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ORIGINAL RESEARCH
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Thiophene-based water-soluble C70 fullerene derivatives as novel antioxidant agents

Margarita Chetyrkina1 Pavel Umriukhin2,3* Elizaveta Ershova2 Elena Proskurnina2 Vasilina Sergeeva2 Ekaterina Savinova2 Svetlana E. Kostyuk2 Larisa Kameneva2 Olga Kraevaya4 Valeriya Bolshakova4 Pavel Troshin4,5 Tatiana Salimova2 Ivan Rodionov2 Sergey Kutsev2 Natalia Veiko2 Svetlana V. Kostyuk2
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1 Higher School of Economics, Moscow, Russia
2 Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
3 Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
4 Department of Kinetics and Catalysis, Federal Research Centre for Problems of Chemical Physics and Medicinal Chemistry of RAS, Chernogolovka, Russia
5 Zhengzhou Research Institute of HIT, Zhengzhou, Henan Province, China
BMT 2025 , 6(3), 359–370; https://doi.org/10.12336/bmt.24.00064
Submitted: 29 September 2024 | Revised: 18 November 2024 | Accepted: 31 December 2024 | Published: 22 September 2025
Copyright © 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution–NonCommercial–ShareAlike 4.0 License.
Abstract

Fullerenes are one of the most popular nanomaterials, and C70 fullerene is the second most common fullerene after C60 buckminsterfullerene. Minor modification of fullerenes derivatives can change their biological effects and antioxidant properties. A plethora of water-soluble derivatives can be synthesised based on buckminsterfullerenes. In the present study, we synthesised three water-soluble C70 fullerene derivatives with thiophene-based solubilising addends and tested their cytotoxicity and the transcriptional activity of genes, which regulate an oxidative metabolism. Aliphatic chain length in the structure of the solubilising addend of the water-soluble fullerene derivative has been varied, and we revealed that a longer chain resulted in more pronounced antioxidant activity. Thus, the surface modification enhances the antioxidant properties of the compound and changes the nanoparticles impact on the genetic apparatus of the cell. Interestingly, even slight modifications of the functional addend’s structure can significantly affect the final cell response. The data obtained can be harnessed to develop novel and efficient medications for the management of ischaemia, stress-related conditions, the prevention of ageing, and the resolution of other practical healthcare challenges.

Keywords
Antioxidants
Fullerenes
NRF2
Reactive oxygen species
Transcription factors
Funding
The synthesis of water-soluble fullerene derivatives was supported by the Russian Science Foundation, project No. 22-43-08005, other research was supported by state assignment of the Ministry of Science and Higher Education.
References

Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.

  1. Kroto HW, Heath JR, O’Brien SC, Curl RF, Smalley RE. C60: Buckminsterfullerene. Nature. 1985;318:162-163. doi: 10.1038/318162a0

 

  1. McNamara K, Tofail SAM. Nanoparticles in biomedical applications. Adv Phys X. 2017;2:54-88. doi: 10.1080/23746149.2016.1254570

 

  1. Blum AP, Kammeyer JK, Rush AM, Callmann CE, Hahn ME, Gianneschi NC. Stimuli-responsive nanomaterials for biomedical applications. J Am Chem Soc. 2015;137:2140-2154. doi: 10.1021/ja510147n

 

  1. Zhao Y, Zhang Z, Pan Z, Liu Y. Advanced bioactive nanomaterials for biomedical applications. Exploration (Beijing). 2021;1:20210089. doi: 10.1002/EXP.20210089

 

  1. Bakry R, Vallant RM, Najam-ul-Haq M, et al. Medicinal applications of fullerenes. Int J Nanomedicine. 2007;2:639-649.

 

  1. Castro E, Garcia AH, Zavala G, Echegoyen L. Fullerenes in biology and medicine. J Mater Chem B. 2017;5:6523-6535. doi: 10.1039/C7TB00855D

 

  1. Yin JJ, Lao F, Fu PP, et al. The scavenging of reactive oxygen species and the potential for cell protection by functionalized fullerene materials. Biomaterials. 2009;30:611-621. doi: 10.1016/j.biomaterials.2008.09.061

 

  1. Çiçek B, Kenar A, Nazir H. Simultaneous determination of C60 and C70 fullerenes by a spectrophotometric method. Fullerene Sci Technol. 2001;9:103-111. doi: 10.1081/FST-100000169

 

  1. Eklund PC, Rao AM, Zhou P, Wang Y, Holden JM. Photochemical transformation of C60 and C70 films. Thin Solid Films. 1995;257:185-203. doi: 10.1016/0040-6090(94)05704-4

 

  1. Catalan J, Elguero J. Fluorescence of fullerenes (C60 and C70). J Am Chem Soc. 1993;115:9249-9252. doi: 10.1021/ja00073a046

