Research Article Study of Spacer Arm Length Influence on ...downloads.hindawi.com/journals/jnm/2015/374218.pdf · Research Article In Silico Study of Spacer Arm Length Influence on

Research ArticleIn Silico Study of Spacer Arm Length Influence on DrugVectorization by Fullerene C60

Haifa Khemir1 Bahoueddine Tangour1 and Fathi Moussa2

1Research Unity of Modeling in Fundamental Sciences and Didactics Universite de Tunis El Manar IPEIEMBP 254 El Manar 2 2096 Tunis Tunisia2LETIAM Lip(Sys)2 University of Paris Sud IUT drsquoOrsay Plateau de Moulon 91400 Orsay France

Correspondence should be addressed to Bahoueddine Tangour bahatangourgmailcom

Received 12 January 2015 Revised 9 May 2015 Accepted 10 May 2015

Academic Editor Miguel A Correa-Duarte

Copyright copy 2015 Haifa Khemir et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

This work studies theoretically the effect of spacer arm lengths on the characteristics of a fullerene C60-based nanovector The

spacer arm is constituted of a carbon chain including a variable number ofmethylene groups (n= 2ndash11) To improve the ability of thefullerene carriage two arms are presented simultaneously through amalonyl bridgeThen the evolution of selected physicochemicalparameters is monitored as a function of the spacer arm length and the angle between the two arms We show here that while thestudied characteristics are almost independent of the spacer arm length or vary monotonically with it the dipole moment andits orientation vary periodically with the parity of the number of carbon atoms This periodicity is related to both modules andorientations of dipole moments of the spacer arms In the field of chemical synthesis these results highlight the importance oftheoretical calculations for the optimization of operating conditions In the field of drug discovery they show that theoreticalcalculations of the chemical properties of a drug candidate can help predict its in vivo behaviour notably its bioavailability andbiodistribution which are known to be tightly dependent of its polarity

1 Introduction

At the beginning of the 21st century the fight against cancerremains one of the major public health problems This ismainly due to some impediments that hinder the achieve-ment of significant therapeutic progress mainly toxic adverseeffects cell resistance to drugs [1] and high cost of research Apromising way to overcome these obstacles consists in usingnatural products or some of their extracts On another handdrug vectorization and targeting are now recognized as thebest way for modulating the bioavailability and thus the toxicadverse effects of an anticancer agent

Among the different platforms for vectoring active prin-ciples (AP) Fullerene C

60[2ndash4] is of particular interest

because this carbon nanostructured compound has veryinteresting biomedical features Indeed the toxicity of C

60

is now well understood [5] and its beneficial health effectsencompass a large variety of biomedical fields includingimaging photodynamic therapy gene delivery [6] oxidativestress [3 4] and even life extension [7ndash9]

There are two possible vectorization routes encapsulationof the AP within the vector or its grafting on the outer wallsThe aim of this study is to explore theoretically the vector-ization process by grafting thymoquinone (TQ) a model ofanticancer natural product on a fullerene molecule which ischaracterized by its nanometric size high lipophilicity andchemical reactivity [8]

Thymoquinone (TQ) the most abundant component ofblack seeds (Nigella sativa) has been used for centuries inthe Middle East as a natural medicine for the treatment ofmany diseases [10 11] Several pharmacological studies havedemonstrated that TQ is able to develop antioxidant anti-inflammatory and antineoplastic effects in vitro as well as invivo against various tumor cells [12ndash15] Nowadays TQ hasattracted considerable interest and many reports have shownthat the inhibitory effects of this compound are specific ofcancer cells including those of breast prostate and pancreascells [14 16 17] A previous report also showed a higheranticancer activity for nanoparticle encapsulated TQ than forfree TQ due to improved cellular uptake and bioavailability

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2015 Article ID 374218 8 pageshttpdxdoiorg1011552015374218

2 Journal of Nanomaterials

1

2

3

4

5

6

7

89

10

111213 14

1516 17

18

19

20

2122

24

23

(a) Trans

1

2

3

4

5

6

7

89

10

1112

13 14

1516 17 18

19

20

21 2223

24

(b) Cis

Figure 1 Optimized structures of thymoquinone

[18] as in vitro experiments have shown that the activity of avectorized drug and the successful operation of vectorizationstrongly depend on the type of linker used [19ndash21]

Polarity is an important characteristic of a moleculebecause it can influence its chemical physical and biolog-ical properties Some in vitro studies [23] on the activitiesof a series of histamine H

2antagonists have shown that

relatively minor structural changes greatly influence theantagonistic activity Because the molecules were very polarthese differences were attributed to the orientations of thedipole moment and interpreted by the relative alignment ofhydrogen bonding For peptides in Aib homooligomers withone two and three intramolecular hydrogen bonds dipolemoments increase with the number of Aib units by roughly23DresidueTheobtained values are 822 1079 and 1234Drespectively [24]

