Macrocycles and Supramolecules As Antioxidants: Excellent Scaﬀolds for Development of Potential Therapeutic Agents

antioxidants

Review Macrocycles and Supramolecules as Antioxidants: Excellent Scaﬀolds for Development of Potential Therapeutic Agents

Jung-Seop Lee 1, In-ho Song 1, Pramod B. Shinde 2 and Satish Balasaheb Nimse 1,* 1 Institute of Applied Chemistry and Department of Chemistry, Hallym University, Chuncheon 200702, Korea; [email protected] (J.-S.L.); [email protected] (I.-h.S.) 2 Natural Products & Green Chemistry Division, CSIR-Central Salt and Marine Chemicals Research Institute (CSIR-CSMCRI), Academy of Scientiﬁc and Innovative Research (AcSIR), Council of Scientiﬁc and Industrial Research (CSIR), Bhavnagar 364002, Gujarat, India; [email protected] * Correspondence: [email protected]; Tel.: +82-33-248-2076

Received: 14 August 2020; Accepted: 6 September 2020; Published: 14 September 2020

Abstract: Oxidative stress due to the high levels of reactive oxygen species (ROS) that damage biomolecules (lipids, proteins, DNA) results in acute inflammation. However, without proper intervention, acute inflammation progresses to chronic inflammation and then to several chronic diseases, including cancer, myocardial infarction, cardiovascular diseases, chronic inflammation, atherosclerosis, and more. There has been extensive research on the antioxidants of natural origin. However, there are myriad possibilities for the development of synthetic antioxidants for pharmacological applications. There is an increasing interest in the identification of novel synthetic antioxidants for the modulation of biochemical processes related to ROS. In this regard, derivatives of supramolecules, such as calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, porphyrin etc. are gaining attention for their abilities to scavenge the free radicals. Supramolecular chemistry offers excellent scaffolds for the development of novel antioxidants that can be used to modulate free radical reactions and to improve the disorders related to oxidative stress. This review focuses on the interdisciplinary approach for the design and development of novel synthetic antioxidants based on supramolecular scaffolds, with potentially protective effects against oxidative stress.

Keywords: supramolecules; calix[n]arene; resorcinarene; calixtyrosol; calixpyrrole; cucurbit[n]uril; porphyrin; antioxidant; radical scavenger; oxidative stress; reactive oxygen species; reactive nitrogen species

1. Introduction Oxidative stress, due to the high levels of reactive oxygen species (ROS) that damage biomolecules (lipids, proteins, DNA), eventually leads to many chronic diseases, including cancer [1,2], myocardial infarction [3,4], cardiovascular diseases (CVD) [5–7], chronic inﬂammation [8], atherosclerosis [9] 2– and more [10,11]. Free radicals such as hydroxyl (OH•), superoxide (O •), and nitric monoxide (NO•) are the major ROS found in cells [12]. Antioxidants are the molecules that scavenge free radicals to combat cellular oxidative damage [13,14]. Antioxidants can slow or prevent the oxidation processes initiated by ROS that damages cells in the body [15]. Based on their activity, antioxidants fall into two categories: enzymatic and non-enzymatic antioxidants [16]. Enzymatic antioxidants break down and remove free radicals, while non-enzymatic antioxidants work by interrupting free radical chain reactions [17]. Antioxidants exert their eﬀect via numerous mechanisms, including inhibition of the formation of free radicals by reducing hydroperoxides (ROO•) and hydrogen peroxides, the scavenging of active free radicals, sequestering metal ions and repairing and clearing oxidative

Antioxidants 2020, 9, 859; doi:10.3390/antiox9090859 www.mdpi.com/journal/antioxidants Antioxidants 2020 9 Antioxidants 2020, , 9,, 859 x FOR PEER REVIEW 2 2of of 21 21

applications in the pharmaceutical industry due to their prophylactic and therapeutic activities damages [18]. Antioxidants, therefore, have tremendous applications in the pharmaceutical industry [19,20]. due to their prophylactic and therapeutic activities [19,20]. There is increasing interest in the identification of novel antioxidants for the modulation of There is increasing interest in the identification of novel antioxidants for the modulation of biochemical processes related to ROS [21,22]. The use of antioxidants, including enzymes, natural biochemical processes related to ROS [21,22]. The use of antioxidants, including enzymes, natural products, and synthetic compounds, is a logical therapeutic intervention for many ROS-related products, and synthetic compounds, is a logical therapeutic intervention for many ROS-related diseases, diseases, including cancer [23,24]. Considerable attention has been given to the design and including cancer [23,24]. Considerable attention has been given to the design and development of development of potent antioxidants and the determination of their radical scavenging ability in potent antioxidants and the determination of their radical scavenging ability in complex samples, complex samples, including cell culture studies and in vivo models. However, the development of includingnovel antioxidants cell culture with studies both and highin pharmacological vivo models. However, activity the and development few side effects of novel is a challenging antioxidants field with both[25]. high In this pharmacological regard, the use activity of supramolecular and few side sca effffolds,ects is aone challenging of the many field approaches [25]. In this that regard, have the been use ofused supramolecular for the development scaffolds, of onenovel of theantioxidants many approaches, can prove that fruitful have in been the usedcoming for years. the development of novelResearch antioxidants, on supramolecules can prove fruitful and intheir the applications coming years. has gained considerable attention in the last decade.Research Several on classes supramolecules of supramolecules and their have applications been developed has gained for considerablevarious applications, attention including in the last decade.chemosensors, Several biosensors, classes of supramolecules drug-delivery vehicles, have been and developed prodrugs. forHowever, various their applications, application including in the chemosensors,development of biosensors, potent antioxidants drug-delivery has yet vehicles,to be explored and prodrugs.to its full capacity. However, Hence, their supramolecular application in thescaffolds development such as of calix[n]arene, potent antioxidants resorcinarene, has yet to ca belixtyrosol, explored tocalixpyrrole, its full capacity. cucurbit[n]uril, Hence, supramolecular porphyrin scaetc.ff oldsprovide such asa calix[n]arene,novel platform resorcinarene, to design calixtyrosol,and develop calixpyrrole, novel antioxidants cucurbit[n]uril, with porphyrin both high etc. providepharmacological a novel platform activity and to design few side and effects. develop The novel development antioxidants of synthetic with both antioxidants high pharmacological is attractive, activityas it allows and one few to side manipulate effects. Thethe physicochemical development of properties synthetic antioxidantsto improve the is antioxidant attractive, asproperties it allows onefor tovarious manipulate applications. the physicochemical It is crucial to notice properties that there to improve are several the reports antioxidant on the properties inclusion complexes for various applications.of these macrocycles, It is crucial including to notice cyclodextrins that there are with several antioxidant reports on activities the inclusion [26–30]. complexes However, of thesethis macrocycles,review is focused including mainly cyclodextrins on the direct with chemical antioxidant modifications activities[ 26of– 30calix[n]arene,]. However, resorcinarene, this review is focusedcalixtyrosol, mainly calixpyrrole, on the direct cucurbit[n]uril, chemical modifications and porphyrin of scaffolds calix[n]arene, to synthesi resorcinarene,ze the novel antioxidant calixtyrosol, calixpyrrole,compounds. cucurbit[n]uril, and porphyrin scaffolds to synthesize the novel antioxidant compounds. ThisThis review review aims aims to exploreto explore the advances the advances in the developmentin the development of antioxidants, of antioxidants, based on calix[n]arene, based on resorcinarene,calix[n]arene, calixtyrosol,resorcinarene, calixpyrrole, calixtyrosol, cucurbit[n]uril, calixpyrrole, cucurbit[n]uril, and porphyrin and (Figure porphyrin1). (Figure 1).

FigureFigure 1.1. SupramolecularSupramolecular scaffolds scaffolds used used in inthe the development development of antioxidants of antioxidants (a) calix[n]arene; (a) calix[n]arene; (b) (bresorcinarene;) resorcinarene; (c) (calixtyrosol;c) calixtyrosol; (d) (calixpyrrole;d) calixpyrrole; (e) (cucurbit[n]uril;e) cucurbit[n]uril; (f) porphyrin. (f) porphyrin. 2. Supramolecular Scaffolds Used for the Development of Antioxidants 2. Supramolecular Scaffolds Used for the Development of Antioxidants 2.1. Calix[n]arene 2.1. Calix[n]arene Calixarenes are cyclic oligomers obtained by the pyrolysis of a polymer produced from Calixarenes are cyclic oligomers obtained by the pyrolysis of a polymer produced from the the condensation of formaldehyde with p-alkylphenols in the presence of a strong base [31,32]. condensation of formaldehyde with p-alkylphenols in the presence of a strong base [31,32]. Depending upon the number of monomers, they can be classified as calix[4]arene 1, calix[6]arene 2, Depending upon the number of monomers, they can be classified as calix[4]arene 1, calix[6]arene 2, and calix[8]arene 3 (Figure2). Calixarenes can be substituted with a variety of functional groups on their and calix[8]arene 3 (Figure 2). Calixarenes can be substituted with a variety of functional groups on upper and lower rims, resulting in molecules with a variety of biological applications [33]. Water-soluble their upper and lower rims, resulting in molecules with a variety of biological applications [33]. calix[4]arene derivatives have been exploited for their molecular recognition properties [34–36]. Water-soluble calix[4]arene derivatives have been exploited for their molecular recognition Since the calixarenes can be tailored to improve their water solubility, they can be excellent platforms properties [34–36]. Since the calixarenes can be tailored to improve their water solubility, they can be for the development of useful antioxidants. Calixarenes are also known to poses antioxidant features excellent platforms for the development of useful antioxidants. Calixarenes are also known to poses forantioxidant over a couple features of decades for over [ 37a couple,38]. of decades [37,38]. Antioxidants 2020, 9, 859 3 of 21 AntioxidantsAntioxidants 2020 ,2020 9, x, FOR9, x FOR PEER PEER REVIEW REVIEW 3 of 213 of 21 Antioxidants 2020, 9, x FOR PEER REVIEW 3 of 21

