Compositions for medicinal Chemistry of fullerenes

The paper presents a quantum-chemical approach to two aspects of fullerene nanomedicine related to the oxidative and antioxidant actions of fullerene. The first topic is concerned in regards photodynamic therapeutic effect of fullerene solutions. A new mechanism of the effect is proposed. The second...

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Datum:	2010
1. Verfasser:	Sheka, E.F.
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Veröffentlicht:	Інститут хімії поверхні ім. О.О. Чуйка НАН України 2010
Schriftenreihe:	Хімія, фізика та технологія поверхні
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spelling	irk-123456789-290212011-11-29T12:05:57Z Compositions for medicinal Chemistry of fullerenes Sheka, E.F. The paper presents a quantum-chemical approach to two aspects of fullerene nanomedicine related to the oxidative and antioxidant actions of fullerene. The first topic is concerned in regards photodynamic therapeutic effect of fullerene solutions. A new mechanism of the effect is proposed. The second aspect is exemplified by the consideration of two fullerene-silica complexes, namely, fullerosil and fullerosilica gel. Стаття присвячена квантово-хімічному розгляду двох аспектів наномедицини фулерену, які стосуються його оксидативної та антиоксидативної функцій. Перший аспект розглянуто по відношенню до фотодинамічного терапевтичного ефекту розчинів фулерену. Запропоновано новий механізм цього ефекту. Другий аспект обговорюється на прикладі двох комплексів фулерену з кремнеземом: фулеросилу та фулеросилікагелю. Статья посвящена квантово-химическому рассмотрению двух аспектов наномедицины фуллерена, относящихся к его оксидативной и антиоксидантной функциям. Первый аспект рассмотрен применительно к фотодинамическому терапевтическому эффекту растворов фуллерена. Предложен новый механизм этого эффекта. Второй аспект обсуждается на примере двух комплексов фуллерена с кремнеземом: фуллеросила и фуллеросиликагеля. 2010 Article Compositions for medicinal Chemistry of fullerenes / E.F. Sheka // Хімія, фізика та технологія поверхні. — 2010. — Т. 1, № 4. — С. 377-388. — Бібліогр.: 51 назв. — англ. 2079-1704 http://dspace.nbuv.gov.ua/handle/123456789/29021 544.77.05+546.26+544.353.3 en Хімія, фізика та технологія поверхні Інститут хімії поверхні ім. О.О. Чуйка НАН України
institution	Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection	DSpace DC
language	English
description	The paper presents a quantum-chemical approach to two aspects of fullerene nanomedicine related to the oxidative and antioxidant actions of fullerene. The first topic is concerned in regards photodynamic therapeutic effect of fullerene solutions. A new mechanism of the effect is proposed. The second aspect is exemplified by the consideration of two fullerene-silica complexes, namely, fullerosil and fullerosilica gel.
format	Article
author	Sheka, E.F.
spellingShingle	Sheka, E.F. Compositions for medicinal Chemistry of fullerenes Хімія, фізика та технологія поверхні
author_facet	Sheka, E.F.
author_sort	Sheka, E.F.
title	Compositions for medicinal Chemistry of fullerenes
title_short	Compositions for medicinal Chemistry of fullerenes
title_full	Compositions for medicinal Chemistry of fullerenes
title_fullStr	Compositions for medicinal Chemistry of fullerenes
title_full_unstemmed	Compositions for medicinal Chemistry of fullerenes
title_sort	compositions for medicinal chemistry of fullerenes
publisher	Інститут хімії поверхні ім. О.О. Чуйка НАН України
publishDate	2010
url	http://dspace.nbuv.gov.ua/handle/123456789/29021
citation_txt	Compositions for medicinal Chemistry of fullerenes / E.F. Sheka // Хімія, фізика та технологія поверхні. — 2010. — Т. 1, № 4. — С. 377-388. — Бібліогр.: 51 назв. — англ.