In the research work of Garbuio et al [25] two series ofcompounds formed by a nitroxide radical linked by a peptidebond to the fullereneC

60are similar to those of our calculated

compounds the authors have shown that the direction ofthe resulting molecular dipole moment could be changed byreversing the position of fullerene and nitroxide with respectto the nitrogen of the peptide The electrochemical analysisand chemical nitroxide reduction experiments indicate thatthe dipole moment significantly affects the redox propertiesof the two electroactive groups

Our calculations are designed to study the characteristicsand properties of the PA TQ graft on the C

60through bra

formed by a carbon chain of variable length ndash(CH2)n (119899 = 2ndash

11) This is a relatively inert motif that minimizes interactionwith different parts of the human body during drug transportIts variable length could allow better control of the overall sizeand physicochemical properties of the studied nanocarrierswhich are important parameters for their therapeutic activity

2 Computational Details

Calculations are computed by the Gaussian [26 27] packetand recovered by GAUSSVIEW program [28] Hartree-Fock

(HF) and density functional theory (DFTB3LYP) methodsare used for geometrical optimization Given the great num-ber of atoms forming the studied compound and in orderto keep the calculations time compatible with our machinesbasis sets STO-3G of moderate dimension were used Forsmall compounds the basis set 6-311G(dp) [29] has alsobeen tested We checked that all vibrational frequencies arepositive which indicates that each studied structure coincideswith a minimum on the potential surface

3 Results and Discussion

DFT technique has been shown to be reliable and commonlyused for the functional study of various nanostructures[30 31] The studied compound has a four-part structureconsisting of (i) TQ the active principle (ii) a spacer arm (iii)a connecting bridge and (iv) C

60molecule the drug carrier

To validate our computational techniques and choice of basissets we first studied the free TQ molecule In the secondsection of this work we focused on the spacer arm and thebridge The final part deals with the drug candidate that canbe synthesized and used in medicine

31 Thymoquinone Thymoquinone is the 2-isopropyl-5-methyl-14-benzoquinone whose molecular formula isC10H12O2corresponding to two geometrical isomers [32 33]

(Figure 1)The structure of TQ is optimized in order to enable the

localization of any geometrical change induced by its bindingto C60 In order to maintain the therapeutic potential of TQ

it is mandatory to avoid any structural modification after itsbinding to C

60

The calculated values of the geometrical parameters areshown in Table 1 These values are in accordance with thosecalculated by other authors [22] Two stable conformationswith C1 (trans) and Cs (cis) symmetries (Figure 1) wereidentified

Theoretical calculations clearly show that the transcon-formation is more stable than the cis oneThus we continued

Journal of Nanomaterials 3

Table 1 (a) Geometric parameters values of free and added TQ (trans) onto C60 (b)Theoretical geometric parameters values of free TQ (cis)(a)

TQ trans TQ + C60

Geometrical parameters STO-3G 6-31G(d) 6-311++G(dp) STO-3GHF B3LYP B3LYP [22] MPW1PW91 [22] MP2 [22] B3LYP [22] MPW1PW91 [22] HF

Distances (A)C4ndashC5 1503 1507 1503 1497 1494 1504 1497 1482C6ndashC1 1482 1481 1479 1474 1475 1478 1473 1503C1ndashC2 1497 1503 1498 1493 1489 1498 1493 1483C2=C3 1336 1359 1347 1343 1352 1344 1340 1336C5=C6 1338 1361 1348 1344 1354 1344 1341 1338C4ndashC3 1483 1482 1479 1475 1475 1479 1473 1497C2ndashC11 1505 1506 1499 1491 1496 1497 1489 1540C5ndashC15 1519 1520 1514 1506 1505 1512 1504 1540C15ndashC17 1547 1558 1546 1537 1536 1545 1536 1540C15ndashC21 1537 1542 1534 1525 1526 1533 1524 1540C4=O9 1227 1261 1228 1222 1240 1222 1217 1227C1=O10 1227 1261 1227 1222 1240 1222 1217 mdash

Angles (∘)C5ndashC4ndashC3 1189 1189 1186 1187 1190 1186 1186 1188C5ndashC4ndashO9 1210 1208 1211 1209 1209 1211 1210 1204C3ndashC4ndashO9 1200 1202 1203 1203 1201 1203 1203 1207

(b)

TQ CisGeometrical parameters STO-3G 6-31G(d) 6-311++G(dp)

HF B3LYP B3LYP [22] MPW1PW91 [22] MP2 [22] B3LYP [22] MPW1PW91 [22]Distances (A)C4ndashC5 1502 1507 1502 1497 1493 1503 1496C6ndashC1 1482 1481 1479 1474 1475 1478 1473C1ndashC2 1497 1503 1497 1493 1488 1498 1492C2=C3 1336 1359 1347 1343 1352 1343 1340C5=C6 1338 1361 1349 1345 1359 1346 1342C4ndashC3 1484 1483 1482 1476 1477 1480 1475C2ndashC11 1505 1506 1499 1491 1496 1497 1489C5ndashC15 1521 1523 1517 1509 1507 1516 1508C15ndashC17 1545 1553 1543 1534 1533 1542 1533C15ndashC21 1545 1553 1543 1534 1533 1542 1533C4=O9 1227 1261 1228 1223 1241 1222 1217C1=O10 1227 1261 1227 1221 1239 1222 1216