Figure 2. Calix[n]arene derivatives 1–6. FigureFigure 2. Calix[n]arene derivatives 11––66.. Figure 2. Calix[n]arene derivatives 1–6. Gorghiu et al. reported the contribution of p-t-butylcalix[n]arenes (4, 5 and 6) (Figure 2) in the Gorghiu et al. reported the contribution of p-tp-butylcalix[n]arenest (4, 54 and5 6) (Figure6 2) in the thermalGorghiu stability et al.of different reported types the contribution of low-density of polyethylenes- -butylcalix[n]arenes (LDPE) [39]. ( , Theyand found) (Figure that2) the in Gorghiuthermal stability et al. reported of different the types contribution of low-density of p-t -butylcalix[n]arenespolyethylenes (LDPE) ([39].4, 5 Theyand 6found) (Figure that 2)the in the theantioxidant thermal feature stability of ofp-t di-butylcalix[4]areneﬀerent types of low-density 4 is higher polyethylenesthan the p-t-butylcalix[6]arene (LDPE) [39]. They 5 and found p-t- thermalantioxidant stability feature of different of p-t-butylcalix[4]arene typesp tof low-density 4 is higher polyethylenes than the p(LDPE)-t-butylcalix[6]arene [39]. They found5 and pthat-t- the thatbutylcalix[8]arene the antioxidant 6 for feature tested of LDPE.- -butylcalix[4]arene The proposed mechanism 4 is higher is presented than the p-t-butylcalix[6]arenein Scheme 1. 5 antioxidantandbutylcalix[8]arene p-t-butylcalix[8]arene feature of 6 pfor-t-butylcalix[4]arene tested6 for LDPE. tested The LDPE. proposed The4 is proposedhigher mechanism than mechanism is the presented p-t is-butylcalix[6]arene presented in Scheme in 1. Scheme 51 .and p-t- butylcalix[8]arene 6 for tested LDPE. The proposed mechanism is presented in Scheme 1.

OOR ROO ROO OOR ROO ROO ROOH ROOH OOR n n n ROO n ROOn n n n OH O OH O OH O OHOH OHOH ROOH OH O OH O OH O n n n n Scheme 1. Mechanism of radical scavenging activity of t-butylcalix[n]arene derivatives. OH OHScheme 1. MechanismOH of radical Oscavenging activityOH of t-butylcalix[n]areneO derivatives.OH O AmongAmong the thethe polyhydroxy polyhydroxypolyhydroxy phenolic phenolicphenolic compounds, compounds, the hydroxycinnamic thethe hydroxycinnamichydroxycinnamic acid derivatives acidacid derivativesderivatives are abundant areare in Scheme 1. Mechanism of radical scavenging activity of t-butylcalix[n]arene derivatives. natureabundantabundant and inarein nature reportednature andand to possess areare reportedreported strong antioxidantto possess propertiesstrong antioxidant [40–42]. The propertiesproperties amide derivatives [40–42].[40–42]. The ofThe cinnamic amide amide acidderivativesderivatives are also ofof reported cinnamiccinnamic to haveacidacid significantareare alsoalso reported radical scavengingto have significantsignificant ability [ 43radicalradical]. Considering scavengingscavenging the abilityability potential [43]. [43]. of Among the polyhydroxy phenolic compounds, the hydroxycinnamic acid derivatives are hydroxycinnamicConsideringConsidering thethe acidpotentialpotential (HA) asofof a hydroxycinnamichydroxycinnamic potent antioxidant, acid Consoli (HA) et al. asas designed aa potentpotent and antioxidant,antioxidant, synthesized ConsoliConsoli the calixarene etet al. al. abundantplatformdesigneddesigned in clusterednatureand and synthesized synthesized and with are HA thethereported [44 calixarene].calixarene to possessplatform strongclustered antioxidant withwith HAHA [44].[44]. properties [40–42]. The amide derivativesTheThe of radicalradicalcinnamic scavengingscavenging acid are andandalso antioxidantreported to activities have significant determineddetermined radical byby usingusing scavenging 2,2-diphenyl-1-2,2-diphenyl-1- ability [43]. Consideringpicrylhydrazylpicrylhydrazyl the potential radical radicalradical (DPPH(DPPH of hydroxycinnamic•••)) ) andand and AIBNAIBN AIBN•–induced•–induced acid linoleic (HA) linoleic acidasacid acida peroxidation peroxidationpotent peroxidation antioxidant, test test testshowed showed showed Consoli that that the thatthe et al. designedthecompoundscompounds compounds and synthesized 7 7 andand7 and 88 showedshowed8 theshowed calixarene enhancedenhanced enhanced activityactivityplatform activity as clusteredcompared as compared withtoto thethe to HA correspondingcorresponding the [44]. corresponding monomers monomers monomers 9 9 and and9 4 and1010 (Figure (Figure10 (Figure 3).3). 3 TheThe). The raterate rate constantconstant constant valuesvalues values (k (1 k> 1.5> 1.5 × 10410) andand) and thethe the stoichiometricstoichiometric stoichiometric factorsfactors factors nn n(number (number(number of of The radical scavenging and antioxidant1 activities× determined by using 2,2-diphenyl-1- •• 7 n 8 n picrylhydrazylDPPHDPPH• quenched/antioxidantquenchedquenched/antioxidant radical/antioxidant (DPPH•) molecule)andmolecule) AIBN for for•–induced 7 ((n = 7.7)7.7) linoleic andand and 88 ( (nacidn == 2.7)2.7) peroxidation indicatedindicated theirtheir test strong strong showed radical radical that the quenchingquenching ability. ability. compoundsquenching 7 andability. 8 showed enhanced activity as compared to the corresponding monomers 9 and 10 (Figure 3). The rate constant values (k1 > 1.5 × 104) and the stoichiometric factors n (number of DPPH• quenched/antioxidant molecule) for 7 (n = 7.7) and 8 (n = 2.7) indicated their strong radical quenching ability.

FigureFigure 3.3. StructuresStructures of calix[4 calix[4]arene]arene derivatives derivatives 77––1919. .

InIn 2012, 2012, Patel Patel et et al. al. reported reportedreported the the synthesissynthesis and and evaluation evaluation ofof of calix[4]arenecalix[4]arene calix[4]arene based based 1,3,4-oxadiazole 1,3,4-oxadiazole andand thiadiazole thiadiazole derivativesderivatives 11–1911–19 (Figure(Figure3 3))[ [45].45]. The conjugation conjugation of of 44 (((tertterttert-butylcalix[4]arene)-butylcalix[4]arene)-butylcalix[4]arene) with with 1,3,4-oxadiazole1,3,4-oxadiazole andand 1,3,4-thiadiazole1,3,4-thiadiazole derivatives allowed themthem toto synthesizesynthesize novelnovel antioxidantantioxidant Figure 3. Structures of calix[4]arene derivatives 7–19.

In 2012, Patel et al. reported the synthesis and evaluation of calix[4]arene based 1,3,4-oxadiazole and thiadiazole derivatives 11–19 (Figure 3) [45]. The conjugation of 4 (tert-butylcalix[4]arene) with 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives allowed them to synthesize novel antioxidant Antioxidants 2020,, 9,, 859x FOR PEER REVIEW 4 of 21 Antioxidants 2020, 9, x FOR PEER REVIEW 4 of 21 calixarene derivatives. All compounds showed significant DPPH• scavenging activity. Notably, the 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives allowed them• to synthesize novel antioxidant calixarenecompounds derivatives. containing All the co oxadiazolempounds showedring were significant more potent DPPH antioxidants scavenging than activity. other Notably,compounds. the calixarene derivatives. All compounds showed signiﬁcant DPPH scavenging activity. Notably, compoundsThe DPPH• containingscavenging theactivity oxadiazole of compound ring were 18 mo(82.6%),re potent containing antioxidants• oxadiazole than otherring andcompounds. S bridge the compounds• containing the oxadiazole ring were more potent antioxidants than other compounds. Theconnecting DPPH to scavenging the calix[4]arene activity moiety, of compound was comparable 18 (82.6%), with containing the ascorbic oxadiazole acid (92.0%), ring whichand S isbridge used The DPPH scavenging activity of compound 18 (82.6%), containing oxadiazole ring and S bridge connectingas a standard •to inthe the calix[4]arene assays. moiety, was comparable with the ascorbic acid (92.0%), which is used connecting to the calix[4]arene moiety, was comparable with the ascorbic acid (92.0%), which is used as a standardJames et inal. the reported assays. the synthesis and evaluation of antioxidant activities of amphiphilic as a standard in the assays. phospholipidJames et calix[4]arenes,al. reported the that synthesis mimic theand mice evaluationllular delivery of antioxidant systems activities[46]. They of evaluated amphiphilic the James et al. reported the synthesis and evaluation of antioxidant activities of amphiphilic phospholipid phospholipidantioxidant activity calix[4]arenes, compounds that 20 mimic, 21 and the 22 ,mice (Figurellular 4) deliveryusing PC12 systems cells that [46]. were They pre-treated evaluated with the antioxidantcalix[4]arenes, activity that mimic compounds the micellular 20, 21 and delivery 22, (Figure systems 4) [using46]. They PC12 evaluated cells that thewere antioxidant pre-treated activity with these compounds and then stressed with either H2O2, menadione, or glutamate. The obtained results compounds 20, 21 and 22, (Figure4) using PC12 cells2 that2 were pre-treated with these compounds and then theseindicated compounds that the andPC12 then cells stressed treated with compounds either H 20O, ,21 menadione, and 22 showed or glutamate. significant The inhibition obtained inresults ROS stressed with either H O , menadione, or glutamate. The obtained results indicated that the PC12 cells indicatedgeneration that than the thePC12 2untreated cells2 treated control compounds groups. 20 Furthermore,, 21 and 22 showed the loading significant of inhibitioncurcumin inin ROS the treated compounds 20, 21 and 22 showed significant inhibition in ROS generation than the untreated generationamphiphiles than of these the compoundsuntreated control not only groups. increases Furthermore, the delivery theof curcumin loading toof thecurcumin cytoplasm, in butthe control groups. Furthermore, the loading of curcumin in the amphiphiles of these compounds not only amphiphilesalso enhances of the these antioxidant compounds capacity. not only The increasesresults es tablishthe delivery that calix[n]arenes of curcumin toare the potentially cytoplasm, useful but increases the delivery of curcumin to the cytoplasm, but also enhances the antioxidant capacity. The results alsosynthetic enhances antioxidants. the antioxidant capacity. The results establish that calix[n]arenes are potentially useful syntheticestablish thatantioxidants. calix[n]arenes are potentially useful synthetic antioxidants.