series	Хімія, фізика та технологія поверхні
work_keys_str_mv	AT shekaef compositionsformedicinalchemistryoffullerenes
first_indexed	2025-07-03T09:12:20Z
last_indexed	2025-07-03T09:12:20Z
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fulltext	Хімія, фізика та технологія поверхні. 2010. Т. 1. № 4. С. 377–388 _____________________________________________________________________________________________ ХФТП 2010. Т. 1. № 4 377 UDC 544.77.05+546.26+544.353.3 COMPOSITIONS FOR MEDICINAL CHEMISTRY OF FULLERENES E.F. Sheka Peoples` Friendship University of the Russian Federation 6 Miklukho-Maklay Street, Moscow 117198, Russia, sheka@icp.ac.ru The paper presents a quantum-chemical approach to two aspects of fullerene nanomedicine related to the oxidative and antioxidant actions of fullerene. The first topic is concerned in regards photodynamic therapeutic effect of fullerene solutions. A new mechanism of the effect is proposed. The second aspect is exemplified by the consideration of two fullerene-silica complexes, namely, fullerosil and fullerosilica gel. Статья посвящается памяти талантливого ученого, креативного лидера и большого человека, любившего науку и считавшего ее делом своей жизни, умевшего одинаково искренне радоваться своим и чужим успехам, Алексея Алексеевича Чуйко. Автору дороги все встречи и беседы с этим неординарным человеком, стимулировавшие, в частности, и это исследование. INTRODUCTION Nanomedicine of fullerene seems to be a beautiful platform to illustrate the synergetic of chemistry, biology and physics in fullerene sci- ence. The modern medicinal fullerenics is a largely explored field, actively developing and enlarging. We are not going to go into the depth of the topic and address readers to some exhausted reviews just recently appeared [1–3]. Our purpose is to show the basic grounds that lay the founda- tion of biological and medicinal applications of fullerenes to be tightly connected with distin- guished properties of fullerenes. This concerns first of all the mechanism of their therapeutic action. For today a large number of efficient bio- medical actions of fullerenes have been found among which there are antiviral, anticancer, neu- roprotective, enzymatic, antiapoptopic and many others [4–6]. The list is worthwhile to supplement by the latest sensational news on a fullerene- based gene delivery in mice [7]. Expert judg- ments suggest that this work opens a large way to test efficacy of fullerenes for in vivo applications such as insulin gene delivery to reduce blood glu- cose levels for diabetes treatment and so forth. Empirically estimated, fullerenes fulfill therapeutic functions acting as either antioxidant or oxidative agent thus revealing seemingly two contradictory behaviors. However, this two-mode behavior is just the manifestation of two appear- ances of fullerenes that are, on one hand, radicals due to the availability of a considerable number of effectively unpaired electrons ND and an effi- cient donor-acceptor (D-A) agent, on the other. Actually, the consideration of chemical behavior of fullerenes discussed in [8] clearly show that they must willingly interact with other radicals forming tightly bound compositions thus provid- ing an efficient radical scavenging. In full consis- tence with this statement, the first exhibited therapeutic function of fullerene C60 was its ac- tion as a radical scavenger [9]. Later on this laid the foundation of the antioxidant administrating of fullerenes in medical practice [10–12]. Estab- lishing the preservation of antioxidant properties in C60 derivatives in general as well as its de- pendence on the chemical structure and, mainly, on the number of attached chemical groups with a clear preference towards monoderivatives, are in a complete accordance with expected behavior of molecular chemical susceptibility and can be quantitatively described in terms of ND. It is enough to remain a clearly justified working out this pull of effectively unpaired electrons under successive fluorination [13] and hydrogenation E.F. Sheka _____________________________________________________________________________________________ 378 ХФТП 2010. Т. 1. № 4 [14]. Therefore, the antioxidant therapeutic func- tion of fullerenes is intimately connected with electronic structure of the molecule itself. Oppositely to individual-molecule character of the antioxidant action, the oxidative action of fullerenes occurs under photoexcitation of their solutions in both molecular and polar solvents in the presence of molecular oxygen. The action consists mainly in the oxidation of targets by singlet oxygen 2 1O produced in due course of photoexcitation of fullerene solutions. The differ- ence in the behavior of singlet and triplet oxygen is obviously connected with the difference in the pairing of the molecule electrons caused by dif- ferent spin multiplicity. A quantitative character- istic of the pairing can be expressed in terms of the total number of unpaired electrons ND. Calcu- lations performed within the framework of the UBS HF approach [15] expose ND = 2 for both spin states. But, if for the triplet state this finding just naturally reflects two electrons that are re- sponsible for maintaining the molecule spin mul- tiplicity, in the singlet state the availability of two effectively unpaired electrons evidences a biradi- cal character of the molecule which explains 2 1O