Abstract
In this work, a series of C-3-aminomethyl derivatives based on alizarin (1) was obtained using Mannich reaction. The antioxidant properties of the compounds were evaluated using in vitro models. It was found that most of the synthesized derivatives were superior to alizarin (1) in radical scavenging activity and Fe2+-chelation ability. The antioxidant activity of alizarin derivatives was confirmed using biologically relevant test systems; all compounds strongly inhibited Fe2+/ascorbate-initiated oxidation of unsaturated fatty acids of animal lipids and most of them increased the survival of red blood cells under conditions of acute oxidative stress. In the cellular model system, the Mannich base containing a thiomorpholinomethyl moiety demonstrated the highest activity.
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Acker CI, Brandão R, Rosário AR, Nogueira CW (2009) Antioxidant effect of alkynylselenoalcohol compounds on liver and brain of rats in vitro. Environ Toxicol Pharmacol 28:280–287. https://doi.org/10.1016/j.etap.2009.05.002
Alam MN, Bristi NJ, Rafiquzzaman M (2013) Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi Pharm J 21:143–152. https://doi.org/10.1016/j.jsps.2012.05.002
Bandgar BP, Patil SA, Totre JV, Korbad BL, Gacche RN, Hote BS, Jalde SS, Chavan HV (2010) Synthesis and biological evaluation of nitrogen-containing benzophenone analogues as TNF-α and IL-6 inhibitors with antioxidant activity. Bioorg Med Chem Lett 20:2292–2296. https://doi.org/10.1016/j.bmcl.2010.02.001
Battula KS, Narsimha S, Thatipamula RK, Reddy YN, Nagavelli VR (2017) Synthesis and biological evaluation of novel thiomorpholine 1,1-dioxide derived 1,2,3-triazole hybrids as potential anticancer agents. ChemistrySelect 2:4001–4005. https://doi.org/10.1002/slct.201700524
Belcher R, Leonard MA, West TS (1958) The preparation and analytical properties of NN-di(carboxymethyl)aminomethyl derivatives of some hydroxyanthraquinones. J Chem Soc. https://doi.org/10.1039/JR9580002390
Buravlev EV, Shevchenko OG (2019) 2-Hydroxy-3-isobornyl-5-methylbenzaldehyde derivatives: Synthesis and antioxidant activity in vitro. Russ Chem Bull 68:79–85. https://doi.org/10.1007/s11172-019-2419-1
Buravlev EV, Shevchenko OG (2020) Synthesis and antioxidant properties of N-substituted aminomethyl derivatives of 2-isobornylphenol. Russ Chem Bull 69:1971–1978. https://doi.org/10.1007/s11172-020-2987-0
Buravlev EV, Shevchenko OG, Kutchin AV (2015) Synthesis and membrane-protective activity of novel derivatives of α-mangostin at the C-4 position. Bioorg Med Chem Lett 25:826–829. https://doi.org/10.1016/j.bmcl.2014.12.075
Buravlev EV, Shevchenko OG, Anisimov AA, Suponitsky KY (2018a) Novel Mannich bases of α- and γ-mangostins: Synthesis and evaluation of antioxidant and membrane-protective activity. Eur J Med Chem 152:10–20. https://doi.org/10.1016/j.ejmech.2018.04.022
Buravlev EV, Shevchenko OG, Chukicheva IY, Kutchin AV (2018b) Synthesis and membrane-protective properties of aminomethyl derivatives of quercetin at the C-8 position. Chem Pap 72:201–208. https://doi.org/10.1007/s11696-017-0272-y
Buravlev EV, Fedorova IV, Shevchenko OG (2019a) Comparative evaluation of antioxidant activity of 2-alkyl-4-methylphenols and their 6-n-octylaminomethyl derivatives. Russ Chem Bull 68:985–992. https://doi.org/10.1007/s11172-019-2508-1
Buravlev EV, Fedorova IV, Shevchenko OG, Kutchin AV (2019b) Novel aminomethyl derivatives of 4-methyl-2-prenylphenol: Synthesis and antioxidant properties. Chem Biodiversity 16:e1800637. https://doi.org/10.1002/cbdv.201800637