 

  1. Liu J, Huang M, Zhang X, et al. Polyoxometalate nanomaterials for enhanced reactive oxygen species theranostics. Coord Chem Rev. 2022;472:214785. doi: 10.1016/j.ccr.2022.214785

 

  1. Joorabloo A, Liu T. Recent advances in reactive oxygen species scavenging nanomaterials for wound healing. Explor (Beijing). 2024;4:20230066. doi: 10.1002/EXP.20230066

 

  1. Zhou Y, Zhen M, Guan M, et al. Amino acid modified [70] fullerene derivatives with high radical scavenging activity as promising bodyguards for chemotherapy protection. Sci Rep. 2018;8:16573. doi: 10.1038/s41598-018-34967-7

 

  1. Bannunah AM, Vllasaliu D, Lord J, Stolnik S. Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: Effect of size and surface charge. Mol Pharm. 2014;11:4363-4373. doi: 10.1021/mp500439c

 

  1. Kopac T. Protein corona, understanding the nanoparticle-protein interactions and future perspectives: A critical review. Int J Biol Macromol. 2021;169:290-301. doi: 10.1016/j.ijbiomac.2020.12.108

 

  1. Kornev AB, Peregudov AS, Martynenko VM, Balzarini J, Hoorelbeke B, Troshin PA. Synthesis and antiviral activity of highly water-soluble polycarboxylic derivatives of [70]fullerene. Chem Commun (Camb). 2011;47:8298-8300. doi: 10.1039/c1cc12209f

 

  1. Huang L, Wang M, Sharma SK, et al. Decacationic [70]fullerene approach for efficient photokilling of infectious bacteria and cancer cells. ECS Trans. 2013;45:10.1149/04520.0065ecst.65 doi: 10.1149/04520.0065ecs

 

  1. Marforio TD, Mattioli EJ, Zerbetto F, Calvaresi M. Fullerenes against COVID-19: Repurposing C60 and C70 to clog the active site of SARS-CoV-2 protease. Molecules. 2022;27:1916. doi: 10.3390/molecules27061916

 

  1. Mikheev IV, Sozarukova MM, Izmailov DY, Kareev IE, Proskurnina EV, Proskurnin MA. Antioxidant potential of aqueous dispersions of fullerenes C60, C70, and Gd@C82. Int J Mol Sci. 2021;22:5838. doi: 10.3390/ijms22115838

 

  1. Mikheev IV, Sozarukova MM, Proskurnina EV, Kareev IE, Proskurnin MA. Non-functionalized fullerenes and endofullerenes in aqueous dispersions as superoxide scavengers. Molecules. 2020;25:2506. doi: 10.3390/molecules25112506

 

  1. Tzirakis MD, Orfanopoulos M. Radical reactions of fullerenes: From synthetic organic chemistry to materials science and biology. Chem Rev. 2013;113:5262-5321. doi: 10.1021/cr300475r

 

  1. Grebowski J, Kazmierska P, Krokosz A. Fullerenols as a new therapeutic approach in nanomedicine. Biomed Res Int. 2013;2013:751913. doi: 10.1155/2013/751913

 

  1. Roman G. Thiophene-containing compounds with antimicrobial activity. Arch Pharm (Weinheim). 2022;355:e2100462. doi: 10.1002/ardp.202100462

 

  1. Singh A, Singh G, Bedi PMS. Thiophene derivatives: A potent multitargeted pharmacological scaffold. J Heterocycl Chem. 2020;57:2658-2703. doi: 10.1002/jhet.3990

 

  1. Mishra R, Sachan N, Kumar N, Mishra I, Chand P. Thiophene scaffold as prospective antimicrobial agent: A review. J Heterocycl Chem. 2018;55:2019-2034. doi: 10.1002/jhet.3249

 

  1. Cetin A, Türkan F, Taslimi P, Gulçin İ. Synthesis and characterization of novel substituted thiophene derivatives and discovery of their carbonic anhydrase and acetylcholinesterase inhibition effects. J Biochem Mol Toxicol. 2019;33:e22261. doi: 10.1002/jbt.22261

 

  1. Alım Z, Köksal Z, Karaman M. Evaluation of some thiophene-based sulfonamides as potent inhibitors of carbonic anhydrase I and II isoenzymes isolated from human erythrocytes by kinetic and molecular modelling studies. Pharmacol Rep. 2020;72:1738-1748. doi: 10.1007/s43440-020-00149-4

 

  1. Xu DG, Lv W, Dai CY, et al. 2-(Pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3- diynyl) thiophene induces apoptosis through reactive oxygen species-mediated JNK activation in human colon cancer SW620 cells. Anat Rec (Hoboken). 2015;298:376-385. doi: 10.1002/ar.23045

 