Figure 4. Structures of calix[4 calix[4]arene]arene derivatives 20–22. Figure 4. Structures of calix[4]arene derivatives 20–22. There have been several reports on the methods to substitute the upper-rim and lower-rim of calix[4]areneThere have [47,48]. [47 ,been48]. Pur Purseveral et et al. al. reportscame came up on upwith the with anmethods idea an idea to tosubstitute to substitute substitute the the upper-rim the upper-rim upper-rim of calix[4]areneand of calix[4]arenelower-rim with of calix[4]arenewithdihydropyrimidine dihydropyrimidine [47,48]. moiety, Pur et moiety, al. as came shown as up shown inwith Scheme inan Schemeidea 2 to[49]. 2substitute[ They49]. Theydevised the devisedupper-rim a method a method of calix[4]areneto substitute to substitute withfour dihydropyrimidinefour dihydropyrimidine moietiesmoiety, moieties as at shownthe at upper-rim the in upper-rim Scheme of calix 2 of[49].[4]arene calix[4]arene They bydevised facial by facial greena method green Biginelli to Biginelli substitute reaction. reaction. fourThe dihydropyrimidineTheresulting resulting clusters clusters of moieties calix[4]arene-based of calix[4]arene-based at the upper-rim dihydropyrimidines dihydropyrimidines of calix[4]arene by (24 facial (24, 25, 25 )green )showed showed Biginelli strong strong reaction. antiradical The resultingactivity compared clusters toof thecalix[4]arene-based corresponding monomers.monomers. dihydropyrimidines (24, 25) showed strong antiradical activity compared to the corresponding monomers.

Scheme 2. SyntheticSynthetic pathway pathway to to substitute upper-rim of calix[4]arene with dihydropyrimidine [[49].49]. Scheme 2. Synthetic pathway to substitute upper-rim of calix[4]arene with dihydropyrimidine [49]. Recently, Stephens et al. reported on the structural requirements for the antioxidant activity of Recently, Stephens et al. reported on the structural requirements for the antioxidant activity of calix[n]arenes and their associated antibacterial activity [50]. In this work, they studied ten calix[n]arene calix[n]arenesRecently, Stephensand their et associatal. reporteded antibacterial on the structur activityal requirements [50]. In thisfor thework, antioxidant they studied activity ten of derivatives 26–35 for their antioxidant and antibacterial activities by linking them to Ag nanoparticles calix[n]arenescalix[n]arene derivatives and their 26associat–35 for edtheir antibacterial antioxidant andactivity antibacterial [50]. In activitiesthis work, by linkingthey studied them to tenAg (Figure5). In this study, they found that the calix[n]arenes bearing sulphonate groups on the upper-rim calix[n]arenenanoparticles derivatives (Figure 5). 26In –this35 for study, their they antioxidant found that and the antibacterial calix[n]arenes activities bearing by linkingsulphonate them groups to Ag and/or lower-rim have intrinsic antioxidant capacity. The less sulfonated calix[n]arenes necessitate nanoparticleson the upper-rim (Figure and/or 5). In thislower-rim study, theyhave found intrinsic that theantioxidant calix[n]arenes capacity. bearing The sulphonate less sulfonated groups oncalix[n]arenes the upper-rim necessitate and/or thelower-rim linkage haveto Ag intrinsicnanoparticles antioxidant in order capacity. to achieve The similarless sulfonated efficacy. calix[n]arenes necessitate the linkage to Ag nanoparticles in order to achieve similar efficacy. Antioxidants 2020, 9, x FOR PEER REVIEW 5 of 21

Therefore, these results indicate that the calix[n]arenes may be used as therapeutic agents in several diseases related to oxidative stress.

Antioxidants 2020, 9, 859 5 of 21 Antioxidants 2020, 9, x FOR PEER REVIEW 5 of 21

Therefore,the linkage these to Ag results nanoparticles indicate inthat order the calix[n]are to achievenes similar may e beﬃcacy. used Therefore,as therapeutic these agents results in indicate several diseasesthat the calix[n]arenesrelated to oxidative may be stress. used as therapeutic agents in several diseases related to oxidative stress.

Figure 5. Structures of calix[4]arene derivatives 26–35.

Lu et al. reported the theoretical study that allowed one to find a way for improving the antioxidative activity of resveratrol by calix[4]arene-like tetramer [51]. In this study, they designed tetra-(3,5-dihydroxy)styryl-calix[4]arene (36, a calix[4]arene-like tetramer of resveratrol) and theoretically studied at the DFT-BP86/6-311+G(d,p) level of theory for antioxidant activity in comparison to resveratrol 37 (Figure 6). The spin density in 4′-phenoxyl radicals and cation radicals are found to delocalize over the whole molecular skeleton of 36, which allows one to form more stable radicals than that of resveratrol. Further, it was revealed that calix[4]arene scaffold plays a crucial Figure 5. Structures of calix[4]arene derivatives 26–35. role in the delocalization Figureof the unpaired 5. Structures electron of calix[4. Therefore,]arene derivatives the synthesis 26–35 of. analogues derived from the conjugation of calix[4]arene and resveratrol derivatives can lead to potentially strong antioxidant Lu et al. reported the theoretical study that allowed one to find a way for improving molecules.Lu et al. reported the theoretical study that allowed one to find a way for improving the the antioxidative activity of resveratrol by calix[4]arene-like tetramer [51]. In this study, they designed antioxidativeRecently, activity Ni et ofal. resveratrol reported bythe calix[4]arenantiradical e-likeand tetramerantioxidative [51]. activityIn this study, of azocalix[4]arene they designed tetra-(3,5-dihydroxy)styryl-calix[4]arene (36, a calix[4]arene-like tetramer of resveratrol) and theoretically tetra-(3,5-dihydroxy)styryl-calix[4]arenederivatives 38, 39 (Figure 6) [52]. In this work,(36, theya calix[4]arene-like developed two azocalix[4]arene tetramer of resveratrol) derivatives byand a studied at the DFT-BP86/6-311+G(d,p) level of theory for antioxidant activity in comparison to resveratrol theoreticallydiazo coupling studied reaction at the between DFT-BP86/6-311+G(d,p) calix[4]arene and level diazonium of theory salts. for Theirantioxidant antiradical activity and in 37 (Figure6). The spin density in 4 -phenoxyl radicals and cation radicals are found to delocalize comparisonantioxidative to activityresveratrol of these 37 (Figure compounds0 6). The was spin eval densityuated by in tow4′-phenoxyl assays (hydroxyl radicals radicaland cation scavenging radicals over the whole molecular skeleton of 36, which allows one to form more stable radicals than that of areassay found and to thedelocalize pyrogallol over autoxidation the whole molecular inhibition skeleton assay). of The 36, whichexperimental allows oneand totheoretical form more results stable resveratrol. Further, it was revealed that calix[4]arene scaffold plays a crucial role in the delocalization of radicalsidentified than both that compounds of resveratrol. 38 and Further, 39 as potentit was revealedantiradical that and ca antioxidantlix[4]arene scaffoldagents. Theplays synergism a crucial the unpaired electron. Therefore, the synthesis of analogues derived from the conjugation of calix[4]arene rolebetween in the thedelocalization calix[4]arene of moietythe unpaired and the electron para-azo. Therefore, substituent the groups synthesis at the of analogues upper rim derived contributed from and resveratrol derivatives can lead to potentially strong antioxidant molecules. thesignificantly conjugation towards of calix[4]arene the antiradical and resveratrol and antioxidant derivatives activity. can lead to potentially strong antioxidant molecules. Recently, Ni et al. reported the antiradical and antioxidative activity of azocalix[4]arene derivatives 38, 39 (Figure 6) [52]. In this work, they developed two azocalix[4]arene derivatives by a diazo coupling reaction between calix[4]arene and diazonium salts. Their antiradical and antioxidative activity of these compounds was evaluated by tow assays (hydroxyl radical scavenging assay and the pyrogallol autoxidation inhibition assay). The experimental and theoretical results identified both compounds 38 and 39 as potent antiradical and antioxidant agents. The synergism between the calix[4]arene moiety and the para-azo substituent groups at the upper rim contributed significantly towards the antiradical and antioxidant activity. FigureFigure 6.6. StructuresStructures ofof calix[4]arenecalix[4]arene derivatives 36–39..

Recently,Iminecalix[4]arene Ni et al. reported derivatives the antiradical are known and toantioxidative possess a deep activity cavity of and azocalix[4]arene hyperconjugation derivatives [53]. 38The, 39 (Figurewater-soluble6)[ 52]. iminecalix[4]arene In this work, they developed derivatives two are azocalix[4]arene reported for derivativesthe molecular by arecognition diazo coupling of reactionvarious betweenorganic calix[4]arenemolecules [54]. and diazoniumHowever, salts.only Theirrecently, antiradical Silva et and al. antioxidative reported the activity novel of theseiminecalix[4]arene compounds was derivatives evaluated (42 by–47 tow) with assays anticandidal (hydroxyl activity radical scavenging(Scheme 3) [55]. assay However, and the pyrogallol there are autoxidation inhibition assay). The experimental and theoretical results identiﬁed both compounds 38 and 39 as potent antiradical and antioxidant agents. The synergism between the calix[4]arene moiety and the para-azo substituent groups at the upper rim contributed signiﬁcantly towards the antiradical and antioxidant activity. Figure 6. Structures of calix[4]arene derivatives 36–39. Iminecalix[4]arene derivatives are known to possess a deep cavity and hyperconjugation [53]. The water-solubleIminecalix[4]arene iminecalix[4]arene derivatives are derivatives known to are posse reportedss a deep for the cavity molecular and hyperconjugation recognition of various [53]. Theorganic water-soluble molecules [iminecalix[4]arene54]. However, only derivatives recently, Silva are etreported al. reported for the the molecular novel iminecalix[4]arene recognition of variousderivatives organic (42–47 molecules) with anticandidal [54]. However, activity (Schemeonly recently,3)[ 55]. Silva However, et al. there reported are no reportsthe novel on iminecalix[4]arene derivatives (42–47) with anticandidal activity (Scheme 3) [55]. However, there are Antioxidants 2020, 9, x FOR PEER REVIEW 6 of 21 Antioxidants 2020, 9, 859 6 of 21 AntioxidantsAntioxidants 2020 2020, 9, ,9 x, xFOR FOR PEER PEER REVIEW REVIEW 6 6of of 21 21 no reports on the antioxidant activity of iminecalixarene derivatives. This class of calixarene has a long pi-aromatic conjugation system, which with proper substitutions, can be exploited for the nonothe reports reports antioxidant on on the the activity antioxidant antioxidant of iminecalixarene activity activity of of iminecalixarene iminecalixarene derivatives. This derivatives. derivatives. class of calixarene This This class class has of of acalixarene calixarene long pi-aromatic has has a a antioxidant activities (Figure 7). longlongconjugation pi pi-aromatic-aromatic system, conjugation conjugation which with system, system, proper which which substitutions, with with prop prop canerer besubstitutions, substitutions, exploited for can can the be antioxidantbe exploited exploited activitiesfor for the the antioxidantantioxidant(Figure7). activities activities (Figure (Figure 7). 7).