high oxidative activity. Therefore, the photo- stimulated 2 1 2 3 OO → transformation in the pres- ence of fullerene molecule just means exempting the molecule two electrons from the spin multi- plicity service thus transforming chemically inac- tive molecule into a biradical. The presence of fullerene for the photostimu- lated 2 1 2 3 OO → transformation is absolutely manda- tory, so that the treatment was called as photody- namic fullerene therapy [16, 17]. For the reason alone that the action is provided by a complex in- volving fullerene and solvent molecules as well as molecular oxygen, it becomes clear that it is re- sulted from a particular intermolecular interaction. However, until now, the mechanism of the photo- dynamic therapy has been hidden behind a slogan "triplet state photochemical mechanism" that implies the excitation transfer over a chain of molecules according to a widely accepted scheme [16–18] 60 1 60 3 60 1 60 1 2 1 2 3 CCCC OO  →→→ →∗∗νh . Scheme 1 The scheme implies the energy transfer from the singlet photoexcited fullerene to the triplet one that further transfers the energy to convenient triplet oxygen thus transforming the latter into singlet oxygen. The first two stages of this "sin- gle-fullerene-molecule" mechanism are quite evi- dent while the third one, the most important for the final output, is quite obscure in spite of a lot of speculations available [18]. Obviously, the stage efficacy depends on the strength of the in- termolecular interaction between fullerene and oxygen molecules. Numerous quantum chemical calculations show that pairwise interaction in the C60–O2 dyad in both singlet and triplet state is practically absent. The AM1 UBS HF computa- tions [15] fully support the previous data disclos- ing the coupling energy of the dyad of cplE − equal to zero in both cases. This puts a serious problem for the explanation of the third stage of the above scheme forcing to suggest the origination of a peculiar intermolecular interaction between C60 and O2 molecules in the excited state, once absent in the ground state. However, exclusive D-A ability of fullerenes strongly influences intermolecular interaction (IMI) [8] and cannot be omitted when considering intermolecular events, particularly under photo- excitation. Let us look at oxidative fullerene- based solutions from this viewpoint. SPIN-FLIP IN THE OXYGEN MOLECULE IN FULLERENE SOLUTIONS The system under consideration consists of fullerene C60, solvent, both polar (water, etc.) and nonpolar (benzene, etc.), and oxygen. Molecules of fullerene and solvent are in singlet ground state while the ground state of oxygen molecule is trip- let. Let us call this system as photodynamic (PD) solutions. There are a few types of IMI in the so- lutions, among which we will be interested in the IMI between fullerene molecules (f–f), between fullerene and solvent molecules (f–s) and between fullerene and oxygen (f–o). So far, we have pointed aside the f–s IMI which might be impor- tant in some cases (see the influence of this inter- action on nanophotonics of fullerene solutions in [8]). In the case of such solvents as benzene and water it is very weak and can be neglected. In contrast, interaction between fullerene molecules is rather significant and causes the fullerene clusterization that is experimentally proven in many cases (see for example [19–22]). Consequently, instead of an ideal solution, the PD one presents a conglomerate of clusterized C60 molecules as shown schematically in Fig. 1. Compositions for Medicinal Chemistry of Fullerenes _____________________________________________________________________________________________ ХФТП 2010. Т. 1. № 4 379 Fig. 1. Schematic presentation of an ideal (a) and real (b) fullerene solution in the presence of molecu- lar oxygen As shown in [8], clusters of any composition of C60 molecules have properties of charge trans- fer complexes. Excitation by the UV visible light of any of them provides the formation of a pair of molecular ions that quickly relax into the ground state of neutral molecule after the light is switched off. In contrast to neutral C60, both molecular ions C60 - and C60 + efficiently interact with oxygen molecule giving coupling energy cplE of -10.03 and -10.05 kcal/mol, respectively, referring to 2 3O molecule and -0.097 and -0.115 kcal/mol in regards to 2 1O . Therefore, oxygen molecule is quite strongly held in the vicinity of both molecu- lar ions forming [ ]−+ 260 OС and [ ]++ 260 OС com- plexes as schematically shown in Fig. 2. -+ νh Fig. 2. The formation of [ ]260 2 OС +− and [ ]260 2 OС ++ complexes under photoexcitation of (C60)5 cluster UBS HF AM1 calculations for the corre- sponding pairs show [15] that the complexes are of [ ]260 2 OС +− and [ ]260 2 OС ++ compositions of the doublet spin multiplicity. Since both fullerene ions take the responsibility over the complex spin state, so that two electrons of the oxygen mole- cule that were on the service of triplet spin multi- plicity of [ ]260 3 )( OС n + dyads in the ground state are not more needed for the job and become ef- fectively unpaired thus adding two electrons to the ND pool of unpaired electrons of complexes [ ]260 2 OС +− and [ ]260 2 OС ++ . The distribution of effec- tively unpaired electrons of both complexes over their atoms, which displays the distribution of the atomic chemical susceptibility of the