  1. Song X, Fanelli MG, Cook JM, Bai F, Parish CA. Mechanisms for the reaction of thiophene and methylthiophene with singlet and triplet molecular oxygen. J Phys Chem A. 2012;116:4934-4946. doi: 10.1021/jp301919g

 

  1. Kucur O, Turan HT, Monari A, Aviyente V. Computational study of photo-oxidative degradation mechanisms of boron-containing oligothiophenes. J Phys Chem A. 2020;124:1390-1398.doi: 10.1021/acs.jpca.9b07858

 

  1. Sumita M, Morihashi K. Theoretical study of singlet oxygen molecule generation via an exciplex with valence-excited thiophene. J Phys Chem A. 2015;119:876-883. doi: 10.1021/jp5123129

 

  1. Kraevaya OA, Peregudov AS, Fedorova NE, et al. Thiophene-based water-soluble fullerene derivatives as highly potent antiherpetic pharmaceuticals. Org Biomol Chem. 2020;18:8702-8708. doi: 10.1039/d0ob01826k

 

  1. Kraevaya OA, Peregudov AS, Godovikov IA, et al. Direct arylation of C60Cl6 and C70Cl8 with carboxylic acids: A synthetic avenue to water-soluble fullerene derivatives with promising antiviral activity. Chem Commun (Camb). 2020;56:1179-1182. doi: 10.1039/c9cc08400b

 

  1. Savinova EA, Salimova TA, Proskurnina EV, et al. Effect of water-soluble chlorine-containing buckminsterfullerene derivative on the metabolism of reactive oxygen species in human embryonic lung fibroblasts. Oxygen. 2023;3:1-19. doi: 10.3390/oxygen3010001

 

  1. Proskurnina EV, Mikheev IV, Savinova EA, et al. Effects of aqueous dispersions of C60, C70 and Gd@C82 fullerenes on genes involved in oxidative stress and anti-inflammatory pathways. Int J Mol Sci. 2021;22:6130. doi: 10.3390/ijms22116130

 

  1. Sergeeva V, Kraevaya O, Ershova E, et al. Antioxidant properties of fullerene derivatives depend on their chemical structure: A study of two fullerene derivatives on HELFs. Oxid Med Cell Longev. 2019;2019:4398695. doi: 10.1155/2019/4398695

 

  1. Guo J, Zhao Z, Shang ZF, Tang Z, Zhu H, Zhang K. Nanodrugs with intrinsic radioprotective exertion: Turning the double-edged sword into a single-edged knife. Exploration (Beijing). 2023;3:20220119. doi: 10.1002/EXP.20220119

 

  1. Huang HJ, Chetyrkina M, Wong CW, et al. Identification of potential descriptors of water-soluble fullerene derivatives responsible for antitumor effects on lung cancer cells via QSAR analysis. Comput Struct Biotechnol J. 2021;19:812-825. doi: 10.1016/j.csbj.2021.01.012

 

  1. Yang H, Sun L, Li W, Liu G, Tang Y. In silico prediction of chemical toxicity for drug design using machine learning methods and structural alerts. Front Chem. 2018;6:30. doi: 10.3389/fchem.2018.00030

 

  1. Knyazev VD. Effects of chain length on the rates of C-C bond dissociation in linear alkanes and polyethylene. J Phys Chem A. 2007;111:3875-3883. doi: 10.1021/jp066419e

 

  1. Wong-Ekkabut J, Baoukina S, Triampo W, Tang IM, Tieleman DP, Monticelli L. Computer simulation study of fullerene translocation through lipid membranes. Nat Nanotechnol. 2008;3:363-368. doi: 10.1038/nnano.2008.130

 

  1. Nalakarn P, Boonnoy P, Nisoh N, Karttunen M, Wong-Ekkabut J. Dependence of fullerene aggregation on lipid saturation due to a balance between entropy and enthalpy. Sci Rep. 2019;9:1037. doi: 10.1038/s41598-018-37659-4

 

  1. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1005-L1028. doi: 10.1152/ajplung.2000.279.6.L1005

 

  1. D’Autréaux B, Toledano MB. ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8:813-824. doi: 10.1038/nrm2256

 

  1. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47-95. doi: 10.1152/physrev.00018.2001

 

  1. Girard-Lalancette K, Pichette A, Legault J. Sensitive cell-based assay using DCFH oxidation for the determination of pro- and antioxidant properties of compounds and mixtures: Analysis of fruit and vegetable juices. Food Chem. 2009;115:720-726. doi: 10.1016/j.foodchem.2008.12.002

 

  1. Markovic Z, Trajkovic V. Biomedical potential of the reactive oxygen species generation and quenching by fullerenes (C60). Biomaterials. 2008;29:3561-3573. doi: 10.1016/j.biomaterials.2008.05.005

 