Angles (∘)C5ndashC4ndashC3 1187 1187 1184 1185 1187 1184 1185C5ndashC4ndashO9 1217 1216 1219 1218 1219 1217 1217C3ndashC4ndashO9 1195 1197 1197 1197 1194 1198 1198

the calculations by using the former one The transisomer isnot a very polar compound because its dipolemoment is onlyequal to 0336 and 0284D as calculated with HFSTO-3Gand DFT6-311G(dp) respectively

32 The Spacer Arm For the spacer arm calculations wereperformed by both HF and DFT The comparison betweenthe two results was used for results validation in orderto compensate the lack of experimental values for these

compounds Each spacer arm is formed by a saturated carbonchain and the number of methylene groups (ndashCH

2) ranged

from 2 to 11 At the chain ends two functions containing OHgroups (one primary alcohol and one carboxylic acid) werefixed to be easily substituted by chlorine atomsThe length ofthe arm is measured between these two fragments (Figure 2)Given the importance of the polarity in the interaction of TQwith the human body [34] a particular attention has beenpaid to the dipole moment


OO

TQThe spacer armC60

(a)

d1

(b)

Figure 2 Description of (a) the compound C60-spacer arm-TQ and (b) the spacer arm length (1198891 (A))

3 5 7 9 11 13 15 17

Energy RHFEnergy DFT

E (u

a)

minus800

minus700

minus600

minus500

minus400

minus300

d1 (Aring)

Figure 3 Variation of the optimization energy (119864(ua)) HF andDFTversus the length of the spacer arm (1198891 (A))

Figure 3 shows the variation of the optimized energy asa function of the spacer arm length By using HF and DFTmethods we obtained a linear relationship between bothparameters (119910 = minus3044119909 minus 22979 (1198772 = 0999) and 119910 =minus3067119909 minus 23093 (1198772 = 0999) resp) thus demonstratingthat all studied spacer arms have similar behaviour

In a multistage synthesis process the yield depends onthe correct choice of operating conditions particularly on thechoice of the appropriate solvent For these reasons a specialattentionwas given to the dipolemoments of all studied com-pounds Table 2 summarizes the dipole moment values dataThese results show large variations as a function of the lengthof the spacer arm A periodic phenomenon is observed withmaxima corresponding to even unit numbers ofmethylene (ndashCH2) and minima associated with odd numbers (Figure 4)The maxima are relatively high which is consistent with

the presence of polar moieties such as carboxylic acids andalcohols For instance Furylfulgide (Aberchrome 540) isknown to exhibit an experimental dipole moment of 72D[35]

As periodicity is observed dipole moments values takesubstantially two different levels depending on the parity ofthe number of the spacer arm carbon atoms The figuresobtained from the vector shape of dipole moments also show

Table 2 Bond length and dipole moment values of the studiedspacer arms

Compound Spacer arm length (A) Dipole moment (D)119899 1198891 HF DFT2 3721 042 0463 4918 395 3524 6254 050 0525 7482 393 3936 8806 053 0537 1005 392 3498 11365 055 0569 12617 392 34710 13998 055 05711 15185 392 349

0

2

4

6

0 3 6 9 12 15 18

HFDFT

120583(D

)

n = 3 n = 5 n = 7 n = 9 n = 11

n = 2 n = 4 n = 6 n = 8 n = 10

d1 (Aring)

Figure 4 Variation of the dipole moment (120583 (D)) versus the spacerlength (1198891 (A))

alternating orientation of direction Each dipole moment isdrawn from the electronic barycenter

To interpret both values and changes in dipole momentswe proceeded step by step First the arm was dividedinto three parts which are alcohol carboxylic acid andthe remaining CH

2chain To take reciprocal fragments

interaction into account we then computed each dipolemoment separately with the remaining atoms being replacedby dummy ones as illustrated in Figure 5 So the threecalculated dipole moments will have the same representationreferential Hence we started with the shortest odd numberof methylene group (119899 = 3) Given that one CH

2is included


AlcoholCarboxylic acid

rarr1205831 rarr

1205832 rarr120583

(a)

Alcohol

Carboxylic acid

rarr1205831

rarr1205832

rarr1205833

rarr120583

(b)

Figure 5 Dipole moment drawn from the electronic barycenter for the shortest linkers (a) 119899 = 3 and (b) 119899 = 2

d3

d2

(a)

1205731

(b)

Figure 6 Descriptors of bridged spacer arms (a)- (1198892 (A)) (1198893 (A)) and (b)- (1205731 (∘)) Optimized structures were performed with a chlorineended atom

