Antioxidant Activity and Cytotoxicity of Aromatic Oligosulfides

Natural or synthetic antioxidants with biomimetic fragments protect the functional and structural integrity of biological molecules at a minimum concentration, and may be used as potential chemotherapeutic agents. This paper is devoted to in silico and in vitro evaluation of the antioxidant and cytotoxic properties of synthetic analogues of natural compounds—aromatic oligosulfides. The antiradical and SOD-protective activity of oligosulfides was demonstrated in the reaction with O2–• generated in enzymatic and non-enzymatic systems. It was found that phenol-containing disulfides significantly reduced the accumulation level of hydroperoxides and secondary carbonyl thiobarbituric acid reactive substances, which are primary products of oleic acid peroxidation. The antioxidant efficiency of bis(3,5-di-tert-butyl-4-hydroxyphenyl) disulfide increased over time due to the synergistic action of the 2,6-di-tert-butylphenol fragment and the disulfide linker. The highest cytotoxicity on the A-549 and HCT-116 cell lines was found for bis(3,4-dimethoxyphenyl) disulfide. Significant induction of apoptosis in HCT-116 cells in the presence of bis(3,4-dimethoxyphenyl) disulfide indicates the prospect of its use as an antitumor agent. The significant and moderate dependences revealed between various types of activities of the studied aromatic oligosulfides can be used in the development of a strategy for the synthesis and study of target-oriented compounds with predictable biological activity.

[1]  D. Mazur,et al.  Cytotoxic activity of organotin compounds containing non-steroidal anti-inflammatory drugs , 2021, Journal of Organometallic Chemistry.

[2]  K. Kwiatkowska,et al.  The effect of Cu, Zn and Fe chelates on the antioxidative status of thigh meat of broiler chickens. , 2021, Animal : an international journal of animal bioscience.

[3]  N. Berberova,et al.  Antioxidant activity of some organosulfur compounds in vitro , 2021 .

[4]  C. Kaushik,et al.  Design, synthesis, anticancer and antioxidant activities of amide linked 1,4-disubstituted 1,2,3-triazoles , 2021 .

[5]  Gloria A Santa-González,et al.  Phenolic compounds of blueberries (Vaccinium spp) as a protective strategy against skin cell damage induced by ROS: A review of antioxidant potential and antiproliferative capacity , 2021, Heliyon.

[6]  M. Valko,et al.  Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study , 2021, International journal of molecular sciences.

[7]  G. Egea,et al.  The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature. , 2020, Free radical biology & medicine.

[8]  E. Novellino,et al.  Plant-derived peptides rubiscolin-6, soymorphin-6 and their c-terminal amide derivatives: Pharmacokinetic properties and biological activity , 2020, Journal of Functional Foods.

[9]  G. Zengin,et al.  The Versatility of Antioxidant Assays in Food Science and Safety—Chemistry, Applications, Strengths, and Limitations , 2020, Antioxidants.

[10]  S. Sahoo,et al.  Phytonanomedicine: a novel avenue to treat recurrent cancer by targeting cancer stem cells. , 2020, Drug discovery today.

[11]  Katsuhiko Suzuki,et al.  Organosulfur Compounds: A Review of Their Anti-inflammatory Effects in Human Health , 2020, Frontiers in Nutrition.

[12]  N. Seeram,et al.  Antioxidant and tyrosinase docking studies of heterocyclic sulfide derivatives containing a thymol moiety , 2020 .

[13]  Sang-Han Lee,et al.  Antioxidant potential of non-oil seed legumes of Indonesian’s ethnobotanical extracts , 2020 .

[14]  A. V. Velikorodov,et al.  Synthesis and antioxidant activity of new hydroxy derivatives of chalcones , 2020, Russian Chemical Bulletin.

[15]  K. Adewole.  Nigerian antimalarial plants and their anticancer potential: A review. , 2020, Journal of integrative medicine.

[16]  Ana D. Amic,et al.  Antioxidative potential of ferulic acid phenoxyl radical. , 2019, Phytochemistry.

[17]  M. Valko,et al.  A Switch between Antioxidant and Prooxidant Properties of the Phenolic Compounds Myricetin, Morin, 3′,4′-Dihydroxyflavone, Taxifolin and 4-Hydroxy-Coumarin in the Presence of Copper(II) Ions: A Spectroscopic, Absorption Titration and DNA Damage Study , 2019, Molecules.

[18]  R. Apak,et al.  Use of modified CUPRAC and dinitrophenylhydrazine colorimetric methods for simultaneous measurement of oxidative protein damage and antioxidant defense against oxidation. , 2019, Talanta.

[19]  A. Okhlobystin,et al.  In silico and in vitro evaluation of the biological activity of some organicsulfur-containing compounds , 2019, TURKISH JOURNAL OF CHEMISTRY.

[20]  M. Yar,et al.  Medicinal prospects of antioxidants: A review. , 2019, European journal of medicinal chemistry.

[21]  Z. Gai,et al.  Arachidonic Acid Metabolism and Kidney Inflammation , 2019, International journal of molecular sciences.