Scheme 3. Synthetic pathway for various derivatives of iminecalix[4]arenes [55]. SchemeSchemeScheme 3. 3. Synthetic SyntheticSynthetic pathway pathway pathway for for for various various various derivatives derivatives derivatives of of of iminecalix[4]arenes iminecalix[4]arenes iminecalix[4]arenes [55]. [55]. [55 ].

Figure 7. Structures of iminecalix[4]arene derivatives 42–47. FigureFigureFigure 7. 7. Structures StructuresStructures of of ofiminecalix[4]arene iminecalix[4]arene iminecalix[4]arene derivatives derivatives 42 42–47–47. .. Recently, Ozgu et al. reported on the iminecalix[4]arenes containing sulphonamide moieties [56]. The novel calix[4]azacrown sulphonamide Schiff bases were synthesized by the condensation of Recently,Recently, Ozgu OzguOzgu et etet al. al. reported reportedreported on on thethe the iminecalix[4]arenesiminecalix[4]arenes iminecalix[4]arenes containing cont containingaining sulphonamide sulphona sulphonamidemide moieties moieties moieties [56 ]. calix[4]azacrown aldehydes with various primary and secondary sulphonamides. The obtained [56].[56].The The The novel novel novel calix[4]azacrown calix[4]azacrown calix[4]azacrown sulphonamide su sulphonamidelphonamide Schiff Schiff Schiff bases bases bases were were were synthesizedsynt synthesizedhesized by by the thethe condensation condensation of of compounds demonstrated relevant antioxidant activity compared with standard antioxidants used calix[4]azacrowncalix[4]azacrown aldehydesaldehydes aldehydes with with with various various various primary primar primar andy ysecondaryand and secondary secondary sulphonamides. sulphonamides. sulphonamides. The obtained The The compoundsobtained obtained in the study. compoundscompoundsdemonstrated demonstrated demonstrated relevant antioxidant relevant relevant activity antioxidant antioxidant compared activity activity with compared standardcompared antioxidantswith with standard standard used antioxidants antioxidants in the study. used used inin the the study. study. 2.2.2.2. ResorcinareneResorcinarene (calix[4]resorcinarene)(calix[4]resorcinarene) 2.2.2.2. Resorcinarene ResorcinareneResorcinarenesResorcinarenes (calix[4]resorcinarene) (calix[4]resorcinarene) areare aa typetype ofof calixarenecalixarene obtainedobtainedby bythe thecondensation condensationof of1,3-dihydroxybenzene 1,3-dihydroxybenzene (Resorcinol)(Resorcinol) withwith anan aldehydealdehyde inin anan acidicacidic environmentenvironment (Scheme(Scheme4 )[4) [57,58].57,58]. SimilarSimilar toto calix[4]arenes,calix[4]arenes, ResorcinarenesResorcinarenes are are a atype type of of calixarene calixarene obtained obtained by by the the condensation condensation of of 1,3-dihydroxybenzene 1,3-dihydroxybenzene resorcinarenesresorcinarenes also also assume assume a a cone cone shape, shape, withwith eighteight hydroxylhydroxylgroups groupson on thethe upper-rimupper-rimand and fourfour alkylalkyl (Resorcinol)(Resorcinol) with with an an aldehyde aldehyde in in an an acidic acidic environment environment (Scheme (Scheme 4) 4) [57,58]. [57,58]. Similar Similar to to calix[4]arenes, calix[4]arenes, groupsgroups onon thethe lower-rimlower-rim [[59,60].59,60]. ResorcinareneResorcinarene hashas beenbeen extensivelyextensively studiedstudied forfor variousvarious applicationsapplications resorcinarenesresorcinarenes also also assume assume a acone cone shape, shape, with with eigh eight hydroxylt hydroxyl groups groups on on the the upper-rim upper-rim and and four four alkyl alkyl alongalong thethe lineslines of of host-guest host-guest chemistry chemistry and and redox-active redox-active macrocycles macrocycles [61 [61–63].–63]. Since Since resorcinarene resorcinarene is ais groupsgroups on on the the lower-rim lower-rim [59,60]. [59,60]. Resorcinarene Resorcinarene has has been been extensively extensively studied studied for for various various applications applications polyhydroxy-supramolecule,a polyhydroxy-supramolecule, it it off offersers a highlya highly e ffiefficientcient sca scaffoldffold for for the the development development of of antioxidants antioxidants alongalong the the lines lines of of host-guest host-guest chemistry chemistry and and redox-active redox-active macrocycles macrocycles [61–63]. [61–63]. Since Since resorcinarene resorcinarene is is thatthat cancan bebe tailoredtailored byby varying varying thethe functional functional groups.groups. StableStable cycliccyclic nitroxidesnitroxides areare knownknown toto possesspossess a apolyhydroxy-supramolecule, polyhydroxy-supramolecule, it it offers offers a ahighly highly effi efficientcient scaffold scaffold for for the the development development of of antioxidants antioxidants remarkableremarkable antioxidantantioxidant activityactivity duedue toto theirtheir abilityability toto scavengescavenge superoxide,superoxide, peroxide,peroxide, andand alkylalkyl thatthat can can be be tailored tailored by by varying varying the the functional functional groups. groups. Stable Stable cyclic cyclic nitroxides nitroxides are are known known to to possess possess radicalsradicals [[64–66].64–66]. remarkableremarkable antioxidant antioxidant activity activity due due to to their their abi abilitylity to to scavenge scavenge superoxide, superoxide, peroxide, peroxide, and and alkyl alkyl radicalsradicals [64–66]. [64–66].

. Scheme 4. General scheme for the synthesis of resorcinarene derivatives. Scheme 4. General scheme for the synthesis of resorcinarene derivatives. . .

SchemeScheme 4. 4. General General scheme scheme for for the the synthesis synthesis of of resorcinarene resorcinarene derivatives. derivatives. AntioxidantsAntioxidants2020 2020, 9,, 9 859, x FOR PEER REVIEW 7 7of of 21 21

In 2009, Vovk et al. reported on the antioxidant and antiradical activities of resorcinarene tetranitroxidesIn 2009, Vovk (Figure et al. reported 8) [67]. onTh theey synthesized antioxidant andthe antiradicalresorcinarene activities (48, 49 of) resorcinarenederivatives (50 tetranitroxides–53) by the (Figureaminomethylation8) [ 67]. They synthesizedof resorcinarene the resorcinarene octols with (48 , 494-amino-TEMPO) derivatives (50 –TEMPO53) by the ((4-Amino-2,2,6,6- aminomethylation oftetramethylpiperidine-1-oxyl), resorcinarene octols with 4-amino-TEMPO and studied their TEMPO antioxidant ((4-Amino-2,2,6,6-tetramethylpiperidine-1-oxyl), activities. They found that the Tetra- andTEMPO studied resorcinarenes their antioxidant (50–53 activities.) are efficient They foundscavengers that theof DPPH Tetra- TEMPOradicals and resorcinarenes showed superoxide (50–53) are efficientdismutase-like scavengers activity. of DPPH These radicals compounds and showed were also superoxide found to dismutase-like have a high efficiency activity. These for inhibition compounds of wereABAP-induced also found toperoxidation have a high efficiencyof linoleic for acid. inhibition The macrocyclic of ABAP-induced structure peroxidation of resorcinarene of linoleic and acid. Theintramolecular macrocyclic hydrogen structure ofbonding resorcinarene had a considerable and intramolecular contribution hydrogen to the bondingantiradical had activity a considerable of these contributioncompounds. to theRecently, antiradical Ngurah activity ofreported these compounds. the antioxidant Recently, activity Ngurah reportedof C-methoxyphenyl the antioxidant activitycalix[4]resorcinarene of C-methoxyphenyl 54 (Figure calix[4]resorcinarene 8) [68]. The compound54 (Figure 856) [showed68]. The reasonable compound 56antioxidantshowed reasonable activity antioxidant(IC50 = 79activity ppm), but (IC50 less= 79than ppm), that butof vitamin less than C that (IC50 of vitamin= 20.96 ppm), C (IC50 which= 20.96 was ppm), used which as a standard was used in as a standardthis study. in Oliveira this study. et al. Oliveira reported et al.the reported synthesis the and synthesis comparative and comparative study on the study antioxidant on the antioxidant and anti- andtoxoplasma anti-toxoplasma activities activities of vanillin of vanillin 56 and56 itsand resorcinarene its resorcinarene derivative derivative 57 (Scheme57 (Scheme 5a) [69].5a) [69].

Antioxidants 2020, 9, x FOR PEER REVIEW 8 of 21 FigureFigure 8.8. StructuresStructures ofof resorcinarene derivatives 4848––5454..

The in vivo acute toxicity assays of 56 and 57 demonstrated a substantial safety margin indicated by lack toxicity up to 300 mg/kg during 14 days after administration. The obtained compound 57 exhibited more significant antioxidant activity (84.9%) as compared to vanillin 56 (19.4%). These results indicate that the resorcinarene has excellent potential for the development of antioxidant and antiradical compounds. Recently, Abosadiya et al. reported the synthesis, characterization, x-ray structure, and biological activities of c-5-bromo-2-hydroxyphenylcalix[4]-2-methyl resorcinarene 60 (Scheme 5b) [70]. The compound 60 was obtained by the condensation of 5-bromo-2- hydroxybenzaldehyde and 2-methylresorcinol in the presence of concentrated HCl. The compound 60 showed a strong activity (84.95%) in scavenging the DPPH free radicals. Since compound 60 is a polyphenolic compound, it inhibited the oxidation of DPPH, preferably using the hydrogen atoms to form the stable non-radical form of DPPH indicated by the formation of a pale-yellow color.