Table 3Dipolemoment values of fragments and their combination

Carboxylic acid Alcohol CH2 119899 = 3 119899 = 2

997888rarr1205831

997888rarr1205832

997888rarr1205833997888rarr1205831 +997888rarr1205832997888rarr1205831 minus997888rarr1205832 +997888rarr1205833

119909 1681 126 0 2941 0421119910 0403 minus199 minus2411 minus1587 minus0018

119911 0 0 0 0 0

120583 (D) 1728 2355 2411 334 042395a 041a

aDFT calculated value for the studied compound

in the alcohol function the remaining carbon motif ndashCH2ndash

CH2ndash is apolar by symmetry Adding dipole moments of

fragments leads to 334D which is very close to the DFTcalculated value of 395D

Details of calculations are summarized in Table 3Roughly the same dipole moment value is obtained for allsimilar compounds with odd number of methylene groupsThis is due to the fact that the central motif is not involvedin the final dipole moment as its partial moment is equal tozero Moving now to the shortest arm that contains only asingle methylene group a carboxylic acid and an alcoholicfunction Here the CH

2group alone becomes polar Its

dipole moment is 241 D One of the other two moments willnecessarily change in direction compared to the previous casewith odd 119899 The vector sum of three contributions changesin direction and value So we get a value of 042D againclose to the DFT calculated one of 041 D A similar reasoningcan be extended to all compounds with an even numberof CH

2groups To summarize these observations whenever

a methylene group is added to the chain one of the two

ended polar fragment moments changes in direction Thusthe addition and the subtraction of their dipole moment willbe alternated

Given that the DFT technique provides consistent resultswith those obtained by the HF method results the latter waschosen for the rest of the calculations as it requires muchless computing time When the number of studied atompatterns is large theoretical calculations are performed todetermine the optimized structures with the different spacerarms attached to C

60on three levels small (119899 = 2) medium

(119899 = 5) and large (119899 = 11) In order to increase the efficiencyof the proposed protocol two spacer arms are grafted ona support to connect them simultaneously to the fullerenemoleculeThe condensation of each spacer armwithmalonyldichloride allows reaching a stable adduct Hydroxyl groupsof the carboxylic end are substituted by chlorine atoms inorder to prepare the final compound for the following stepof condensation on TQ Figure 6 depicts the descriptors 1198892and 1198893 and the 1205731 angle

Thedipolemoment of the diagram (Figure 7) is a functionof the chlorinated compound length There is a periodicityof dipole moment as a function of the spacer arm lengthHowever an inversion of the dipole moment is observed withrespect to the arm alone The highest values are obtained forodd numbers while the lowest values are linked to even onesThe HF results of the descriptors 1198892 1198893 120583 and 1205731 for thechlorinated arms are summarized in Table 4

33The Final Compound [Arm-TQ] Theoretical HF calcula-tions were performed to determine the optimized structuresof the various compounds of arm spacerrsquos condensationalong with different lengths with TQ (Figure 8)


Table 4 HF results for the chlorinated spacer arms

119899 1198892 (A) 1198893 (A) 120583 (D) 1205731 (∘)2 3736 10293 537 119213 4974 12143 385 119334 6254 14583 558 119965 7538 16567 394 120036 8853 18941 563 119917 10105 21011 397 120258 11414 23371 566 120279 12677 25453 400 1202010 13977 27783 566 1202311 15245 29891 402 12019

3

4

5

6

0 3 6 9 12 15 18

120583(D

)

n = 2 n = 4 n = 6 n = 8 n = 10

n = 3 n = 5 n = 7 n = 9 n = 11

d2 (Aring)

Figure 7 Dipole moment (120583 (D)) values versus the length (1198892 (A))of the bridged and chlorinated linker

d4

d5

1205732

Figure 8 The distances (1198894 (A)) (1198895 (A)) and (1205732 (∘)) of thecompound arm and TQ

Table 5 Characteristics of studied compounds [arm-TQ]

Compounds119899

1198894 (A) 1198895 (A) 120583 (D) 1205732 (∘)

2 374351 1325676 1165 101559295 748692 1767825 648 902277211 1491388 3209813 798 8076277

The relationship between the distance and the angle of thearm shown in Figure 9 obeys the following equation (Table 5)119910 = minus1778119909 + 1063 (1198772 = 0943)

The angle of the two support arms decreases when thedistance from the spacer arm increases

34 Grafting the Final Compound [Arm-TQ] on C60 Theeffect of grafting on TQ structure and the experimentalgeometric parameters for the free TQ grafted onto fullerene

70

80

90

100

110

0 5 10 15 20

1205732(∘

)

n = 2

n = 5 n = 11

d4 (Aring)

(a)

0

4

8

12

16

0 5 10 15 20

n = 2

n = 5

n = 11

d6 (Aring)

120583(D

)

120583 + C60 (D)120583 (D)

(b)