Buravlev EV, Shevchenko OG, Suponitsky KY (2021) Synthesis and antioxidant capacity of some derivatives of sesamol at the C-6 position. Chem Biodiversity 18:e2100221. https://doi.org/10.1002/cbdv.202100221
Cai Y, Sun M, Xing J, Corke H (2004) Antioxidant phenolic constituents in roots of Rheum officinale and Rubia cordifolia: Structure–radical scavenging activity relationships. J Agric Food Chem 52:7884–7890. https://doi.org/10.1021/jf0489116
Chawla R, Arora R, Kumar R, Sharma A, Prasad J, Singh S, Sagar R, Chaudhary P, Shukla S, Kaur G, Sharma RK, Puri SC, Dhar KL, Handa G, Gupta VK, Qazi GN (2005) Antioxidant activity of fractionated extracts of rhizomes of high-altitude Podophyllum hexandrum: Role in radiation protection. Mol Cell Biochem 273:193–208. https://doi.org/10.1007/s11010-005-0821-5
Chien SC, Wu YC, Chen ZW, Yang WC (2015) Naturally occurring anthraquinones: Chemistry and therapeutic potential in autoimmune diabetes. Evid-Based Complement Alternat Med 2015:357357. https://doi.org/10.1155/2015/357357
de Alves ACS, Mainardes RM, Khalil NM (2016) Nanoencapsulation of gallic acid and evaluation of its cytotoxicity and antioxidant activity. Mater Sci Eng C 60:126–134. https://doi.org/10.1016/j.msec.2015.11.014
Diaz-Muñoz G, Miranda IL, Sartori SK, de Rezende DC, Diaz MAN (2018) Chapeter–11 Anthraquinones: an overview. Stud Nat Prod Chem 58:313–338. https://doi.org/10.1016/B978-0-444-64056-7.00011-8
Farag MR, Alagawany M (2018) Erythrocytes as a biological model for screening of xenobiotics toxicity. Chem-Biol Interact 279:73–83. https://doi.org/10.1016/j.cbi.2017.11.007
Fernandes JC, Eaton P, Nascimento H, Gião MS, Ramos ÓS, Belo L, Santos-Silva A, Pintado ME, Malcata FX (2010) Antioxidant activity of chitooligosaccharides upon two biological systems: Erythrocytes and bacteriophages. Carbohyd Polym 79:1101–1106. https://doi.org/10.1016/j.carbpol.2009.10.050
Gecibesler IH, Disli F, Bayindir S, Toprak M, Tufekci AR, Yaglıoglu AS, Altun M, Kocak A, Demirtas I, Adem S (2021) The isolation of secondary metabolites from Rheum ribes L. and the synthesis of new semi-synthetic anthraquinones: Isolation, synthesis and biological activity. Food Chem 342:128378. https://doi.org/10.1016/j.foodchem.2020.128378
Henkelman S, Rakhorst G, Blanton J, van Oeveren W (2009) Standardization of incubation conditions for hemolysis testing of biomaterials. Mater Sci Eng C 29:1650–1654. https://doi.org/10.1016/j.msec.2009.01.002
Inoue K, Yoshida M, Takahashi M, Shibutani M, Takagi H, Hirose M, Nishikawa A (2009) Induction of kidney and liver cancers by the natural food additive madder color in a 2-year rat carcinogenicity study. Food Chem Toxicol 47:184–191. https://doi.org/10.1016/j.fct.2008.10.031
Joshi D, Field J, Murphy J, Abdelrahim M, Schönherr H, Sparrow JR, Ellestad G, Nakanishi K, Zask A (2013) Synthesis of antioxidants for prevention of age-related macular degeneration. J Nat Prod 76(450):454. https://doi.org/10.1021/np300769c
Kaur P, Chandel M, Kumar S, Kumar N, Singh B, Kaur S (2010) Modulatory role of alizarin from Rubia cordifolia L. against genotoxicity of mutagens. Food Chem Toxicol 48:320–325. https://doi.org/10.1016/j.fct.2009.10.019
Kim JS (2013) Preliminary evaluation for comparative antioxidant activity in the water and ethanol extracts of dried citrus fruit (Citrus unshiu) peel using chemical and biochemical in vitro assays. Food Nutr Sci 4:177–188. https://doi.org/10.4236/fns.2013.42025