SchemeScheme 5. General 5. General scheme scheme for for the the synthesis synthesis of of resorcinarene resorcinarene derivative derivative (a )(a compound) compound57 containing 57 containing vanillin arms; (b) compound 60 containing 5-bromo-2-hydroxybenzene arms. vanillin arms; (b) compound 60 containing 5-bromo-2-hydroxybenzene arms.

2.3. Calixtyrosol Tyrosol is an essential antioxidant molecule with various biological activities. There has been an increasing interest in the development of strategies for the clustering of single drug units in order to design novel drugs. It is understood that the cluster effect can increase the pharmacological effect of a drug to a single drug unit [71]. Keeping this in mind, Pur et al. developed a novel calixtyrosol 64, which is a novel cluster of tyrosol (Scheme 6) [72]. The free radical scavenging assay demonstrated that the calixtyrosol 64 has superior antioxidant activity (>5 fold) as compared to the single tyrosol unit. The enhanced antioxidant activity is attributed to the cluster of four impacted tyrosol units that show a synergistic effect in interactions with radicals.

Scheme 6. General scheme for the synthesis of calixtyrosol.

2.4. Calix[4]pyrrole Calix[4]pyrroles have attracted substantial attention as supramolecular containers during the past two decades [73,74]. The calix[4]pyrroles are obtained by the condensation of pyrrole with acetone in the presence of an acid (Scheme 7a) [75]. Therefore, based on the use of ketone, the reaction with pyrrole, various derivatives of calix[4]pyrroles can be synthesized (Scheme 7b) by slight modifications in the reaction conditions [76]. Antioxidants 2020, 9, x FOR PEER REVIEW 8 of 21

Antioxidants 2020, 9, 859 8 of 21

The in vivo acute toxicity assays of 56 and 57 demonstrated a substantial safety margin indicated by lack toxicity up to 300 mg/kg during 14 days after administration. The obtained compound 57 exhibited more significant antioxidant activity (84.9%) as compared to vanillin 56 (19.4%). These results indicate that the resorcinarene has excellent potential for the development of antioxidant and antiradical compounds. Recently, Abosadiya et al. reported the synthesis, characterization, x-ray structure, and biological activities of c-5-bromo-2-hydroxyphenylcalix[4]-2-methyl resorcinarene 60 (Scheme5b) [ 70]. The compound 60 was obtained by the condensation of 5-bromo-2-hydroxybenzaldehyde and 2-methylresorcinol in the presence of concentrated HCl. The compound 60 showed a strong activity (84.95%) in scavenging the DPPH free radicals. Since compound 60 is a polyphenolic compound, it inhibitedScheme the 5. General oxidation scheme of DPPH, for the preferably synthesis of using resorcinarene the hydrogen derivative atoms (a to) compound form the stable57 containing non-radical formvanillin of DPPH arms; indicated (b) compound by the formation60 containing of 5-bromo-2-hydroxybenzene a pale-yellow color. arms.

2.3. Calixtyrosol Tyrosol isis anan essentialessential antioxidantantioxidant moleculemolecule withwith variousvarious biologicalbiological activities.activities. There has been an increasing interest in thethe development of strategies for the clustering of single drug units in order to design novel drugs.drugs. It is understoodunderstood thatthat thethe clustercluster eeffectffect can can increase increase the the pharmacological pharmacological e ffeffectect of of a druga drug to to a singlea single drug drug unit unit [71 [71].]. Keeping this in mind, Pur et al.al. developed a novel calixtyrosol 64, which is a novel cluster of tyrosol (Scheme6 6))[ [72].72]. The free radical scavengingscavenging assay demonstrated that the calixtyrosol 64 has superior antioxidantantioxidant activity activity (> 5(>5 fold) fold) as compared as comp toared the singleto the tyrosol single unit. tyrosol The enhancedunit. The antioxidant enhanced activityantioxidant is attributed activity is to attributed the cluster to the offour cluster impacted of four tyrosolimpacted units tyrosol that units show that a synergistic show a synergistic effect in interactionseffect in interactions with radicals. with radicals.

Scheme 6. General scheme for the synthesis of calixtyrosol. 2.4. Calix[4]pyrrole 2.4. Calix[4]pyrrole Calix[4]pyrroles have attracted substantial attention as supramolecular containers during the past Calix[4]pyrroles have attracted substantial attention as supramolecular containers during the two decades [73,74]. The calix[4]pyrroles are obtained by the condensation of pyrrole with acetone past two decades [73,74]. The calix[4]pyrroles are obtained by the condensation of pyrrole with in the presence of an acid (Scheme7a) [ 75]. Therefore, based on the use of ketone, the reaction with acetone in the presence of an acid (Scheme 7a) [75]. Therefore, based on the use of ketone, the reaction pyrrole, various derivatives of calix[4]pyrroles can be synthesized (Scheme7b) by slight modifications with pyrrole, various derivatives of calix[4]pyrroles can be synthesized (Scheme 7b) by slight in the reaction conditions [76]. modifications in the reaction conditions [76]. Even though the calix[4]pyrrole offers an excellent scaffold that can be tailored for the development of potent antioxidants, it has been understudied in this regard. However, the complex of Au and calix[4]pyrrole has been studied for the antioxidant and radical scavenging efficiencies. Kongor et al. reported the synthesis and modeling of calix[4]pyrrole derivative 70 wrapped Au nanoprobes for the detection of Pb(II), antioxidant, and radical scavenging activities [77]. The calix[4]pyrrole wrapped Au nanoprobes were found to scavenge 76.4% of DPPH free radicles. They also found that the calix[4]pyrrole 70 had low antioxidant activity in comparison to its complex with the Au. More study on the development of antioxidants based on calix[4]pyrrole scaffold is required. Antioxidants 2020, 9, x FOR PEER REVIEW 9 of 21

H2NHNOOCH2CO OCH2COONHNH2 (a) N H N H H HN N Acetone NH NH HN HCl H N H N

OCH COONHNH 65 66 H NHNOOCH CO 2 2 2 2 70

NH2NH2 reflux; 72h Antioxidants 2020, 9, 859 9 of 21 Antioxidants(b) 2020, 9, x FOR PEER REVIEW 9 of 21 C2H5OOCH2CO HO OCH2COOC2H5 OH OH N N H H H H NHNOOCH CO N 2 2 NH HN OCH COONHNH BH3Et2O K2CO3;BrCH2COOC2H5 2 2 + NH HN (a) 8h, 25 oC reflux, 5 days N HH N H N H N H NH HN O N CH Acetone 3 NH HN HCl H N H N OCH2COOC2H5 OH C2H5OOCH2CO 67 HO 68 69

65 OCH2COONHNH2 66 H2NHNOOCH2CO Scheme 7. (a) General scheme for the synthesis of calix[4]pyrrole 66; (b) Scheme70 for the synthesis of

calix[4]pyrrole tetrahydrazide 70. NH2NH2 reflux; 72h (b)

Even though the calix[4]pyrrole offers an excellentC2H5OOCH2 COscaffold that can be tailored for the HO OCH2COOC2H5 OH developmentOH of potent antioxidants, it has been understudied in this regard.N However, the complex N H H H N of Au and calix[4]pyrroleBH Et O has been studied forK CO th;BrCHe antioxidantCOOC H and NHradicalHN scavenging efficiencies. 3 2 NH HN 2 3 2 2 5 + o 8h, 25 C reflux, 5 days H Kongor et al. reported the synthesisH and modeling of calix[4]pyrrole Nderivative 70 wrapped Au N nanoprobesO CHfor3 the detection of Pb(II), antioxidant, and radical scavenging activities [77]. The calix[4]pyrrole wrapped Au nanoprobes were found to scavenge 76.4% of DPPH free radicles. They OCH2COOC2H5 OH C2H5OOCH2CO also found that67 the calix[4]pyrroleHO 7068 had low antioxidant activity in comparison69 to its complex with the Au. More study on the development of antioxidants based on calix[4]pyrrole scaffold is required. Scheme 7. (a) General scheme for the synthesis of calix[4]pyrrole 66;(b) Scheme for the synthesis of Scheme 7. (a) General scheme for the synthesis of calix[4]pyrrole 66; (b) Scheme for the synthesis of calix[4]pyrrole tetrahydrazide 70. 2.5. Cucurbiturilcalix[4]pyrrole (CB) tetrahydrazide 70. 2.5. CucurbiturilCucurbituril, (CB) denoted as cucurbit[n]uril, is a supramolecule obtained by the condensation of Even though the calix[4]pyrrole offers an excellent scaffold that can be tailored for the glycolurilCucurbituril, 73 with denotedformaldehyde as cucurbit[n]uril, in the presence is a supramoleculeof strong acid [78]. obtained The bymacrocycle the condensation was named of development of potent antioxidants, it has been understudied in this regard. However, the complex glycolurilcucurbituril,73 owingwith formaldehyde to its similarity in theto a presence pumpkin of ( strongcucurbitaceae acid [78family).]. The The macrocycle cucurbituril was is named often of Au and calix[4]pyrrole has been studied for the antioxidant and radical scavenging efficiencies. cucurbituril,abbreviated as owing CB[n], to highlighting its similarity the to n a glycoluril pumpkin building (cucurbitaceae blocksfamily). in the macrocycle The cucurbituril [79,80] (Scheme is often Kongor et al. reported the synthesis and modeling of calix[4]pyrrole derivative 70 wrapped Au abbreviated8). as CB[n], highlighting the n glycoluril building blocks in the macrocycle [79,80] (Scheme8). nanoprobes for the detection of Pb(II), antioxidant, and radical scavenging activities [77]. The calix[4]pyrrole wrapped Au nanoprobes were found to scavenge 76.4% of DPPH free radicles. They also found that the calix[4]pyrrole 70 had low antioxidant activity in comparison to its complex with the Au. More study on the development of antioxidants based on calix[4]pyrrole scaffold is required.

