provide greater advantages than α-tocopherol in terms of inhibitory effects on mitochondrial complex II (CII).

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References

Bandara AB, Drake JC, Brown DA. Complex II subunit SDHD is critical for cell growth and metabolism, which can be partially restored with a synthetic ubiquinone analog. BMC Mol Cell Biol. 2021;22(1):35. doi: 10.1186/s12860-021-00370-w, PMID 34118887.

Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005;121(7):1043-57. doi: 10.1016/j.cell.2005.05.025, PMID 15989954.

Miyadera H, Shiomi K, Ui H, Yamaguchi Y, Masuma R, Tomoda H. Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase). Proc Natl Acad Sci USA. 2003;100(2):473-7. doi: 10.1073/pnas.0237315100, PMID 12515859.

Russell CT, Kivelson MG. Detection of SO in Io’s exosphere. Science. 2000;287(5460):1998-9. doi: 10.1126/science.287.5460.1998.

Jusman SWA, Azzizah IN, Sadikin M, Hardiany NS. Is the mitochondrial function of keloid fibroblasts affected by cytoglobin? Malays J Med Sci. 2021;28(2):39-47. doi: 10.21315/mjms2021.28.2.4, PMID 33958959.

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 2005;7(1):77-85. doi: 10.1016/j.ccr.2004.11.022. PMID 15652751.

Aldera AP, Govender D. Gene of the month: SDH. J Clin Pathol. 2018;71(2):95-7. doi: 10.1136/jclinpath-2017-204677, PMID 29070651.

Owens KM, Aykin Burns N, Dayal D, Coleman MC, Domann FE, Spitz DR. Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2−• and H2O2. Free Radic Biol Med. 2012;52(1):160-6. doi: 10.1016/j.freeradbiomed.2011.10.435, PMID 22041456.

Wang YM, Gu ML, Ji F. Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol. 2015;21(8):2303-14. doi: 10.3748/wjg.v21.i8.2303, PMID 25741136.

Cairns P. Renal cell carcinoma. Cancer Biomark. 2010;9(1-6):461-73. doi: 10.3233/CBM-2011-0176, PMID 22112490.

Pinzariu O, Georgescu B, Georgescu CE. Metabolomics-a promising approach to pituitary adenomas. Front Endocrinol. 2018;9:814. doi: 10.3389/fendo.2018.00814, PMID 30705668.

Akirov A, Larouche V, Alshehri S, Asa SL, Ezzat S. Treatment options for pancreatic neuroendocrine tumors. Cancers. 2019;11(6):1-13. doi: 10.3390/cancers11060828, PMID 31207914.

Ugboko HU, Nwinyi OC, Oranusi SU, Fatoki TH, Omonhinmin CA. Antimicrobial importance of medicinal plants in Nigeria. Scientific World Journal. 2020;2020:7059323. doi: 10.1155/2020/7059323, PMID 33029108.

Lauritano C, Andersen JH, Hansen E, Albrigtsen M, Escalera L, Esposito F. Bioactivity screening of microalgae for antioxidant, anti-inflammatory, anticancer, anti-diabetes, and antibacterial activities. Front Mar Sci. 2016;3(68):1-2. doi: 10.3389/fmars.2016.00068.

Shahidi F, De Camargo AC. Tocopherols and tocotrienols in common and emerging dietary sources: occurrence, applications, and health benefits. Int J Mol Sci. 2016;17(10):1-29. doi: 10.3390/ijms17101745, PMID 27775605.

Traber MG, Atkinson J. Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007;43(1):4-15. doi: 10.1016/j.freeradbiomed.2007.03.024, PMID 17561088.

Baharuddin NSB, Nasir NSB, Kamal NNSBNM, Saifuddin SNB, Mohamad SB. Vitamin E: an antioxidant with anticancer properties? Malays J Med Heal Sci. 2019;15(9):183-93.

Mohd Zaffarin AS, Ng SF, Ng MH, Hassan H, Alias E. Pharmacology and pharmacokinetics of vitamin e: nano formulations to enhance bioavailability. Int J Nanomedicine. 2020;15:9961-74. doi: 10.2147/IJN.S276355, PMID 33324057.

Yin C, Zhang C, Gao M. Enzyme-catalyzed synthesis of vitamin E succinate using a chemically modified nobody-435. Chin J Chem Eng. 2011;19(1):135-9. doi: 10.1016/S1004-9541(09)60189-0.

Liang L, Qiu L. Vitamin E succinate with multiple functions: a versatile agent in nanomedicine-based cancer therapy and its delivery strategies. Int J Pharm. 2021;600:120457. doi: 10.1016/j.ijpharm.2021.120457, PMID 33676991.

Panda V, Khambat P, Patil S. Mitocans as novel agents for anticancer therapy: an overview. Int J Clin Med. 2011;02(4):515-29. doi: 10.4236/ijcm.2011.24086.

Shiau CW, Huang JW, Wang DS, Weng JR, Yang CC, Lin CH. α-tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function. J Biol Chem. 2006;281(17):11819-25. doi: 10.1074/jbc.M511015200, PMID 16520381.

States U (12) Patent Application Publication (10) Pub. No: US. 2004/0092606A1;1(09); 2002-5.

Smolarek AK, Suh N. Chemopreventive activity of vitamin E in breast cancer: a focus on γ and δ-tocopherol. Nutrients. 2011;3(11):962-86. doi: 10.3390/nu3110962, PMID 22254089.