complexes, is shown in Fig. 3. A dominant contribution of electrons located on oxygen atoms 61 and 62 is clearly seen thus revealing the most active sites of the complexes. It should be noted that these dis- tributions are intimate characteristics of both complexes so that not oxygen itself but both complexes as a whole provide the oxidative ef- fect. The effect is lasted until the complexes exist and is practically immediately terminated if the latter disappear when the light is switched off. 0 0.2 0.4 0.6 0.8 1 1.2 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 5557 59 61 Atom number A to m ic c h em ic al s u sc e pt ib ili ty N D A , e Fig. 3. Distribution of atomic chemical susceptibility NDA over atoms of [ ]260 2 OС +− (black bars) and [ ]260 2 OС ++ (light gray bars) complexes [15]. Curve with black dots plots distribution over atoms of C60. UBS HF AM1 doublet and singlet states The obtained results make it possible to sug- gest the following mechanism that lays the foun- dation of the photodynamic effect of fullerene solutions schematically presented as [ ]260 3 )( OC n + ( )[ ]260260 2 OСC n +− − ( )[ ]260260 2 OСС n ++ −νh . Scheme 2 Here ( ) + − 60260 CС n and ( ) − − 60260 CС n present fullerene clusters incorporating molecular ions. The transformation of the triplet ground state complex into two doublet ones under photoexcitation is accompanied with a spin flip of the oxygen molecule electrons in the presence of fullerene molecule which is shown scematically in Fig. 4. This approach allows attributing photody- namical effect of fullerene solutions to a new type of chemical reactions in the modern spin chemistry. E.F. Sheka _____________________________________________________________________________________________ 380 ХФТП 2010. Т. 1. № 4 + + νh+ + - Fig. 4. Schematic presentation of the spin-flip in oxy- gen molecule under photoexcitation Since fullerene derivatives preserve D-A properties of pristine fullerene, Scheme 2 is fully applied in this case as well. So that not only C60 or C70 themselves but their derivatives can be used in PD solutions. However, parameters of the photodynamic therapy occur therewith to be dif- ferent depending on the fullerene derivative struc- ture [23]. Changing solute molecules it is possible to influence the efficacy of their clusterization that, in its turn, may either enhance or press the therapeutic effect [2, 18]. The situation appears to be similar to that occurred in nanophotonics of fullerene solution. In more details this similarity is discussed in [8]. FULLERENE–SILICA COMPLEXES FOR MEDICINAL CHEMISTRY If photodynamical therapy is mainly adminis- tered by using aqueous solution, the delivery of fullerene-based antioxidant in a living body pre- sents a serious problem. A few types of tech- niques have been suggested for medical practice until now among them there are the following mostly used [2]: 1. films or fullerene-coated surfaces containing immobilized fullerene [24] 2. aqueous suspensions of micronized crystal- line fullerene [25, 26] 3. stable colloidal fullerene solutions in water [27] 4. water soluble fullerene-based complexes [28] 5. water soluble fullerene derivatives [29]. Each of these techniques covers a large field of investigations and has own advantages and disadvantages. The author previous experience in amorphous silica study [30], complemented by knowledge about high medicinal activity of nanosize silica (NSS) [31], forced to think about a possibility of conjugation of silica and fullerene to provide an easy delivery of the medicament in the body just using NSS as a carrier of immobi- lized fullerene molecules as well as about strengthening therapeutic effects of each compo- nents in a synergetic manner [32]. As known, there are a few technological polymorphs of NSS [30, 33], among which the most popular are pyrogenic nanosized silica (PNSS, or Aerosil), silica gel (SCG), and aerogel. Either component of a possible NSS–C60 complex exhibits an appreciable medico-biological effect; for example, SCG-based enterosorbents are widely used in medicine. More versatile, the me- dicinal chemistry of PNSS has made even more impressive progress [31]. One result of these stud- ies is SILICS [34], a wide-spectrum-effect drug, which proved to be not only a highly efficient en- terosorbent, superior to all known sorbents, but also an effective medicinal agent for monotherapy of various diseases [31]. The biomedical activity of fullerenes has been discussed earlier. The main factors that make them biologically active are summarized in Table. In this connection, it is seems natural to find out what effect these two component would produce when combined. Table 1. Main factors underlying the biomedical activ- ity of pyrogenic nanosized silica (PNSS) and C60 fullerene SILICS [34] C60 fullerene [2] high hydrophobicity of the PNSS surface antioxidant activity high efficiency in the sorp- tion of proteins neuroprotective activity agglutination of a large number of microorganisms and microbial toxins antivirus and antimicrobial effect adsorption of low- molecular-weight com- pounds inhibition of enzymatic activity enhancement of the action of immunoactive drugs gene delivery inhibition of the aggrega- tion of thrombocyte, etc. The idea of creating complex drugs on the basis of NSS is not new. For example, experi- ments with PNSS covered with various medicinal