2.5. Cucurbituril (CB) Cucurbituril, denoted as cucurbit[n]uril, is a supramolecule obtained by the condensation of glycoluril 73 with formaldehyde in the presence of strong acid [78]. The macrocycle was named cucurbituril, owing to its similarity to a pumpkin (cucurbitaceae family). The cucurbituril is often abbreviated as CB[n], highlighting the n glycoluril building blocks in the macrocycle [79,80] (Scheme Scheme 8. General scheme for the synthesis of cucurbituril (CB). 8). Scheme 8. General scheme for the synthesis of cucurbituril (CB). Depending on the number of glycoluril units, there are various derivatives of cucurbit[n]uril, Depending on the number of glycoluril units, there are various derivatives of cucurbit[n]uril, including CB[5] 74, CB[6] 75, CB[7] 76, CB[8], CB[10], CB[13], CB[14], CB[15] [81–83] (Figure9). including CB[5] 74, CB[6] 75, CB[7] 76, CB[8], CB[10], CB[13], CB[14], CB[15] [81–83] (Figure 9). Cucurbiturils have been studied for a variety of applications in chemistry, biology, and drug Cucurbiturils have been studied for a variety of applications in chemistry, biology, and drug delivery deliveryAntioxidants [84 2020]. , 9, x FOR PEER REVIEW 10 of 21 [84].

Scheme 8. General scheme for the synthesis of cucurbituril (CB).

Depending on the number of glycoluril units, there are various derivatives of cucurbit[n]uril, including CB[5] 74, CB[6] 75, CB[7] 76, CB[8], CB[10], CB[13], CB[14], CB[15] [81–83] (Figure 9).

Cucurbiturils have been studied for a variety of applications in chemistry, biology, and drug delivery Figure 9. Structures of cucurbit[n]uril derivatives 74–76. [84]. Figure 9. Structures of cucurbit[n]uril derivatives 74–76.

Due to the excellent guest-binding ability of cucurbiturils in aqueous solutions, they play a significant role in the development of supramolecular nanostructures [85]. In 2013, Hou et al. constructed protein nanowires (Figure 10) through cucurbit[8]uril-based highly specific host-guest interaction [86]. The highly specific noncovalent interactions of CB[8] and a tripeptide FGG-tag, which was attached to the N-termini of dimeric glutathione S-transferase (GST), resulted in the formation of self-assembled protein nanowires. Then, the active site of selenoenzyme glutathione peroxidase (GPx) was introduced into GST for the construction of the functional protein nanowires. The functional protein nanowires that mimic the GPx-like activity showed high stability and exhibited substantial antioxidative properties to protect the mitochondria from oxidative stress. Therefore, the combination of cucurbituril host-guest interactions with proteins and enzymes presents a powerful tool for the construction of biologically active protein nanostructures.

Figure 10. Formation of protein nanowires by CB[8]-based host–guest interactions.

Since cucurbituril has been extensively studied for its host-guest chemistry, it was used for the enhancement of the antioxidant activity of known antioxidants such as resveratrol. Recently, Lu et al. reported on the use of cucurbiturils to form inclusion complexes with resveratrol (Figure 11), in order to enhance the radical scavenging activity of the resveratrol [87]. Generally, the phenolic antioxidants resveratrol demonstrate their radical scavenging activity based on three mechanisms, such as the H atom transfer (HAT) mechanism, sequential proton loss electron transfer (SPLET) Antioxidants 2020, 9, x FOR PEER REVIEW 10 of 21

Figure 9. Structures of cucurbit[n]uril derivatives 74–76. Antioxidants 2020, 9, 859 10 of 21

Due to the excellent guest-binding ability of cucurbiturils in aqueous solutions, they play a significantDue role to thein excellentthe development guest-binding of supramolecular ability of cucurbiturils nanostructures in aqueous [85]. solutions, In 2013, they playHou aet al. constructedsignificant protein role in nanowires the development (Figure of 10) supramolecular through cucurbit[8]uril-based nanostructures [85 ].highly In 2013, specific Hou host-guest et al. interactionconstructed [86]. protein The highly nanowires specific (Figure noncovalent 10) through interactions cucurbit[8]uril-based of CB[8] highly and specifica tripeptide host-guest FGG-tag, interaction [86]. The highly specific noncovalent interactions of CB[8] and a tripeptide FGG-tag, which which was attached to the N-termini of dimeric glutathione S-transferase (GST), resulted in the was attached to the N-termini of dimeric glutathione S-transferase (GST), resulted in the formation of formation of self-assembled protein nanowires. Then, the active site of selenoenzyme glutathione self-assembled protein nanowires. Then, the active site of selenoenzyme glutathione peroxidase (GPx) peroxidasewas introduced (GPx) intowas GSTintroduced for the construction into GST offor the the functional construction protein of nanowires. the functi Theonal functional protein proteinnanowires. The nanowiresfunctional that protein mimic the nanowires GPx-like activity that showedmimic highthe stabilityGPx-like and activity exhibited showed substantial high antioxidative stability and exhibitedproperties substantial to protect antioxidative the mitochondria properties from oxidative to protect stress. Therefore,the mitochondria the combination from of oxidative cucurbituril stress. Therefore,host-guest the interactions combination with of proteins cucurbituril and enzymes host-guest presents interactions a powerful toolwith for proteins the construction and enzymes of presentsbiologically a powerful active tool protein for nanostructures.the construction of biologically active protein nanostructures.

Figure 10. Formation of protein nanowires by CB[8]-based host–guest interactions. Figure 10. Formation of protein nanowires by CB[8]-based host–guest interactions. Since cucurbituril has been extensively studied for its host-guest chemistry, it was used for theSince enhancement cucurbituril of thehas antioxidantbeen extensively activity studied of known for antioxidants its host-guest such chemistry, as resveratrol. it was Recently, used for the enhancementLu et al. reported of the onantioxidant the use of cucurbiturilsactivity of known to form inclusionantioxidants complexes such as with resveratrol. resveratrol Recently, (Figure 11), Lu et al. reportedin order toon enhance the use theof cucurbiturils radical scavenging to form activity inclusion of the resveratrolcomplexes [with87]. Generally, resveratrol the (Figure phenolic 11), in orderantioxidants to enhance resveratrol the radical demonstrate scavenging their activity radical scavengingof the resveratrol activity based [87]. onGenerally, three mechanisms, the phenolic such as the H atom transfer (HAT) mechanism, sequential proton loss electron transfer (SPLET) antioxidants resveratrol demonstrate their radical scavenging activity based on three mechanisms, mechanism, and single electron transfer (SET) mechanism. Lu et al. found that the inclusion complexes such as the H atom transfer (HAT) mechanism, sequential proton loss electron transfer (SPLET) res@CB[5] 77, res@CB[5] 78, and res@CB[5] 79 show the enhanced antioxidant capacity of resveratrol (Figure 11). Recently, Kubota et al. developed a new class of artificial enzyme composed of cucurbit[10]uril, Mn-porphyrin, and imidazole [88]. They investigated a new class of artificial enzymes obtained by simply mixing the Mn-porphyrin, imidazole, and CB[10] in the aqueous solution. In this research study, they selected Mn(III)-5,10,15,20-tetrakis(1,3-dimethylimidazolium-2-yl)porphyrin (MndMIm4P) as a novel guest for CB[10]. Their simplified process has a great advantage over earlier reports that required a multi-step synthesis for the generation of artificial catalases. The preliminary in vitro study Antioxidants 2020, 9, x FOR PEER REVIEW 11 of 21

mechanism, and single electron transfer (SET) mechanism. Lu et al. found that the inclusion complexes res@CB[5] 77, res@CB[5] 78, and res@CB[5] 79 show the enhanced antioxidant capacity of resveratrol (Figure 11).

Antioxidants 2020, 9, 859 11 of 21 Antioxidants 2020, 9, x FOR PEER REVIEW 11 of 21 mechanism,in human celland lines single suggested electron that thetransfer constructed (SET) artiﬁcial mechanism. enzyme (FigureLu et 12al.) catalyticallyfound that eliminated the inclusion the ROS, including H O . The use of CB[10] in the construction of this artiﬁcial enzyme was crucial complexes res@CB[5] 772 , res@CB[5]2 78, and res@CB[5] 79 show the enhanced antioxidant capacity of to increase its bioavailability. This study is one of a kind that demonstrates the meticulous use of resveratrol (Figure 11). supramolecules has a high potential to generate novel molecules as therapeutic antioxidants.

Figure 11. Inclusion complexes of resveratrol in cucurbiturils [87].

Recently, Kubota et al. developed a new class of artificial enzyme composed of cucurbit[10]uril, Mn-porphyrin, and imidazole [88]. They investigated a new class of artificial enzymes obtained by simply mixing the Mn-porphyrin, imidazole, and CB[10] in the aqueous solution. In this research study, they selected Mn(III)-5,10,15,20-tetrakis(1,3-dimethylimidazolium-2-yl)porphyrin (MndMIm4P) as a novel guest for CB[10]. Their simplified process has a great advantage over earlier reports that required a multi-step synthesis for the generation of artificial catalases. The preliminary in vitro study in human cell lines suggested that the constructed artificial enzyme (Figure 12) catalytically eliminated the ROS, including H2O2. The use of CB[10] in the construction of this artificial enzyme was crucial to increase its bioavailability. This study is one of a kind that demonstrates the meticulous use of supramolecules has a high potential to generate novel molecules as therapeutic antioxidants. Figure 11. Inclusion complexes of resveratrol in cucurbiturils [87]. Figure 11. Inclusion complexes of resveratrol in cucurbiturils [87].

FigureFigure 12.12. AA new class of artiﬁcialartificial enzymeenzyme (MndMIm4P@CB[10];Im)(MndMIm4P@CB[10];Im) for the development of aa therapeutictherapeutic antioxidantantioxidant [[88].88]. 2.6. Porphyrin

Porphyrins, metalloporphyrins, and related tetrapyrrolic macrocyclic compounds are a class of important heterocycles due to their wide applications in chemistry and biology [89,90]. They have been employed successfully in the areas of catalysis, medicine, and material science [91]. As shown in Scheme9, a one-pot condensation of an aldehyde with pyrrole in acidic conditions can generate various derivatives of porphyrin 80. Mackensen et al. reported the neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant [92]. They found that the administration of a metalloporphyrin had a signiﬁcant neuroprotective eﬀect, as it decreases postischemic superoxide mediated oxidative stress.

Figure 12. A new class of artificial enzyme (MndMIm4P@CB[10];Im) for the development of a therapeutic antioxidant [88].