Figure 9 (a) Variation of the angle of opening (1205732 (∘)) of compound[arm-TQ] as a function of the distance of the spacer arm (1198894 (A)) (b)Variation of the dipole moment (120583 (D)) as a function of the lengthof the spacer arm (1198896 (A)) of the compound [Spacer arm-TQ-C

60]

Table 6 Descriptors 1198896 and 1198897 and dipole moment of compoundarm TQ-C60

Compounds 1198896 (A) 1198897 (A) 120583 (D)119899 = 2 404684 1395476 70695119899 = 5 748692 1771344 102224119899 = 11 1520008 2716047 43283

C60

are summarized in Table 1(b) Small changes in the 1range are observed This demonstrates the conservation ofthe original structure of TQ thus meeting the first require-ment of the vectorization process Figure 10 shows the finalcompound corresponding to TQ grafted onto C

60via a spacer

arm and its descriptors 1198896 and 1198897 (Table 6)

4 Conclusion

In this paper we studied the effects of the spacer arm lengthon the synthesis conditions of a fullerene C

60-based drug-

vector As a drug sample we selected thymoquinone anatural product with anticancer properties The spacer arm


d7

d6

Figure 10 Structure of the final compound [Arm-TQ-C60] and its

descriptors (1198896 (A)) and (1198897 (A))

was chosen for its biocompatibility since it is composed ofa carbon chain including a variable number of methylenegroups (119899 = 2ndash11) ending with alcohol and carboxylic acidfunctions To improve the ability of the fullerene carriage twoarms were grafted simultaneously through a malonyl bridge[36]

All parts of the resulting nanosystem were studied sepa-rately Their geometry was optimized and selected physico-chemical parameters were calculated The evolution of theseparameters was monitored as a function of the spacer armlength and the angle between the two arms While allthe studied characteristics were almost independent of thespacer arm length or varied monotonically with it the dipolemoment exhibited periodicity depending on the parity ofthe number of carbon atoms in the chain All other studiedcompounds exhibited the same periodic behaviour Thisphenomenon is explained by the alternation of vector addi-tionsubtraction when the parity of carbon atoms numberwas changed

In the field of chemical synthesis these results highlightthe importance of theoretical calculations for the optimiza-tion of operating conditions Indeed the knowledge of chem-ical properties notably the polarity of synthesised productsand intermediates is mandatory for the right choice of thesolvents In the field of C

60-derivatives synthesis the rule

ldquolike dissolves likerdquo remains of high relevance Indeed C60rsquos

solubility is known to be very sensitive to the polarity of thesolvent For instance its solubility in 1-chloro-naphthalene (119878= 50mgsdotmLminus1) is considerably higher than in methanol (119878 =001mgsdotmLminus1) [37] Hence changes in the parity of the spacerarm will have a great significance in the synthesis of a C

60

based nanovectorAs the synthesis process requires several steps we have

to find the appropriate solvent for each combination stepthat means that the solvent polarity should be controlledaccording to the parity of the spacer arm and the polarityof each synthesis product or synthesis intermediate Finallyour results show that theoretical calculations of the chemicalproperties of a drug candidate can help predict its in vivobehaviour notably its bioavailability and biodistributionwhich are known to be tightly dependent of its polarity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding to the publication of this paper

References

[1] J Davies ldquoInactivation of antibiotics and the dissemination ofresistance genesrdquo Science vol 264 no 5157 pp 375ndash382 1994

[2] H W Kroto J R Heath S C OrsquoBrien R F Curl and R ESmalley ldquoC

60 buckminsterfullerenerdquoNature vol 318 no 6042

pp 162ndash163 1985[3] A W Jensen S R Wilson and D I Schuster ldquoBiological

applications of fullerenesrdquo Bioorganic andMedicinal Chemistryvol 4 no 6 pp 767ndash779 1996

[4] H Szwarc and F Moussa ldquo[60] Fullerene and derivatives inbiology and medicinerdquo in Handbook of Fullerene SynthesisProperties and Applications R F Verner and C Benvegn Edspp 403ndash420 Nova Science Publishers New York NY USA2012

[5] J Kolosnjaj H Szwarc and F Moussa ldquoToxicity studies offullerenes and derivativesrdquo Advances in Experimental Medicineand Biology vol 620 pp 168ndash180 2007

[6] R Maeda-Mamiya E Noiri H Isobe et al ldquoIn vivo genedelivery by cationic tetraamino fullerenerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 107 no 12 pp 5339ndash5344 2010

[7] K L Quick S S Ali R Arch C Xiong D Wozniak and L LDugan ldquoA carboxyfullerene SOD mimetic improves cognitionand extends the lifespan of micerdquoNeurobiology of Aging vol 29no 1 pp 117ndash128 2008

[8] J Gao Y Wang K M Folta et al ldquoPolyhydroxy fullerenes(fullerols or fullerenols) beneficial effects on growth andlifespan in diverse biological modelsrdquo PLoS ONE vol 6 no 5Article ID e19976 2011