agents, such as amphotericin and highly dispersed medicinal plants, demonstrated [35] that the use of such composite systems with a prolonged ac- tion of the drug may decrease its dose and en- hance its bioaccessibility, features indicative of a synergistic action of the ingredients. Moreover, composite system on the basis of fullerene and highly dispersed silica were also used [36–39]. The carrier was a highly porous SCG. It was Compositions for Medicinal Chemistry of Fullerenes _____________________________________________________________________________________________ ХФТП 2010. Т. 1. № 4 381 demonstrated that appreciable amounts of fullerene are adsorbed and/or retained in the SCG pores. Fullerene–SCG composites (fullerenized SCG, in the terminology of [36]) selectively ad- sorb low-density lipoproteins (LDLP), a property that makes them effective immunosorbents for treating atherosclerosis. But it remains unknown how C60 fullerene is bound to the carrier and how its properties change because of this binding. Empirically is known that C60 is a poor ad- sorbate in regards to NSS substrates. Thus, the specific amount of C60 fullerene (a hydrophobic substance) adsorbed on unmodified PNSS, a hy- drophilic carrier, proved extremely low. When the surface of PNSS was modified, for example, with amines, the amount of fullerene adsorbed increased substantially [40]. The specific amount of fullerene on aerogel was also very low [41]. And only SCG, according to [36–39] investiga- tions, seemed to be promising. Let us look what is going on the PNSS surface or inside SCG pore in the presence of fullerene C60. C60 FULLERENE–HIGHLY DISPERSED SILICA COMPOSITE NSSs are formed during the condensation or polymerization that accompanies the hydrolysis of silicon tetrahalides, their organic orthoesters, and silicic acid salts [33]. The commercial prod- ucts manufactured in these ways are known as Aerosil, aerogel, and SCG. A special series of experiments aimed at examining the vibrational spectra of these products (summarized in the re- view [30]) showed that the spectra of the frame- works and surface zones of these three types of silicas differ so radically that they should be con- sidered as different structural formations. The finding has led to exhibiting new structural phe- nomenon called technological polymorphism of NSS. A comprehensive understanding of the mo- tivation leading to the formation of different polymorphs gave rise to a new algorithmic ap- proach to modeling NSSs [30]. Let us briefly consider the main point of the approach. Aerosil (PNSS). Aerosil is prepared by the hydrolysis of silicon tetrachloride in an oxygen– hydrogen flame with the subsequent polyconden- sation of orthosilic acid formed at the first stage. Agglomerated solid-phase nuclei look like virtu- ally ideal particles. The particles are composed of closely packed silicon-oxygen tetrahedra (SOT) with Si–O lengths lying in a narrow interval (Fig. 5a). That the frequencies of bending (Si–O–Si and O–Si–O) and torsional vibrations are small allows the corresponding angles vary within wide limits, leading to the amorphization of the sub- stance. The most abundant functional group on the surface of the particle is the isolated silanol group. Silanediol groups are located at structural defects of the surface, but their concentration is below 10–15% [42]. Later, based on the princi- ples underlying the modeling of structures, the authors of [43–45] developed models of the inter- faces between PNSS particles and polysiloxane polymers, models that made it possible, in par- ticular, to understand why the polymer becomes stiffer upon being filled with PNSS. a b c Fig. 5. Cluster models of nanosized silica: (a) a frag- ment of an Aerosil particle comprised of 48 SOT (Si48), (b) siloxane cycle of silica gel composed of 17 SOT (Si17sg), and (c) polymer chain of aerogel composed of 12SOT (Si12ag) Silica gel (SCG). Silica gel is normally pre- pared in aqueous solutions of silicates of alkali metals in the presence of an acid [33]. The hy- E.F. Sheka _____________________________________________________________________________________________ 382 ХФТП 2010. Т. 1. № 4 drolysis of a metal silicate in an aqueous me- dium produces SOT chains of varying length, such that each silicon atom is bonded to two hy- droxyl groups (Fig. 5b). At a high concentration, chains close to form cycles composed of differ- ent numbers of silicon atoms. Brought in con- tact, such cycles form a silica gel pore in the form of a deflated football with faces of differ- ent sizes. Aerogel. The industrial technology for manu- facturing this product is the hydrolysis of tetra- ethylorthosilicate catalyzed by an acid or alkali [46]. The hydrolysis is accompanied by the for- mation of a silicate polymer in which each atom is bonded to a hydroxyl group (Fig. 5c). Inter- twining and bonding to each other, such chains form a gel. As can be seen in Fig. 5, distinctions in sili- con–oxygen structures give rise to the diversity in the structure of hydroxyl covering of these prod- ucts, a feature that manifests itself through vibra- tional spectra recorded by means of inelastic neu- tron scattering [30]. NSS models presented in Fig. 5 allow for examining the interaction of a C60 molecule with PNSS modeled by a Si48 cluster (Fig. 5a) and with SCG modeled by one or two Si17sg linear cycles. The main focus is therewith