Antioxidants 2020, 9, x FOR PEER REVIEW 12 of 21 Antioxidants 2020, 9, x FOR PEER REVIEW 12 of 21 2.6. Porphyrin 2.6. Porphyrin Porphyrins, metalloporphyrins, and related tetrapyrrolic macrocyclic compounds are a class of Porphyrins, metalloporphyrins, and related tetrapyrrolic macrocyclic compounds are a class of important heterocycles due to their wide applications in chemistry and biology [89,90]. They have important heterocycles due to their wide applications in chemistry and biology [89,90]. They have been employed successfully in the areas of catalysis, medicine, and material science [91]. As shown been employed successfully in the areas of catalysis, medicine, and material science [91]. As shown in Scheme 9, a one-pot condensation of an aldehyde with pyrrole in acidic conditions can generate in Scheme 9, a one-pot condensation of an aldehyde with pyrrole in acidic conditions can generate various derivatives of porphyrin 80. Mackensen et al. reported the neuroprotection from delayed various derivatives of porphyrin 80. Mackensen et al. reported the neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant [92]. They found that the postischemic administration of a metalloporphyrin catalytic antioxidant [92]. They found that the administration of a metalloporphyrin had a significant neuroprotective effect, as it decreases Antioxidantsadministration2020, 9, 859of a metalloporphyrin had a significant neuroprotective effect, as it decreases12 of 21 postischemic superoxide mediated oxidative stress. postischemic superoxide mediated oxidative stress.

SchemeScheme 9.9. Scheme Scheme for for the the synthesis synthesis of porphyrin. Asayama et al. reported the manganese porphyrins (81, 82) functionalized with the biomolecules AsayamaAsayama et et al. al. reported reported the the manganese manganese porphyrinsporphyrins (81,, 82) functionalized withwith thethe biomoleculesbiomolecules (Figure 13)[93]. The developed porphyrin derivatives were studied for a potential role as antioxidants. (Figure(Figure 13)13) [93].[93]. TheThe developeddeveloped porphyrinporphyrin derivaderivativestives were studied forfor aa potentialpotential rolerole asas The Mn-porphyrin (MnP) conjugated to catalase (81) was evaluated for its ability to catalyze antioxidants.antioxidants. The The Mn-porphyrin Mn-porphyrin (MnP)(MnP) conjugatedconjugated toto catalase (81) was evaluated forfor itsits abilityability toto the reduction of H2O2 to H2O. This derivative was found to possess a dual function as SOD and catalase. catalyzecatalyze the the reduction reduction of of H H2O2O2 2to to H H22O.O. ThisThis derivativederivative was found to possess a dualdual functionfunction asas SODSOD Theandand carbohydratecatalase. catalase. The The carbohydrate conjugatedcarbohydrate MnP conjugated conjugated (82) facilitated MnPMnP ((82 the82)) facilitated anchoringfacilitated the of the anchoring conjugate ofof onthethe the conjugateconjugate cell surface on on the the by cellbindingcell surface surface to a by receptor.by binding binding The to to results aa receptor.receptor. of this TheThe study resultsresults suggest ofof this thatthis study thestudy porphyrins suggest thatthat can bethethe modiﬁed porphyrinsporphyrins to generate cancan bebe modifiedanaloguesmodified to withto generate generate potent analogues analogues antioxidant wi with activities.th potent potent antioxidantantioxidant activities.activities.

FigureFigure 13. 13. Structures StructuresStructures ofof Mn-porphyrinMn-porphyrin (MnP) conjugates 81,, 8282..

FaddaFadda et etet al. al. reported reported reported the the the pharmacological pharmacological pharmacological activitiactiviti activitieseses of novel of novel porphyrin porphyrin derivatives derivatives [94,95].[94,95]. [ 94They They,95]. Theyusedused a used acapping capping a capping mechanismmechanism mechanism toto produceproduce to produce aa seriesseries a series ofof porphyrinporphyrin of porphyrin derivatives derivatives 8383––888883 (Figure(Figure–88 (Figure 14).14). All14All). Allcompoundscompounds compounds were were were found found found to to inhibit toinhibit inhibit thethe the peroxidationperoxidation peroxidation reactionsreactions reactions in in rat rat brain brain and and kidneykidney kidney homogenateshomogenates homogenates andand rat rat erythrocyteerythrocyte erythrocyte hemolysis.hemolysis. hemolysis. TheThe The results resultsresults of ofof the thethe ABTS ABTSABTS assay assayassay indicated indicated that that the thethe compounds compoundscompounds86 8686and andand88 88haveAntioxidants88 have have a robust a arobust 2020robust antioxidant, 9, antioxidantx antioxidant FOR PEER activity, REVIEW activity, activity, indicated indicated indicated by byby the thethe 74.3% 74.3%74.3% and andand 79.5% 79.5% ABTS ABTS inhibition, inhibition,inhibition, respectively. respectively.respectively.13 of 21

Figure 14. Structures of of porphyrin porphyrin derivatives derivatives 8383––9191. .

In 2013, Tyurin et al. reported the redox characteristics and antioxidant activity of porphyrins with 2,6-dialkylphenol groups 89–91 (Figure 14) [96]. All compounds demonstrated significant DPPH scavenging activity. The antioxidant activity was attributed to the readily delocalized unpaired electron, resulting in the increased stability of a product after reaction with the radical. Kubota et al. reported a synthesis of water-soluble MnP with antioxidant activities [97]. The Mn- porphyrin derivative 92 had a fair water-solubility and possessed SOD-like catalase-like activity. As shown in Scheme 10, the mechanistic study indicated the synergism of two Mn active sites gives a catalase-like activity to the compound. The restoration of the treadmill-running ability of SOD- deficient mouse indicates that the derivative 92 exhibited strong antioxidative activity in vivo.

Scheme 10. Multiple antioxidant activities of water-soluble di-nuclear Mn-Porphyrin.

Batini-Haberle et al. reviewed the SOD mimicking the activity of Mn porphyrins [98]. As shown in Figure 15, the dismutation process involves of two steps (i) SOD enzyme or MnP-based molecule acts as a (pro)oxidant in a first step, and as an antioxidant in the second step and closes the catalytic cycle, and (ii) acting as an oxidant, they produce H2O2 in the second step. Therefore, similar to SOD, Antioxidants 2020, 9, x FOR PEER REVIEW 13 of 21

Figure 14. Structures of porphyrin derivatives 83–91. Antioxidants 2020, 9, 859 13 of 21

In 2013, Tyurin et al. reported the redox characteristics and antioxidant activity of porphyrins with 2,6-dialkyIn 2013,lphenol Tyurin groups et al. reported 89–91 (Figure the redox 14) characteristics [96]. All compounds and antioxidant demonstrated activity ofsignificant porphyrins DPPH scavengingwith 2,6-dialkylphenol activity. The groupsantioxidant89–91 (Figureactivity 14 )[was96]. attributed All compounds to the demonstrated readily delocalized signiﬁcant DPPHunpaired electron,scavenging resulting activity. in the The increased antioxidant stability activity of was a product attributed after to the reaction readily delocalized with the radical. unpaired electron, resulting in the increased stability of a product after reaction with the radical. Kubota et al. reported a synthesis of water-soluble MnP with antioxidant activities [97]. The Mn- Kubota et al. reported a synthesis of water-soluble MnP with antioxidant activities [97]. porphyrin derivative 92 had a fair water-solubility and possessed SOD-like catalase-like activity. As The Mn-porphyrin derivative 92 had a fair water-solubility and possessed SOD-like catalase-like shownactivity. in Scheme As shown 10, the in Schememechanistic 10, the study mechanistic indicate studyd the indicated synergism the synergismof two Mn of active two Mn sites active gives a catalase-likesites gives activity a catalase-like to the activity compound. to the compound.The restoration The restoration of the treadmill-running of the treadmill-running ability ability of ofSOD- deficientSOD-deﬁcient mouse indicates mouse indicates that the that derivative the derivative 92 exhibited92 exhibited strong strong antioxidative antioxidative activity activity in in vivo. vivo.

SchemeScheme 10. 10.MultipleMultiple antioxidant antioxidant activities activities of water-solublewater-soluble di-nuclear di-nuclear Mn-Porphyrin. Mn-Porphyrin. Batini-Haberle et al. reviewed the SOD mimicking the activity of Mn porphyrins [98]. As shown inBatini-Haberle Figure 15, the dismutation et al. reviewed process the involves SOD mimicking of two steps the (i) SODactivity enzyme of Mn or MnP-basedporphyrins molecule [98]. As acts shown in Figureas a (pro)oxidant 15, the dismutation in a ﬁrst step, process andas involves an antioxidant of two in steps the second (i) SOD step enzyme and closes or MnP-based the catalytic cycle,molecule acts asand a (ii)(pro)oxidant acting as an oxidant,in a first they step, produce and as H an2O 2anintioxidant the second in step. the Therefore,second step similar and to closes SOD, itsthe mimic catalytic cycle,MnPs and can(ii) beacting considered as an oxidant, to have applications they produce in antioxidative H2O2 in the defensesecond instep. physiological Therefore, conditions. similar to SOD, Tesakova et al. reported the tetraphenylporphyrene (93) and evaluation of its antioxidant activity by electrochemistry [99]. Abu-Melha reported the synthesis of meso-substituted porphyrins 94–101 and the evaluation of their antioxidant activity (Figure 16)[100]. Among derivatives 94–101, compounds 96, 98 and 101 exhibited the strongest antioxidant activity. The strong radical-scavenging activity of compounds 96 and 98 was credited to the presence of N and S atoms in their structures. It is well known that the presence of sulfur in compounds improves their radical-scavenging activity [101]. Porphyrins can be tailored to desired physicochemical properties by complexing with diﬀerent metal ions, such as manganese, copper, zinc, silver, nickel etc. [102,103]. The meso-substituted porphyrins have gained considerable interest due to their ability to act as ligands for metal ions forming the complexes that have high applicability for therapeutic purposes [104,105]. Recently, Ahmed et al. synthesized and evaluated the antioxidant and anticancer activities of porphyrin derivatives 102–106 and their metalloporphyrin counterparts 107–114 (Figure 17)[106]. All compounds showed radical-scavenging activity. However, in particular, compounds 105 and 111 showed exceptional antioxidant activity as compared to ascorbic acid, which was used as a reference. Antioxidants 2020, 9, x FOR PEER REVIEW 14 of 21

its mimic MnPs can be considered to have applications in antioxidative defense in physiological conditions.

Antioxidants 2020, 9, x FOR PEER REVIEW 14 of 21 itsAntioxidants mimic 2020MnPs, 9, 859can be considered to have applications in antioxidative defense in physiological14 of 21 conditions.