[9] T Baati F Bourasset N Gharbi et al ldquoThe prolongation of thelifespan of rats by repeated oral administration of [60]fullerenerdquoBiomaterials vol 33 no 19 pp 4936ndash4946 2012

[10] M S Butt and M T Sultan ldquoNigella sativa reduces the riskof various maladiesrdquo Critical Reviews in Food Science andNutrition vol 50 no 7 pp 654ndash665 2010

[11] N Ilaiyaraja and F Khanum ldquoNigella sativa L a reviewof therapeutic applicationrdquo Journal of Herbal Medicine andToxicology vol 4 pp 1ndash8 2010

[12] S Padhye S Banerjee A Ahmad R Mohammad and FH Sarkar ldquoFrom here to eternitymdashthe secret of Pharaohstherapeutic potential of black cumin seeds and beyondrdquo CancerTherapy vol 6 no b pp 495ndash510 2008

[13] C C Woo A P Kumar G Sethi and K H B Tan ldquoThymo-quinone potential cure for inflammatory disorders and cancerrdquoBiochemical Pharmacology vol 83 no 4 pp 443ndash451 2012

[14] M N Nagi and M A Mansour ldquoProtective effect of thymo-quinone against doxorubicin-induced cardiotoxicity in rats apossible mechanism of protectionrdquo Pharmacological Researchvol 41 no 3 pp 283ndash289 2000

[15] O A Al-Shabanah O A Badary M N Nagi N M Al-Ghar-ably A C Al-Rikabi and A M Al-Bekairi ldquoThymoquinoneprotects against doxorubicin-induced cardiotoxicity withoutcompromising its antitumor activityrdquo Journal of Experimentaland Clinical Cancer Research vol 17 no 2 pp 193ndash198 1998


[16] A E Edris ldquoAnti-cancer properties of Nigella spp essential oilsand their major constituents thymoquinone and 120573-elemenerdquoCurrent Clinical Pharmacology vol 4 no 1 pp 43ndash46 2009

[17] R Keyhanmanesh M H Boskabady S Khamneh and YDoostar ldquoEffect of thymoquinone on the lung pathology andcytokine levels of ovalbumin-sensitized guinea pigsrdquo Pharma-cological Reports vol 62 no 5 pp 910ndash916 2010

[18] J Ravindran H B Nair B Sung S Prasad R R Tek-mal and B B Aggarwal ldquoThymoquinone poly (lactide-co-glycolide) nanoparticles exhibit enhanced anti-proliferativeanti-inflammatory and chemosensitization potentialrdquo Bio-chemical Pharmacology vol 79 no 11 pp 1640ndash1647 2010

[19] S Kiyonaka K Sada I Yoshimura S Shinkai N Kato and IHamachi ldquoSemi-wet peptideprotein array using supramolecu-lar hydrogelrdquo Nature Materials vol 3 no 1 pp 58ndash64 2004

[20] S J Lee and S Y Lee ldquoMicroarrays of peptides elevated onthe protein layer for efficient protein kinase assayrdquo AnalyticalBiochemistry vol 330 no 2 pp 311ndash316 2004

[21] G J Wegner H J Lee and R M Corn ldquoCharacterization andoptimization of peptide arrays for the study of epitope-antibodyinteractions using surface plasmon resonance imagingrdquoAnalyt-ical Chemistry vol 74 no 20 pp 5161ndash5168 2002

[22] A B Raschi E Romano A M Benavente A B Altabef andM E Tuttolomondo ldquoStructural and vibrational analysis ofthymoquinonerdquo Spectrochimica ActamdashPart A Molecular andBiomolecular Spectroscopy vol 77 no 2 pp 497ndash505 2010

[23] R C Young G J Durant J C Emmett et al ldquoDipole momentin relation to H

2receptor histamine antagonist activity for

cimetidine analoguesrdquoThe Journal of Medicinal Chemistry vol29 no 1 pp 44ndash49 1986

[24] A H Holm M Ceccato R L Donkers L Fabris G Pace andFMaran ldquoEffect of peptide ligand dipolemoments on the redoxpotentials of Au 38 andAu140 nanoparticlesrdquo Langmuir vol 22no 25 pp 10584ndash10589 2006

[25] L Garbuio S Antonello I Guryanov et al ldquoEffect of orien-tation of the peptide-bridge dipole moment on the propertiesof fullerene-peptide-radical systemsrdquo Journal of the AmericanChemical Society vol 134 no 25 pp 10628ndash10637 2012

[26] M J Frisch G W Trucks H B Schlegel et al Gaussian 03Revision C 02 Gaussian Wallingford Conn USA 2004

[27] M J Frisch G W Trucks H B Schlegel et al Gaussian 09Revision A1 Gaussian Wallingford Conn USA 2009

[28] A Frisch A B Nielsen and A J Holder GAUSSIANVIEWUsers Manual Gaussian Pittsburgh Pa USA 2000