on the possibility of formation of fullerosil and fullerosilica gel. FULLEROSIL Given that the hydroxyl covering of the clus- ter is heterogeneous, let us examine how a fullerene molecule is adsorbed at two areas of its surface with different compositions of hydroxyl groups. In the first case, the molecule position is characterized by the shortest distance, Cf –Osiln, between one of its atoms and the oxygen atom of a silanol group. In the second case, the initial distance from Cf to the oxygen atom of a si- lanediol group, Osild, was determined. The at- tacking carbon atom was selected among those characterized by the highest atomic chemical susceptibility NDA [32]. It turns out that the pa- rameters of the equilibrium structures of the complex obtained by full optimization of the initial structures depend on the initial distances Cf–Osiln and Cf–Osild. At Cf–Osiln ≤ 1.2 Å and Cf–Osild ≤ 1.6 Å, the fullerene molecule is bonded to the particle surface in the configura- tions displayed in Fig. 6. At larger initial dis- tances, it is not bonded to the particle surface. a b Fig. 6. Equilibrium configurations of the Si48–C60 complex, with the fullerene molecule located near (a) silanol and (b) silanediol groups [32]. UBS HF AM1 singlet state As seen in Fig. 6, in both cases the binding of the C60 molecule to the surface occurs via the for- mation of Si–Cf bond. The carbon atom substitutes previously bound hydroxyl that after releasing is coupled to another carbon atom that is a partner by a short bond to the first one. The final configura- tion shown in Fig. 6b differs from that shown in Fig. 6a in that the silicon atom has a second hy- droxyl attached, a factor that produces a substantial effect on the coupling energy of the C60 molecule to the surface, +10.38 and –6.42 kcal/mol for the structures shown in Fig. 6a and Fig. 6b, respec- tively. Since silanediol groups reside predomi- nantly in defective areas of the particle hydroxyl covering, their characteristics vary, which is manifested as a ±1.32 kcal/mol variation in the energy of coupling the fullerene molecule to the model cluster. Thus, for the configuration shown in Fig. 6a, the attachment a fullerene molecule to a PNSS particle is an endothermic process and, there- fore, cannot occur under normal conditions. Exothermic, as it is, the formation of the second Compositions for Medicinal Chemistry of Fullerenes _____________________________________________________________________________________________ ХФТП 2010. Т. 1. № 4 383 configuration (Fig. 6b) is feasible. We believe that this process is responsible for the adsorption of small amounts of C60 on PNSS observed in [40]. According to these experimental data, the coupling energy of C60 with this substrate is on the order of a few kcal/mol. The product formed can be termed fullerosil. The sharp dependence of whether the addition occurs or not on the ini- tial distance between the molecule and the parti- cle surface is suggestive of the existence of a substantial barrier. The reaction is accompanied by 0.42 a.u. charge transfer from the particle to the fullerene. Owing to the presence of C60 molecules, fullerosil exhibits high donor- acceptor properties with the ionization potential and electron affinity being 9.58 and 2.35 eV, respectively. The obtained characteristics of fullerosil sug- gest that it may prove to be a highly efficient me- dicinal agent. A relatively low energy of binding of the C60 molecule to the surface signifies that it can be readily detached in a biological medium from the particle on which it was transported. Thus, the pharmacological activity of either com- ponent can reveal itself in the best way. At the same time, limited by the concentration of si- lanediol groups, the concentration of C60 mole- cules is low, a characteristic that may prove fa- vorable for the possible pharmacological uses of the complex in light of the specificity of the ac- tion of medicinal agents administered in ex- tremely small concentrations [47]. FULLEROSILICA GEL As discussed above, the surface covering of nanosized pores in silica gels is largely formed by silanediols. Since the presence of silanediols was demonstrated to be the necessary prerequisite for the formation fullerosil, we assumed that C60 fullerene would readily attach to siloxane rings; nevertheless, quantum-chemical calculations did not support this assumption. Fig. 7 shows the ini- tial and equilibrium configurations of the NSS– C60 complex imitated by a C60 molecule bonded to the Si17sg ring. At all reasonable values of the initial Cf–Osild distances, the C60 molecule was ejected out of the ring irrespective of whether the atoms comprising the Si–O–Si chain were al- lowed to optimize their positions or not. This means that, if silica gel were composed of indi- vidual rings, it could have not retained C60 fullerene. a b Fig. 7. Initial (a) and equilibrium (b) configurations of the Si17sg–C60 complex [32] However, SCG has a porous structure and Fig. 8 displays calculation results for an element of an SCG pore modeled by two Si17sg siloxane rings. During the optimization of the geometry of the complex the structures of the siloxane chains were fixed to reproduce the properties of the ac- tual SCG silica gel framework while the positions of the hydroxyl groups were optimized. As can be seen in Fig. 8a, the fullerene molecule remains inside the pore. No