Ko FN, Hsiao G, Kuo YH (1997) Protection of oxidative hemolysis by demethyldiisoeugenol in normal and β-thalassemic red blood cells. Free Radic Biol Med 22:215–222. https://doi.org/10.1016/S0891-5849(96)00295-X
Kumar M, Chandel M, Kumar S, Kaur S (2012) Amelioration of oxidative stress by anthraquinones in various in vitro assays. Asian Pac J Trop Dis 2S:S692–S698. https://doi.org/10.1016/S2222-1808(12)60245-X
Laguerre M, Lecomte J, Villeneuve P (2007) Evaluation of the ability of antioxidants to counteract lipid oxidation: Existing methods, new trends and challenges. Prog Lipid Res 46:244–282. https://doi.org/10.1016/j.plipres.2007.05.002
Lee JH, Kim YG, Ryu SY, Lee J (2016) Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and the hemolytic activity of Staphylococcus aureus. Sci Rep 6:19267. https://doi.org/10.1038/srep19267
Lee HW, Ryu HW, Kang MG, Park D, Oh SR, Kim H (2017) Selective inhibition of monoamine oxidase A by purpurin, an anthraquinone. Bioorg Med Chem Lett 27:1136–1140. https://doi.org/10.1016/j.bmcl.2017.01.085
Lin J, Gao Y, Li H, Zhang L, Li X (2014) DNA protective effect of mangosteen xanthones: an in Vitro study on possible mechanisms. Adv Pharm Bull 4:147–153. https://doi.org/10.5681/apb.2014.022
Liu R, Zhao B, Wang DE, Yao T, Pang L, Tu Q, Ahmed SM, Liu JJ, Wang J (2012) Nitrogen-containing apigenin analogs: preparation and biological activity. Molecules 17:14748–14764. https://doi.org/10.3390/molecules171214748
Lu Y, Huang S, Liu Y, He S, Zhao L, Zeng X (2011) Highly selective and sensitive fluorescent turn-on chemosensor for Al3+ based on a novel photoinduced electron transfer approach. Org Lett 13:5274–5277. https://doi.org/10.1021/ol202054v
Ma L, Xiao Y, Li C, Xie ZL, Li DD, Wang YT, Ma HT, Zhu HL, Wang MH, Ye YH (2013) Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan. Bioorg Med Chem 21:6763–6770. https://doi.org/10.1016/j.bmc.2013.08.002
Malik EM, Müller CE (2016) Anthraquinones as pharmacological tools and drugs. Med Res Rev 36:705–748. https://doi.org/10.1002/med.21391
Marković Z, Filipović M, Manojlović N, Amić A, Jeremić S, Milenković D (2018) QSAR of the free radical scavenging potency of selected hydroxyanthraquinones. Chem Pap 72:2785–2793. https://doi.org/10.1007/s11696-018-0534-3
Martakov IS, Shevchenko OG, Torlopov MA, Sitnikov PA (2022) Colloidally stable conjugates of phenolic acids with γ-AlOOH nanoparticles as efficient and biocompatible nanoantioxidants. J Mol Struct 1248:131471. https://doi.org/10.1016/j.molstruc.2021.131471
Miki M, Tamai H, Mino M, Yamamoto Y, Niki E (1987) Free-radical chain oxidation of rat red blood cells by molecular oxygen and its inhibition by α-tocopherol. Arch Biochem Biophys 258:373–380. https://doi.org/10.1016/0003-9861(87)90358-4
Mistry B, Patel RV, Keum YS, Kim DH (2017) Synthesis of N-Mannich bases of berberine linking piperazine moieties revealing anticancer and antioxidant effects. Saudi J Biol Sci 24:36–44. https://doi.org/10.1016/j.sjbs.2015.09.005
Muzychkina RA (1998) Natural anthraquinones: Biological properties and physicochemical characteristics. Phasis, Moscow
Nam W, Kim SP, Nam SH, Friedman M (2017) Structure-antioxidative and anti-inflammatory activity relationships of purpurin and related anthraquinones in chemical and cell assays. Molecules 22:265. https://doi.org/10.3390/molecules22020265
Niki E (2010) Assessment of antioxidant capacity in vitro and in vivo. Free Radical Biol Med 49:503–515. https://doi.org/10.1016/j.freeradbiomed.2010.04.016