[22]  J. Stanslas,et al.  Advances and challenges in developing andrographolide and its analogues as cancer therapeutic agents. , 2019, Drug discovery today.

[23]  D. Pratt,et al.  The antioxidant activity of polysulfides: it's radical!† †Electronic supplementary information (ESI) available: Synthesis and characterization data, additional autoxidation data, optimized geometries and energies for computational results. See DOI: 10.1039/c9sc00276f , 2019, Chemical science.

[24]  A. Tsopmo,et al.  Antioxidant properties and potential mechanisms of hydrolyzed proteins and peptides from cereals , 2019, Heliyon.

[25]  K. Mallikarjunan,et al.  An overview of organosulfur compounds from Allium spp.: From processing and preservation to evaluation of their bioavailability, antimicrobial, and anti-inflammatory properties. , 2019, Food chemistry.

[26]  N. Berberova,et al.  The Redox Properties and Antiradical Activity of Terpenophenols , 2019, Doklady. Chemistry.

[27]  Hua-Li Qin,et al.  Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review , 2018, European Journal of Medicinal Chemistry.

[28]  S. Sajjadifar,et al.  Biological and Pharmaceutical Organosulfur Molecules , 2018, Journal of Medicinal and Chemical Sciences.

[29]  Dmitry S Druzhilovskiy,et al.  CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds , 2018, PloS one.

[30]  K. P. Bhabak,et al.  Design, Synthesis and Anti‐Cancer Activities of Benzyl Analogues of Garlic‐Derived Diallyl Disulfide (DADS) and the Corresponding Diselenides , 2017 .

[31]  D. Saluja,et al.  Novel synthetic analogs of diallyl disulfide triggers cell cycle arrest and apoptosis via ROS generation in MIA PaCa-2 cells , 2017, Pharmacological reports : PR.

[32]  M. Nieger,et al.  The Cytotoxicity of the Ajoene Analogue BisPMB in WHCO1 Oesophageal Cancer Cells Is Mediated by CHOP/GADD153 , 2017, Molecules.

[33]  G. Jackson,et al.  The cytotoxicity of garlic-related disulphides and thiosulfonates in WHCO1 oesophageal cancer cells is dependent on S-thiolation and not production of ROS. , 2016, Biochimica et biophysica acta.

[34]  T. Sirota,et al.  The effect of fixed valence metal ions on the free radical process of epinephrine autoxidation , 2016 .

[35]  V. Saini,et al.  Multifunctional novel Diallyl disulfide (DADS) derivatives with β-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease. , 2015, Bioorganic & medicinal chemistry.

[36]  D. Pal,et al.  Free radicals, natural antioxidants, and their reaction mechanisms , 2015 .

[37]  Tiao-Lai Huang,et al.  Thiobarbituric acid reactive substances (TBARS) is a state biomarker of oxidative stress in bipolar patients in a manic phase. , 2015, Journal of affective disorders.

[38]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[39]  J. Milner,et al.  Garlic and Onions: Their Cancer Prevention Properties , 2015, Cancer Prevention Research.

[40]  N. Berberova,et al.  Synthesis, antiradical activity and in vitro cytotoxicity of novel organotin complexes based on 2,6-di-tert-butyl-4-mercaptophenol. , 2014, Dalton transactions.

[41]  N. Mimica-Dukić,et al.  Phenolic profile, antioxidant, anti-inflammatory and cytotoxic activities of small yellow onion (Allium flavum L. subsp. flavum, Alliaceae) , 2013 .

[42]  P. S. Rao,et al.  Free Radicals and Tissue Damage: Role of Antioxidants , 2011 .

[43]  H. Hassan,et al.  Anti-Proliferative Activity of Synthetic Ajoene Analogues on Cancer Cell-Lines , 2011 .

[44]  D. Lestan,et al.  Redistribution of residual Pb, Zn, and Cd in soil remediated with EDTA leaching and exposed to earthworms (Eisenia fetida) , 2010, Environmental technology.

[45]  J. Balzarini,et al.  Structural motifs and biological studies of new antimony(III) iodide complexes with thiones. , 2010, Inorganic chemistry.

[46]  Peng Huang,et al.  Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? , 2009, Nature Reviews Drug Discovery.

[47]  E. Lesaffre.  Statistical and Methodological Aspects of Oral Health Research , 2009 .

[48]  Jing Yi,et al.  Cancer cell killing via ROS: To increase or decrease, that is the question , 2008, Cancer biology & therapy.

[49]  A. Ullrich,et al.  Paul Ehrlich's magic bullet concept: 100 years of progress , 2008, Nature Reviews Cancer.

[50]  N. Berberova,et al.  Study of the antioxidant properties of phosphorylated phenols , 2008 .

[51]  M. Xanthopoulou,et al.  Biological studies of new organotin(IV) complexes of thioamide ligands. , 2008, European journal of medicinal chemistry.

[52]  Z. Nie,et al.  Enhanced radical scavenging activity by antioxidant-functionalized gold nanoparticles: a novel inspiration for development of new artificial antioxidants. , 2007, Free radical biology & medicine.