chemical contacts with the pore body via Si–C bonds as in the PNSS case are formed. To within 0.0004 a.u., no charge transfer occurs between the C60 molecule and the sur- rounding siloxane rings. Nevertheless, the cou- pling energy of this complex is quite noticeable and constitutes -4.13 kcal/mol. To make the fullerene molecule chemi- cally interact with one of the siloxane rings comprising the pore, the rings were made ap- proach each other, as shown in Fig. 8b. E.F. Sheka _____________________________________________________________________________________________ 384 ХФТП 2010. Т. 1. № 4 a b Fig. 8. Equilibrium configurations of the Si17sg–C60– Si17sg complex at normal (a) and compresed (b) configuration of siloxane rings [32] Under these conditions, the fullerene mole- cule remains inside one of the rings borrowing a hydroxyl group and a hydrogen atom from its silanediol covering. However, the coupling en- ergy of such a complex has a large positive quan- tity (41.64 kcal/mol), rendering this configuration energetically unfavorable. Therefore, when exam- ining the retention of fullerene molecules in SCG pore, such in ring configurations should be ex- cluded from consideration. Thus, the retention of a C60 molecule in a SCG is a result of the bal- anced forcing out of the molecule from each of the rings comprising the pore without the forma- tion of new chemical bonds. There is good reason to believe that such a situation will be realized in an SCG pore of arbitrary shape. Clearly, in some pores the resultant force acts so as to eject the molecule while in others, the molecule is re- tained, with the coupling energy being dependent on the characteristics of the pore. Based on these results, a generalized model of fullerosilica gel is presented in Fig. 9. Let us look how this construction makes it possible to explain the main experimental observations for fullerized SCG. Fig. 9. A model of fullerosilica gel. The pore in silica gel was built of three cycles: Si34sg, Si28sg, and Si17sg (1) The two-step adsorption isotherms for LDLP on fullerosilica gel, in contrast to single- step ones for SCG modified by aromatic mole- cules, was explained in [36, 38] by the existence of a 3D adsorption element. This explanation is in full agreement with our concept that a 3D SCG pore with a fullerene molecule retained in it can be considered as a single whole. (2) The adsorption of LDLP linearly increas- ing with the fullerene concentration points to the fullerene molecule being incorporated into the composition of a complex adsorption element in the monomeric form. This finding is fully coher- ent with the suggested general view on fullerene molecule incorporating inside the SCG pores. Consequently, the number of elements increases with the concentration of molecules introduced being limited only by the number of pores suit- able for accommodating fullerene. (3) The LDLP is adsorbed by fullerosilica gel more effectively than lipoproteins with other struc- tures can also be explained by the spatial structure of the adsorption element. As discussed in [33], the size of linear siloxane cycles only rarely exceeds 20–30 units. As can be seen in Fig. 9, the internal size of a pore composed of cycles comprised of 17, 28, and 34 SOT is commensurate with the diame- ter of the fullerene molecule, so that the latter oc- cupies a significant fraction of the pore, a configu- ration that prevents high-molecular-weight lipo- proteins from penetrating into the pore. Compositions for Medicinal Chemistry of Fullerenes _____________________________________________________________________________________________ ХФТП 2010. Т. 1. № 4 385 (4) Another feature favorable for the selective adsorption of LDLP on fullerosilica gel is the do- nor-acceptor interaction between LDLP and C60. The observed electron-exchange adsorption of LDLP [37, 38] is a direct result of this interaction in which LDLP and C60 act as a donor and an ac- ceptor, respectively. According to calculations, the high donor-acceptor characteristics of the C60 molecule experience virtually no change upon its inclusion into the composition of fullerosilica gel. For example, the ionization potential and electron affinity for the adsorption element shown in Fig. 8a were found to be 9.60 and 2.41 eV, re- spectively, as compared to 9.86 and 2.66 eV for the free molecule. It is its high electron affinity that makes the fullerene molecule so effective in donor-acceptor interactions with both LDLP and simple amines. CONCLUDING REMARKS ON NATURE OF BIOLOGICAL ACTIVITY OF FULLERENE To imagine the character of medicinal effi- ciency of drugs based on NSS-fullerene composi- tions let us come back to basics of chemical activ- ity of fullerenes. It is known that reactive oxygen- containing species, such as singlet oxygen (1O2) and superoxide ( _ 2 •O ), hydroxy (HO•), and hy- droperoxy (HOO•) radicals play an important role in regulating a predominant majority of biological processes in a living body. Normal or pathologi- cal conditions of the vital activity of biosystems are characterized by the corresponding levels of these species [47]. As other vitally important hu- man being characteristics, such as temperature, blood pressure, glucose level in blood, and so forth, a normal level of the reactive oxygen- containing species must be kept within a rather narrow interval. Thus, many pathological condi- tions