Niki E, Komuro E, Takahashi M, Urano S, Ito E, Terao K (1988) Oxidative hemolysis of erythrocytes and its inhibition by free radical scavengers. J Biol Chem 263:19809–19814. https://doi.org/10.1016/S0021-9258(19)77707-2
Podsiedlik M, Markowicz-Piasecka M, Sikora J (2020) Erythrocytes as model cells for biocompatibility assessment, cytotoxicity screening of xenobiotics and drug delivery. Chem-Biol Interact 332:109305. https://doi.org/10.1016/j.cbi.2020.109305
Quintanar-Escorza MA, González-Martínez MT, del Pilar IOM, Calderón-Salinas JV (2010) Oxidative damage increases intracellular free calcium [Ca2+]i concentration in human erythrocytes incubated with lead. Toxicol in Vitro 24:1338–1346. https://doi.org/10.1016/j.tiv.2010.05.002
Roman G (2015) Mannich bases in medicinal chemistry and drug design. Eur J Med Chem 89:743–816. https://doi.org/10.1016/j.ejmech.2014.10.076
Roman G (2022) Anticancer activity of Mannich bases: a review of recent literature. ChemMedChem 17:e202200258. https://doi.org/10.1002/cmdc.202200258
Rozin YA, Tat’yanenko LV, Buryndina EI, Barybin AS, Popova VG (1996) Alizarin derivatives as inhibitors of calcium transport. Pharm Chem J 30:520–522. https://doi.org/10.1007/BF02334638
Russkikh VV, Fokin EP (1971) α-Aminoalkylation of quinone derivatives. I. Mannich reaction with hydroxyanthraquinones. Zh Org Khim 7:371–376
Sadatsharifi M, Purgel M (2021) Radical scavenger competition of alizarin and curcumin: a mechanistic DFT study on antioxidant activity. J Mol Model 27:166. https://doi.org/10.1007/s00894-021-04778-1
Santos DB, Schiar VPP, Paixão MW, Meinerz DF, Nogueira CW, Aschner M, Rocha JBT, Barbosa NBV (2009) Hemolytic and genotoxic evaluation of organochalcogens in human blood cells in vitro. Toxicol in Vitro 23:1195–1204. https://doi.org/10.1016/j.tiv.2009.05.010
Sevgi K, Tepe B, Sarikurkcu C (2015) Antioxidant and DNA damage protection potentials of selected phenolic acids. Food Chem Toxicol 77:12–21. https://doi.org/10.1016/j.fct.2014.12.006
Shen AY, Huang MH, Liao LF, Wang TS (2005) Thymol analogues with antioxidant and L-type calcium current inhibitory activity. Drug Dev Res 64:195–202. https://doi.org/10.1002/ddr.10436
Shi DH, Huang W, Li C, Wang LT, Wang SF (2013) Synthesis, biological evaluation and molecular modeling of aloe-emodin derivatives as new acetylcholinesterase inhibitors. Bioorg Med Chem 21:1064–1073. https://doi.org/10.1016/j.bmc.2013.01.015
Singh R, Geetanjali CSMS (2004) 9,10-Anthraquinones and other biologically active compounds from the genus Rubia. Chem Biodiversity 1:1241–1264. https://doi.org/10.1002/cbdv.200490088
Singh S, Singh RP (2008) In vitro methods of assay of antioxidants: an overview. Food Rev Int 24:392–415. https://doi.org/10.1080/87559120802304269
Stefanello ST, Prestes AS, Ogunmoyole T, Salman SM, Schwab RS, Brender CR, Dornelles L, Rocha JBT, Soares FAA (2013) Evaluation of in vitro antioxidant effect of new mono and diselenides. Toxicol in Vitro 27:1433–1439. https://doi.org/10.1016/j.tiv.2013.03.001
Su GY, Chen ML, Wang KW (2020) Natural new bioactive anthraquinones from Rubiaceae. Mini-Rev Org Chem 17:872–883. https://doi.org/10.2174/1570193X17666200107092510
Sukatta U, Takenaka M, Ono H, Okadome H, Sotome I, Nanayama K, Thanapase W, Isobe S (2013) Distribution of major xanthones in the pericarp, aril, and yellow gum of mangosteen (Garcinia mangostana Linn.) fruit and their contribution to antioxidative activity. Biosci Biotechnol Biochem 77:984–987. https://doi.org/10.1271/bbb.120931