[53]  H. Ahsan,et al.  Reactive oxygen species: role in the development of cancer and various chronic conditions , 2006, Journal of carcinogenesis.

[54]  G. D’Andrea.  Use of Antioxidants During Chemotherapy and Radiotherapy Should Be Avoided , 2005, CA: a cancer journal for clinicians.

[55]  R. Apak,et al.  Novel total antioxidant capacity index for dietary polyphenols and vitamins C and E, using their cupric ion reducing capability in the presence of neocuproine: CUPRAC method. , 2004, Journal of agricultural and food chemistry.

[56]  D. N. Harpp,et al.  Optimization of the synthesis of symmetric aromatic tri- and tetrasulfides. , 2003, The Journal of organic chemistry.

[57]  I. Grigor’ev,et al.  Synthesis and Antioxidant Properties of Bis[ω-(3,5-dialkyl-4-hydroxyphenyl)alkyl] Sulfides , 2003 .

[58]  M. H. Ali,et al.  Oxidation of Thiols to Disulfides with Molecular Bromine on Hydrated Silica Gel Support. , 2002 .

[59]  S. Baek,et al.  Diallyl disulfide (DADS) induces the antitumorigenic NSAID-activated gene (NAG-1) by a p53-dependent mechanism in human colorectal HCT 116 cells. , 2002, The Journal of nutrition.

[60]  E. Andrade,et al.  Volatile constituents from Adenocalymma alliaceum Miers and Petiveria alliacea L., two medicinal herbs of the Amazon , 2002 .

[61]  K. Tsuta,et al.  Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines. , 2001, Carcinogenesis.

[62]  Jhingook Kim,et al.  Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines , 2000, Experimental & Molecular Medicine.

[63]  P. Somerharju,et al.  Lateral organisation of membrane lipids. The superlattice view. , 1999, Biochimica et biophysica acta.

[64]  T. Dinis,et al.  Action of phenolic derivatives (acetaminophen, salicylate, and 5-aminosalicylate) as inhibitors of membrane lipid peroxidation and as peroxyl radical scavengers. , 1994, Archives of biochemistry and biophysics.

[65]  N. Porter,et al.  A MECHANISTIC STUDY OF OLEATE AUTOXIDATION : COMPETING PEROXYL H-ATOM ABSTRACTION AND REARRANGEMENT , 1994 .

[66]  S. Toda,et al.  Effects of Phenolcarboxylic Acids on Superoxide Anion and Lipid Peroxidation Induced by Superoxide Anion , 1991, Planta medica.

[67]  M Niks,et al.  Towards an optimized MTT assay. , 1990, Journal of immunological methods.

[68]  Saleem Ahmad,et al.  The chemistry of alkyl thiosulfinate esters. 9. Antithrombotic organosulfur compounds from garlic: structural, mechanistic, and synthetic studies , 1986 .

[69]  N. Emanuel.  Kinetics and mechanism of chain reactions of liquid-phase oxidation of hydrocarbons , 1974 .

[70]  B. D. Vineyard.  Mercaptan—Sulfur Reaction. Alkyl Trisulfides , 1966 .

[71]  H. B. Stegmann,et al.  über Sauerstoffradikale, XXI. Untersuchungen an schwefelhaltigen Aroxylen mittels der Elektronenresonanz , 1961 .

[72]  D. Love,et al.  Polarographic Study of Various Diphenyl Disulfides , 1953 .

[73]  Ji-Han Kim,et al.  In vitro antioxidant actions of sulfur-containing amino acids , 2018 .

[74]  D. Granato,et al.  High-throughput assay comparison and standardization for metal chelating capacity screening: A proposal and application. , 2017, Food chemistry.

[75]  J. Vacek,et al.  Flavonolignan 2,3-dehydroderivatives: Preparation, antiradical and cytoprotective activity. , 2016, Free radical biology & medicine.

[76]  H. Kimura.  Physiological Roles of Hydrogen Sulfide and Polysulfides. , 2015, Handbook of experimental pharmacology.

[77]  P. Moore,et al.  Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide , 2015, Handbook of Experimental Pharmacology.

[78]  Deepshikha Gupta.  METHODS FOR DETERMINATION OF ANTIOXIDANT CAPACITY: A REVIEW , 2015 .

[79]  A. Phaniendra,et al.  Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases , 2014, Indian Journal of Clinical Biochemistry.

[80]  T. V. Sirota.  Involvement of carbonate/bicarbonate ions in the superoxide generating reaction of adrenaline autooxidation , 2014, Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry.

[81]  M. Viuda‐Martos,et al.  Antioxidant activity of essential oils of five spice plants widely used in a Mediterranean diet. , 2010 .

[82]  M. Battino,et al.  Oxygen, a paradoxical element? , 2008, Romanian journal of internal medicine = Revue roumaine de medecine interne.

[83]  Wolf-Dietrich Ihlenfeldt,et al.  PASS Biological Activity Spectrum Predictions in the Enhanced Open NCI Database Browser , 2003, J. Chem. Inf. Comput. Sci..

[84]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[85]  C. Berset,et al.  Use of a Free Radical Method to Evaluate Antioxidant Activity , 1995 .