Figure 15. Mn porphyrins that mimic the SOD [98].

Tesakova et al. reported the tetraphenylporphyrene (93) and evaluation of its antioxidant activity by electrochemistry [99]. Abu-Melha reported the synthesis of meso-substituted porphyrins 94–101 and the evaluation of their antioxidant activity (Figure 16) [100]. Among derivatives 94–101, compounds 96, 98 and 101 exhibited the strongest antioxidant activity. The strong radical-scavenging activity of compounds 96 and 98 was credited to the presence of N and S atoms in their structures. It is well known that the presence of sulfur in compounds improves their radical-scavenging activity [101]. Figure 15. MnMn porphyrins porphyrins that that mimic mimic the the SOD [98]. [98].

Tesakova et al. reported the tetraphenylporphyrene (93) and evaluation of its antioxidant Antioxidants 2020, 9, x FOR PEER REVIEW 15 of 21 activity by electrochemistry [99]. Abu-Melha reported the synthesis of meso-substituted porphyrins 94–101Porphyrins and the evaluation can be tailored of their to antioxidantdesired physicoche activitymical (Figure properties 16) [100]. by Among complexing derivatives with different 94–101 , compoundsmetal ions, 96 such, 98 andas manganese,101 exhibited copper, the strongest zinc, silver,antioxidant nickel activity. etc. [102,103]. The strong The radical-scavenging meso-substituted activityporphyrins of compounds have gained 96 andconsiderable 98 was credited interest to due the topresence their ability of N andto act S atoms as ligands in their for structures. metal ions It isforming well known the complexes that the presence that have of sulfurhigh applicabilit in compoundsy for improvestherapeutic their purposes radical-scavenging [104,105]. Recently, activity [101].Ahmed et al. synthesized and evaluated the antioxidant and anticancer activities of porphyrin derivatives 102–106 and their metalloporphyrin counterparts 107–114 (Figure 17) [106]. All compounds showed radical-scavenging activity. However, in particular, compounds 105 and 111 showed exceptional antioxidant activity as compared to ascorbic acid, which was used as a reference. Figure 16. Structures of porphyrin derivatives 93–101. Figure 16. Structures of porphyrin derivatives 93–101.

Figure 16. Structures of porphyrin derivatives 93–101. FigureFigure 17.17. Structures of porphyrin derivatives 102102––114114..

3. Discussion ROS are highly reactive molecules that, in many cases, function as regulators of critical signaling pathways in living cells. The moderate levels of ROS are essential for various cellular processes, including gene expression. The elevated ROS levels alter the cell’s microenvironment and damage the several biomolecules, including proteins, DNA leading to severe diseases like cancer and CVD. The generation of ROS and other free radicals in living cells is an inevitable consequence of aerobic metabolism. The levels of these highly reactive molecules is controlled by various antioxidant enzymatic and non-enzymatic pathways in the same cells. However, as evident from the disorders as a result of dysregulation of levels of ROS, the therapeutic use of external ROS modulators is inevitable. In the last decade, the development of radical scavengers that mimic the activities of cellular enzymes such as SOD, catalase etc. has gained a tremendous interest of various scientific communities. The compounds that mimic enzyme activity function by one of the two methods, (i) by favoring a disproportionation process (SOD, catalase mimics) (ii) by undergoing reduction during the oxidation reactions (glutathione peroxidase mimics). There has been a tremendous amount of research on the identification of antioxidants from various natural sources. However, the development of synthetic antioxidants for therapeutic applications is a comparatively understudied field. The design, development, and synthesis of highly functional molecules with strong radical- scavenging activity warrants a suitable molecular scaffold that can be tailored for required physical, chemical, and biological properties. Supramolecules such as calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin were used for the development of radical scavengers (Table 1). Calix[n]arens are the excellent scaffolds for the design of synthetic antioxidants, as the upper and lower rims of these molecules can be readily transformed by using various chemical reactions. The calix[n]arenes show a considerable amount of radical scavenging ability, owing to the aromatic hydroxyl groups that help in quenching the free radicals. Similar to the resveratrol derived analogues of calix[4]arenes, several other known antioxidant moieties can be substituted on the calixarene scaffold to afford stronger radical-scavengers. The resorcinarenes, as discussed earlier, can be used for the synthesis of functional compounds that may have significant applications in redox biology. The resorcinarene derivatives are efficient DPPH radical scavengers and were found to have SOD-like activity. The ability of resorcinarene to quench the free radicals is attributed to the intramolecular hydrogen bonding of these compounds. Calixtyrosol and calixpyrrole derived compounds were found to be Antioxidants 2020, 9, 859 15 of 21

3. Discussion ROS are highly reactive molecules that, in many cases, function as regulators of critical signaling pathways in living cells. The moderate levels of ROS are essential for various cellular processes, including gene expression. The elevated ROS levels alter the cell’s microenvironment and damage the several biomolecules, including proteins, DNA leading to severe diseases like cancer and CVD. The generation of ROS and other free radicals in living cells is an inevitable consequence of aerobic metabolism. The levels of these highly reactive molecules is controlled by various antioxidant enzymatic and non-enzymatic pathways in the same cells. However, as evident from the disorders as a result of dysregulation of levels of ROS, the therapeutic use of external ROS modulators is inevitable. In the last decade, the development of radical scavengers that mimic the activities of cellular enzymes such as SOD, catalase etc. has gained a tremendous interest of various scientific communities. The compounds that mimic enzyme activity function by one of the two methods, (i) by favoring a disproportionation process (SOD, catalase mimics) (ii) by undergoing reduction during the oxidation reactions (glutathione peroxidase mimics). There has been a tremendous amount of research on the identification of antioxidants from various natural sources. However, the development of synthetic antioxidants for therapeutic applications is a comparatively understudied field. The design, development, and synthesis of highly functional molecules with strong radical-scavenging activity warrants a suitable molecular scaffold that can be tailored for required physical, chemical, and biological properties. Supramolecules such as calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin were used for the development of radical scavengers (Table1). Calix[n]arens are the excellent scaffolds for the design of synthetic antioxidants, as the upper and lower rims of these molecules can be readily transformed by using various chemical reactions. The calix[n]arenes show a considerable amount of radical scavenging ability, owing to the aromatic hydroxyl groups that help in quenching the free radicals. Similar to the resveratrol derived analogues of calix[4]arenes, several other known antioxidant moieties can be substituted on the calixarene scaffold to afford stronger radical-scavengers. The resorcinarenes, as discussed earlier, can be used for the synthesis of functional compounds that may have significant applications in redox biology. The resorcinarene derivatives are efficient DPPH radical scavengers and were found to have SOD-like activity. The ability of resorcinarene to quench the free radicals is attributed to the intramolecular hydrogen bonding of these compounds. Calixtyrosol and calixpyrrole derived compounds were found to be excellent ROS modulators. However, these classes of macromolecules warrant further investigation in the development of therapeutically useful antioxidant compounds. The cucurbituril scaffold has been used for the development of molecular containers for various applications, including the enhancement of the radical-scavenger abilities of known antioxidants. The inclusion complexes of cucurbituril with molecules like resveratrol already proved beneficial to increase the reductive power of resveratrol and similar compounds. Furthermore, the enormous study on the reaction mechanisms for the generation of novel derivatives, the cucurbituril scaffold, can be fine-tuned for the desired purposes. Hence, to see the novel antioxidants based on the cucurbituril scaffold in the near future is highly awaited. Among all supramolecules described in this review, porphyrins and their metal-complexed analogues are studied extensively; both in vitro and in vivo experiments for the radical-scavenging activities. As mentioned earlier, the porphyrin derivatives mimic the SOD and catalase like activities and thus have a great potential to be used therapeutically. Antioxidants 2020, 9, 859 16 of 21

Table 1. Antioxidant activity of selected derivatives of calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin.

DPPH Radical kinh/kp kSOD Activity Supramolecular Scaffold Compound 1 1 a 1 1 Ref. Scavenging (%) (M− S− ) (M− s− ) 7 - 7.25 105 - × [44] 8 - 5.75 105 - × Calix[n]arene 18 82.6 - - [45] 38 b 71.7 - [52] 39 b 63.2 - 50 c 0.19 0.04 - - ± 52 c 0.18 0.01 - - [67] ± Resorcinarene 54 86.3 - - 57 84.9 - - [70] 60 85.0 - - Calixtyrosol 64 Significant - - [72] Calixpyrrole 70 76.4% - - [77] 77–79 d Significant --[87] Cucurbit[n]uril MndMIm4P@CB[10];Im -- 1 107 [88] × 80 - - 5.4 105 [92] × 86 74.3 - - [95] Porphyrin 88 79.5 - - 90 77.36 - - [96] 113 83.40 - - [106] a kinhand kp—rate constant of inhibition of free radical and propagation rate constant of the chain reaction, respectively. b c [•OH] radical scavenging (%) activity. DPPH = 2,2-diphenyl-1-picrylhydrazyl radical. ECR50 = [scavenger]/[DPPH] producing 50% scavenging of DPPH after 5min reaction time. d antioxidant activity was higher than resveratrol.

4. Conclusions In conclusion, supramolecular chemistry offers several classes of macrocycles, including calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin. There are several reports on the modification reactions of these molecules to product functional compounds of desired properties. However, the application of these macromolecular scaffolds for the development of potent radical scavengers with pharmacological activities are not studied to its full potential. Therefore, this review elaborated on the derivatives of various supramolecules and their antioxidant activities. Porphyrin derivatives have a significant amount of research on their radical-scavenging abilities and reaction mechanisms supporting them. Similar to porphyrins, the calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, and cucurbit[n]uril derivatives offer great potential for the development of ROS modulators with significant pharmacological activities to prevent and treat the disorders resulting from oxidative stress.

Author Contributions: Conceptualization, J.-S.L.; I.-h.S.; P.B.S. and S.B.N.; resources, S.B.N.; data curation, J.-S.L.; I.-h.S. and S.B.N.; writing—original draft preparation, J.-S.L.; I.-h.S. and S.B.N.; writing—review and editing, P.B.S. and S.B.N.; supervision, S.B.N.; funding acquisition, S.B.N. All authors have read and agreed to the published version of the manuscript. Funding: Hallym University Research Fund (HRF-201911-008) supported this research. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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