Suttirak W, Manurakchinakorn S (2014) In vitro antioxidant properties of mangosteen peel extract. J Food Sci Technol 51:3546–3558. https://doi.org/10.1007/s13197-012-0887-5
Suwalsky M, Villena F, Norris B, Cuevas YF, Sotomayor CP, Zatta P (2003) Effects of lead on the human erythrocyte membrane and molecular models. J Inorg Biochem 97:308–313. https://doi.org/10.1016/S0162-0134(03)00292-7
Tabart J, Kevers C, Pincemail J, Defraigne JO, Dommes J (2009) Comparative antioxidant capacities of phenolic compounds measured by various tests. Food Chem 113:1226–1233. https://doi.org/10.1016/j.foodchem.2008.08.013
Takebayashi J, Chen J, Tai A (2010) Chapter 20, A method for evaluation of antioxidant activity based on inhibition of free radical-induced erythrocyte hemolysis. In: Armstrong A (ed) Advanced protocols in oxidative stress II (methods in molecular biology). Humana Press, New York. https://doi.org/10.1007/978-1-60761-411-1_20
Thomson RH (1971) Naturally occurring quinines. Academic Press, London
van den Berg JJM, Op den Kamp JAF, Lubin BH, Roelofsen B, Kuypers FA (1992) Kinetics and site specificity of hydroperoxide-induced oxidative damage in red blood cells. Free Radic Biol Med 12:487–498. https://doi.org/10.1016/0891-5849(92)90102-M
Wong SP, Leong LP, Koh JHW (2006) Antioxidant activities of aqueous extracts of selected plants. Food Chem 99:775–783. https://doi.org/10.1016/j.foodchem.2005.07.058
Wrobel J, Green D, Jetter J, Kao W, Rogers J, Pérez MC, Hardenburg J, Deecher DC, López FJ, Arey BJ, Shen ES (2002) Synthesis of (bis)sulfonic acid, (bis)benzamides as follicle-stimulating hormone (FSH) antagonists. Bioorg Med Chem 10:639–656. https://doi.org/10.1016/S0968-0896(01)00324-8
Xu K, Wang P, Wang L, Liu C, Xu S, Cheng Y, Wang Y, Li Q, Lei H (2014) Quinone derivatives from the genus Rubia and their bioactivities. Chem Biodiversity 11:341–363. https://doi.org/10.1002/cbdv.201200173
Yao G, Dai W, Ye M, Huang R, Ym P, Liao ZX, Hs W (2014) Synthesis and antitumor properties of novel alizarin analogs. Med Chem Res 23:5031–5042. https://doi.org/10.1007/s00044-014-1062-5
Yen GC, Duh PD, Chuang DY (2000) Antioxidant activity of anthraquinones and anthrone. Food Chem 70:437–441. https://doi.org/10.1016/S0308-8146(00)00108-4
Zengin G, Degirmenci NS, Alpsoy L, Aktumsek A (2016) Evaluation of antioxidant, enzyme inhibition, and cytotoxic activity of three anthraquinones (alizarin, purpurin, and quinizarin). Hum Exp Toxicol 35:544–553. https://doi.org/10.1177/0960327115595687
Zhao GR, Xiang ZJ, Ye TX, Yuan YJ, Guo ZX (2006) Antioxidant activities of Salvia miltiorrhiza and Panax notoginseng. Food Chem 99:767–774. https://doi.org/10.1016/j.foodchem.2005.09.002
Zhu L, Bai YL, Zhao Y, Xing F, Li MX, Zhu S (2019) Bis(2-pyridylmethyl)amine-functionalized alizarin: an efficient and simple colorimetric sensor for fluoride and a fluorescence turn-on sensor for Al3+ in an organic solution. Dalton Trans 48:5035–5047. https://doi.org/10.1039/C9DT00859D
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This work was supported by the Ministry of Science and Higher Education of the Russian Federation (State Assignments No. 122040600073-3 and No. 122040600022-1).
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Buravlev, E.V., Shevchenko, O.G. Mannich bases of alizarin: synthesis and evaluation of antioxidant capacity. Chem. Pap. 77, 499–508 (2023). https://doi.org/10.1007/s11696-022-02492-7
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DOI: https://doi.org/10.1007/s11696-022-02492-7