[29] R Ditchfield W J Hehre and J A Pople ldquoSelf-consistentmolecular orbital methods 9 Extended Gaussian-type basis formolecular-orbital studies of organic moleculesrdquo The Journal ofChemical Physics vol 54 no 2 pp 724ndash728 1971

[30] A Ahmadi N L Hadipour M Kamfiroozi and Z BagherildquoTheoretical study of aluminum nitride nanotubes for chemicalsensing of formaldehyderdquo Sensors and Actuators B Chemicalvol 161 no 1 pp 1025ndash1029 2012

[31] A Ahmadi J Beheshtian and N L Hadipour ldquoChemisorptionof NH3 at the open ends of boron nitride nanotubes a DFTstudyrdquo Structural Chemistry vol 22 no 1 pp 183ndash188 2011

[32] P J Houghton R Zarka B de las Heras and J R S HoultldquoFixed oil of Nigella sativa and derived thymoquinone inhibiteicosanoid generation in leukocytes and membrane lipid per-oxidationrdquo Planta Medica vol 61 no 1 pp 33ndash36 1995

[33] N Chakravarty ldquoInhibition of histamine release frommast cellsby nigellonerdquo Annals of Allergy vol 70 no 3 pp 237ndash242 1993

[34] O A Badary O A Al-Shabanah M N Nagi A C Al-Rikabiand M M A Elmazar ldquoInhibition of benzo(a)pyrene-inducedforestomach carcinogenesis in mice by thymoquinonerdquo Euro-pean Journal of Cancer Prevention vol 8 no 5 pp 435ndash4401999

[35] J A Delaire and K Nakatani ldquoLinear and nonlinear opticalproperties of photochromicmolecules andmaterialsrdquoChemicalReviews vol 100 no 5 pp 1817ndash1845 2000

[36] C Bingel ldquoCyclopropanierung von fullerenenrdquo ChemischeBerichte vol 126 no 8 pp 1957ndash1959 1993

[37] R S Ruoff D S Tse R Malhotra and D C Lorents ldquoSolubilityof C60 in a variety of solventsrdquo The Journal of Physical Chem-istry vol 97 no 13 pp 3379ndash3383 1993

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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NanoparticlesJournal of



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Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

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CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


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Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


BioMed Research International

MaterialsJournal of


Nano

materials


Journal ofNanomaterials


1

2

3

4

5

6

7

89

10

111213 14

1516 17

18

19

20

2122

24

23

(a) Trans

1

2

3

4

5

6

7

89

10

1112

13 14

1516 17 18

19

20

21 2223

24

(b) Cis

Figure 1 Optimized structures of thymoquinone

[18] as in vitro experiments have shown that the activity of avectorized drug and the successful operation of vectorizationstrongly depend on the type of linker used [19ndash21]

Polarity is an important characteristic of a moleculebecause it can influence its chemical physical and biolog-ical properties Some in vitro studies [23] on the activitiesof a series of histamine H

2antagonists have shown that

relatively minor structural changes greatly influence theantagonistic activity Because the molecules were very polarthese differences were attributed to the orientations of thedipole moment and interpreted by the relative alignment ofhydrogen bonding For peptides in Aib homooligomers withone two and three intramolecular hydrogen bonds dipolemoments increase with the number of Aib units by roughly23DresidueTheobtained values are 822 1079 and 1234Drespectively [24]

In the research work of Garbuio et al [25] two series ofcompounds formed by a nitroxide radical linked by a peptidebond to the fullereneC

60are similar to those of our calculated

compounds the authors have shown that the direction ofthe resulting molecular dipole moment could be changed byreversing the position of fullerene and nitroxide with respectto the nitrogen of the peptide The electrochemical analysisand chemical nitroxide reduction experiments indicate thatthe dipole moment significantly affects the redox propertiesof the two electroactive groups

Our calculations are designed to study the characteristicsand properties of the PA TQ graft on the C

60through bra

formed by a carbon chain of variable length ndash(CH2)n (119899 = 2ndash

11) This is a relatively inert motif that minimizes interactionwith different parts of the human body during drug transportIts variable length could allow better control of the overall sizeand physicochemical properties of the studied nanocarrierswhich are important parameters for their therapeutic activity

2 Computational Details

Calculations are computed by the Gaussian [26 27] packetand recovered by GAUSSVIEW program [28] Hartree-Fock

(HF) and density functional theory (DFTB3LYP) methodsare used for geometrical optimization Given the great num-ber of atoms forming the studied compound and in orderto keep the calculations time compatible with our machinesbasis sets STO-3G of moderate dimension were used Forsmall compounds the basis set 6-311G(dp) [29] has alsobeen tested We checked that all vibrational frequencies arepositive which indicates that each studied structure coincideswith a minimum on the potential surface

3 Results and Discussion

DFT technique has been shown to be reliable and commonlyused for the functional study of various nanostructures[30 31] The studied compound has a four-part structureconsisting of (i) TQ the active principle (ii) a spacer arm (iii)a connecting bridge and (iv) C