  1. Kong L, Zepp RG. Production and consumption of reactive oxygen species by fullerenes. Environ Toxicol Chem. 2012;31:136-143. doi: 10.1002/etc.711

 

  1. De Araújo Neto LN, De Lima M, De Oliveira JF, et al. Thiophene-thiosemicarbazone derivative (L10) exerts antifungal activity mediated by oxidative stress and apoptosis in C. Albicans. Chem Biol Interact. 2020;320:109028. doi: 10.1016/j.cbi.2020.109028

 

  1. Cai G, Wang S, Zhao L, et al. Thiophene derivatives as anticancer agents and their delivery to tumor cells using albumin nanoparticles. Molecules. 2019;24:192. doi: 10.3390/molecules24010192

 

  1. Amara N, Goven D, Prost F, Muloway R, Crestani B, Boczkowski J. NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts. Thorax. 2010;65:733-738. doi: 10.1136/thx.2009.113456

 

  1. Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox Biol. 2014;2:267-272. doi: 10.1016/j.redox.2014.01.012

 

  1. Rojo De La Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018;34:21-43. doi: 10.1016/j.ccell.2018.03.022

 

  1. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401-426. doi: 10.1146/annurev-pharmtox-011112-140320

 

  1. Smyrnias I, Zhang X, Zhang M, et al. Nicotinamide adenine dinucleotide phosphate oxidase-4-dependent upregulation of nuclear factor erythroid-derived 2-like 2 protects the heart during chronic pressure overload. Hypertension. 2015;65:547-553. doi: 10.1161/HYPERTENSIONAHA.114.04208

 

  1. Mir S, Ormsbee Golden BD, Griess BJ, et al. Upregulation of Nox4 induces a pro-survival Nrf2 response in cancer-associated fibroblasts that promotes tumorigenesis and metastasis in part via Birc5 induction. Breast Cancer Res. 2022;24:48. doi: 10.1186/s13058-022-01548-6

 

  1. Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol. 2004;37:139-143. doi: 10.5483/bmbrep.2004.37.2.139

 

  1. Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules. 2020;25:5474. doi: 10.3390/molecules25225474

 

  1. Ross D, Siegel D. Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Front Physiol. 2017;8:595. doi: 10.3389/fphys.2017.00595

 

  1. Araujo JA, Zhang M, Yin F. Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol. 2012;3:119. doi: 10.3389/fphar.2012.00119

 

  1. Weimann A, Belling D, Poulsen HE. Quantification of 8-oxo-guanine and guanine as the nucleobase nucleoside and deoxynucleoside forms in human urine by high-performance liquid chromatography-electrospray tandem mass spectrometry. Nucleic Acids Res. 2002;30:E7. doi: 10.1093/nar/30.2.e7

 

  1. Collins PL, Purman C, Porter SI, et al. DNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner. Nat Commun. 2020;11:3158. doi: 10.1038/s41467-020-16926-x

 

  1. Moreno-Bueno G, Rodríguez-Perales S, Sánchez-Estévez C, et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene. 2003;22:6115-6118. doi: 10.1038/sj.onc.1206868

 

  1. Cazzalini O, Scovassi AI, Savio M, Stivala LA, Prosperi E. Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res. 2010;704:12-20.doi: 10.1016/j.mrrev.2010.01.009

 

  1. Liang J, Fan J, Wang M, et al. CDKN2A inhibits formation of homotypic cell-in-cell structures. Oncogenesis. 2018;7:50. doi: 10.1038/s41389-018-0056-4

 

  1. Uxa S, Castillo-Binder P, Kohler R, Stangner K, Müller GA, Engeland K. Ki-67 gene expression. Cell Death Differ. 2021;28:3357-3370. doi: 10.1038/s41418-021-00823-x

 

  1. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nat Rev Cancer. 2011;12:68-78. doi: 10.1038/nrc3181

 

  1. Gorodetska I, Kozeretska I, Dubrovska A. BRCA genes: The role in genome stability, cancer stemness and therapy resistance. J Cancer. 2019;10:2109-2127. doi: 10.7150/jca.30410

 

  1. Tzifi F, Economopoulou C, Gourgiotis D, Ardavanis A, Papageorgiou S, Scorilas A. The role of BCL2 family of apoptosis regulator proteins in acute and chronic leukemias. Adv Hematol. 2012;2012:524308. doi: 10.1155/2012/524308

 

  1. Hardwick JM, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5:a008722. doi: 10.1101/cshperspect.a008722

 

  1. Gross A, Katz SG. Non-apoptotic functions of BCL-2 family proteins. Cell Death Differ. 2017;24:1348-1358. doi: 10.1038/cdd.2017.22

 

  1. Klionsky DJ. Autophagy: From phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007;8:931-937. doi: 10.1038/nrm2245
Conflict of interest
The authors declare no conflict of interest.
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