are associated with an anomalously high level of overoxidation of biomolecules [47], spe- cially, lipids in cellular membranes. At the same time, it is known that a decrease in the overoxida- tion level is accompanied by the attenuation of inflammatory processes. That is why the antioxi- dant therapy is the most effective if it can support a normal overoxidation level and thus treat a wide spectrum of pathological conditions. To analyze the therapeutic activity of composi- tions based on NSS-fullerene it is necessary to compare their characteristics at atomic level with those related to fullerene-based drugs experienced in practice. Molecular-colloid solutions containing hydrated C60 molecules (C60HyFn=C60{H2O}n) [27, 48–51] seem to be a proper analog. A wide spectrum of positive therapeutic effects of C60HyFn administered in small doses, sometimes comparable with homeopathic ones, led the au- thors of [50] to assume that "…the C60HyFn show "wise" and long-term anti-oxidative activity, maybe due to the universal mechanism of the level regulation of free radicals (FR) in aqueous medium that is determined by properties of or- dered water structures". The above peculiarities of the antioxidant ac- tion of C60HyFn are undoubtedly associated with the C60 molecule being virtually free within the hydrate complex. Fullerosil and fullerosilica gel are expected to exhibit a similar antioxidant activ- ity due to the weak binding between the fullerene molecules and solid carrier. As to the specific and "wise" action of C60 fullerene, it is clearly associ- ated with the radical-type properties of the C60 molecule so that the mechanism of the scaveng- ing action of the C60 molecule and its hydrate complex is obvious. Given that each C60 molecule is capable of trapping tens of radicals, it becomes self-evident why its antioxidant ability increases with the concentration of reactive oxygen- containing species. What remains unclear is the regulatory func- tion of the fullerene. In the case of C60HyFn hy- drates, the feature is connected with a particular role of the ordered water structure that influences a recombination of free radicals. As for NSS compositions, some clues as to how this function is realized can be obtained by examining the in- teraction of a fullerene molecule with a PNSS particle. As can be seen in Fig. 6, the fullerene molecule tears the hydroxyl group away from the surface silicon atom while interacting with either a silanol or a silanediols group. Note, however, that the energies of these reactions differ signifi- cantly, even in sign. Thus, while in the former case, it is energetically more favorable for the fullerene molecule to return the hydroxy group back to the surface, in the latter one, it is more profitable to retain it. Since the electronic charac- teristics of the radical on the surface (the charges on the atoms, bond lengths, and valence indices) are similar in both cases, the distinctions in the character of the intermolecular interaction are probably associated with a cooperative effect, the characteristics of which are determined by the E.F. Sheka _____________________________________________________________________________________________ 386 ХФТП 2010. Т. 1. № 4 configuration of the atoms surrounding the at- tacked hydroxyl radical. 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Wang I.C., Tai L.A., Lee D.D. et al. C60 and water-soluble fullerene derivatives as anti- oxidants against radical-initiated lipid per- oxidation // J. Med. Chem. – 1999. – V. 42. –P. 4614–4620. 49. Andrievsky G., Klochkov V., Bordyuh A., Dovbeshko G. Comparative analysis of two aqueous-colloidal solutions of C60 fullerene with help of Ft-IR reflectance and UV-Vis spectroscopy // Chem. Phys. Lett. – 2002. – V. 364. – P. 8–17. 50. Andrievsky G., Klochkov V., Der- evyanchenko L. Is C60 fullerene molecule toxic?! // Fullerenes Nanotubes Carbon Nanostruct. – 2005. – V. 13. – P. 363–376. 51. Andrievsky G.V., Bruskov V.I., Tykhomy- rov A.A., Gudkov S.V. Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostuctures in vi- tro and in vivo // Free Rad. Biol. Med. – 2009. – V. 47. – P. 786–793. Received 25.08.2010, accepted 24.09.2010 Структури фулеренів в медичній хімії О.Ф. Шека Російський університет дружби народів вул. Миклухо-Маклая 6, Москва 117198, Росія, sheka@icp.ac.ru Стаття присвячена квантово-хімічному розгляду двох аспектів наномедицини фулерену, які стосуються його оксидативної та антиоксидативної функцій. Перший аспект розглянуто по відно- шенню до фотодинамічного терапевтичного ефекту розчинів фулерену. Запропоновано новий меха- нізм цього ефекту. Другий аспект обговорюється на прикладі двох комплексів фулерену з крем- неземом: фулеросилу та фулеросилікагелю. Структуры фуллеренов в медицинской химии Е.Ф. Шека Российский университет дружбы народов ул. Миклухо-Маклая 6, Москва 117198, Россия, sheka@icp.ac.ru Статья посвящена квантово-химическому рассмотрению двух аспектов наномедицины фуллерена, относящихся к его оксидативной и антиоксидантной функциям. Первый аспект рассмотрен применительно к фотодинамическому терапевтическому эффекту растворов фуллерена. Предложен новый механизм этого эффекта. Второй аспект обсуждается на примере двух комплексов фуллерена с кремнеземом: фуллеросила и фуллеросиликагеля.

Compositions for medicinal Chemistry of fullerenes

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