Lee E, Choi MK, Lee YJ, Ku JL, Kim KH, Choi JS. Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells. Carcinogenesis. 2006;27(11):2308-15. doi: 10.1093/carcin/bgl073, PMID 16714329.

Han R, Nusbaum O, Chen X, Zhu Y. Valeric acid suppresses liver cancer development by acting as a novel HDAC inhibitor. Mol Ther Oncolytics. 2020;19:8-18. doi: 10.1016/j.omto.2020.08.017, PMID 33024815.

Jayaraj RL, Beiram R, Azimullah S, Mf NM, Ojha SK, Adem A. Valeric acid protects dopaminergic neurons by suppressing oxidative stress, neuroinflammation and modulating autophagy pathways. Int J Mol Sci. 2020;21(20):1-18. doi: 10.3390/ijms21207670, PMID 33081327.

Huang L, Gao L, Chen C. Role of medium-chain fatty acids in healthy metabolism: a clinical perspective. Trends Endocrinol Metab. 2021;32(6):351-66. doi: 10.1016/j.tem.2021.03.002, PMID 33832826.

Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA. 2011;108(19):8030-5. doi: 10.1073/pnas.1016088108, PMID 21518883.

Narayanan A, Baskaran SA, Amalaradjou MAR, Venkitanarayanan K. Anticarcinogenic properties of medium chain fatty acids on human colorectal, skin and breast cancer cells in vitro. Int J Mol Sci. 2015;16(3):5014-27. doi: 10.3390/ijms16035014, PMID 25749477.

Zhang X, Xue C, Xu Q, Zhang Y, Li H, Li F. Caprylic acid suppresses inflammation via TLR4/NF-κB signaling and improves atherosclerosis in ApoE-deficient mice. Nutr Metab (Lond). 2019;16(1):40. doi: 10.1186/s12986-019-0359-2, PMID 31182969.

Neises B, Steglich W. Simple method for the esterification of carboxylic acids. Angew Chem Int Ed Engl. 1978;17(7):522-4. doi: 10.1002/anie.197805221.

Gong H, Gao Y, Zhou X, Xiao Y, Wang W, Tang Y. Cryo-EM structure of trimeric mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF. Nat Commun. 2020;11(1):4245. doi: 10.1038/s41467-020-18011-9, PMID 32843629.

Cecchini G, Schroder I, Gunsalus RP, Maklashina E. Succinate dehydrogenase and fumarate reductase from Escherichia coli. Biochim Biophys Acta. 2002;1553(1-2):140-57. doi: 10.1016/s0005-2728(01)00238-9, PMID 11803023.

Zuhri UM, Purwaningsih EH, Fadilah F, Yuliana ND. Network pharmacology integrated molecular dynamics reveals the bioactive compounds and potential targets of Tinospora crispa Linn. as insulin sensitizer. Plos One. 2022;17(6):e0251837. doi: 10.1371/journal.pone.0251837, PMID 35737707.

Ernawati T. In silico analysis of the inhibitory potential of Zingiber officinale roscoe compounds against SARS-CoV-2. In: Proceedings of the 1st international conference for health research–BRIN (ICHR 2022); 2023. p. 360-73. doi: 10.2991/978-94-6463-112-8_34.

Jain NK, Agrawal A, Kulkarni GT, Tailang M. Molecular docking study on phytoconstituents of traditional ayurvedic drug tulsi (ocimum sanctum linn.) against COVID-19 mpro enzyme: an in silico study. Int J Pharm Pharm Sci. 2022;14(4):44-50. doi: 10.22159/ijpps.2022v14i4.43181.

Astiani R, Sadikin M, Eff ARY, Firdayani SFD. in silico identification testing of triterpene saponines on Centella asiatica on inhibitor renin activity antihypertensive. v14s2.44737. Int J Appl Pharm. 2022;14 Special Issue 2:1-4. doi: 10.22159/ijap.2022.

Mathew C, Lal N, SL, TRA, Varkey J. Antioxidant, anticancer and molecular docking studiesof novel 5-benzylidene substituted rhodanine derivatives. Int J Pharm Pharm Sci. 2023;15(7):7-19. doi: 10.22159/ijpps.2023v15i7.47421.

Teni Ernawati TE, Abdul Mun’im AM, Muhamad Hanafi MH, Arry Yanuar AY. Synthesis of cinnamamide derivatives and their α-glucosidase inhibitory activities. Sains Malays. 2020;49(2):315-22. doi: 10.17576/jsm-2020-4902-09.

Widiyarti G, Sundowo A, Megawati M, Ernawati T. Synthesis, characterization, anticancer and in silico ADME properties of caproic acid derivatives against P388 cancer cell lines. Indonesian J Pharm Sci Technol. 2019;1(2):1-8. doi: 10.24198/ijpst.v1i2.20192.

Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull. 2017;7(3):339-48. doi: 10.15171/apb.2017.041, PMID 29071215.

Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLOS Med. 2013;10(5):e1001453. doi: 10.1371/journal.pmed.1001453, PMID 23700391.

Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755-68. doi: 10.1038/nrc2499, PMID 18784658.

Guinney J, Dienstmann R, Wang X, De Reynies A, Schlicker A, Soneson C. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-6. doi: 10.1038/nm.3967, PMID 26457759.

O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106-10, doi: 10.1038/nature05372, PMID 17122772.

Neuzil J, Dyason JC, Freeman R, Dong LF, Prochazka L, Wang XF. Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II. J Bioenerg Biomembr. 2007;39(1):65-72. doi: 10.1007/s10863-006-9060-z, PMID 17294131.