60molecule the drug carrier

To validate our computational techniques and choice of basissets we first studied the free TQ molecule In the secondsection of this work we focused on the spacer arm and thebridge The final part deals with the drug candidate that canbe synthesized and used in medicine

31 Thymoquinone Thymoquinone is the 2-isopropyl-5-methyl-14-benzoquinone whose molecular formula isC10H12O2corresponding to two geometrical isomers [32 33]

(Figure 1)The structure of TQ is optimized in order to enable the

localization of any geometrical change induced by its bindingto C60 In order to maintain the therapeutic potential of TQ

it is mandatory to avoid any structural modification after itsbinding to C

60

The calculated values of the geometrical parameters areshown in Table 1 These values are in accordance with thosecalculated by other authors [22] Two stable conformationswith C1 (trans) and Cs (cis) symmetries (Figure 1) wereidentified

Theoretical calculations clearly show that the transcon-formation is more stable than the cis oneThus we continued



TQ trans TQ + C60




(b)







2) ranged



OO

TQThe spacer armC60

(a)

d1

(b)


3 5 7 9 11 13 15 17


E (u

a)

minus800

minus700

minus600

minus500

minus400

minus300

d1 (Aring)








0

2

4

6

0 3 6 9 12 15 18

HFDFT

120583(D

)

n = 3 n = 5 n = 7 n = 9 n = 11

n = 2 n = 4 n = 6 n = 8 n = 10

d1 (Aring)






2is included



rarr1205831 rarr

1205832 rarr120583

(a)

Alcohol

Carboxylic acid

rarr1205831

rarr1205832

rarr1205833

rarr120583

(b)


d3

d2

(a)

1205731

(b)




997888rarr1205831

997888rarr1205832



119911 0 0 0 0 0

120583 (D) 1728 2355 2411 334 042395a 041a


















119899 1198892 (A) 1198893 (A) 120583 (D) 1205731 (∘)2 3736 10293 537 119213 4974 12143 385 119334 6254 14583 558 119965 7538 16567 394 120036 8853 18941 563 119917 10105 21011 397 120258 11414 23371 566 120279 12677 25453 400 1202010 13977 27783 566 1202311 15245 29891 402 12019

3

4

5

6

0 3 6 9 12 15 18

120583(D

)

n = 2 n = 4 n = 6 n = 8 n = 10

n = 3 n = 5 n = 7 n = 9 n = 11

d2 (Aring)


d4

d5

1205732



Compounds119899

1198894 (A) 1198895 (A) 120583 (D) 1205732 (∘)

2 374351 1325676 1165 101559295 748692 1767825 648 902277211 1491388 3209813 798 8076277




70

80

90

100

110

0 5 10 15 20

1205732(∘

)

n = 2

n = 5 n = 11

d4 (Aring)

(a)

0

4

8

12

16

0 5 10 15 20

n = 2

n = 5

n = 11

d6 (Aring)

120583(D

)

120583 + C60 (D)120583 (D)

(b)


60]


Compounds 1198896 (A) 1198897 (A) 120583 (D)119899 = 2 404684 1395476 70695119899 = 5 748692 1771344 102224119899 = 11 1520008 2716047 43283

C60


60via a spacer


4 Conclusion


60-based drug-



d7

d6









60





References


















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





TQ trans TQ + C60




(b)







2) ranged



OO

TQThe spacer armC60

(a)

d1

(b)


3 5 7 9 11 13 15 17


E (u

a)

minus800

minus700

minus600

minus500

minus400

minus300

d1 (Aring)








0

2

4

6

0 3 6 9 12 15 18

HFDFT

120583(D

)

n = 3 n = 5 n = 7 n = 9 n = 11

n = 2 n = 4 n = 6 n = 8 n = 10

d1 (Aring)






2is included



rarr1205831 rarr

1205832 rarr120583

(a)

Alcohol

Carboxylic acid

rarr1205831

rarr1205832

rarr1205833

rarr120583

(b)


d3

d2

(a)

1205731

(b)




997888rarr1205831

997888rarr1205832



119911 0 0 0 0 0

120583 (D) 1728 2355 2411 334 042395a 041a


















119899 1198892 (A) 1198893 (A) 120583 (D) 1205731 (∘)2 3736 10293 537 119213 4974 12143 385 119334 6254 14583 558 119965 7538 16567 394 120036 8853 18941 563 119917 10105 21011 397 120258 11414 23371 566 120279 12677 25453 400 1202010 13977 27783 566 1202311 15245 29891 402 12019

3

4

5

6

0 3 6 9 12 15 18

120583(D

)

n = 2 n = 4 n = 6 n = 8 n = 10

n = 3 n = 5 n = 7 n = 9 n = 11

d2 (Aring)


d4

d5

1205732



Compounds119899

1198894 (A) 1198895 (A) 120583 (D) 1205732 (∘)

2 374351 1325676 1165 101559295 748692 1767825 648 902277211 1491388 3209813 798 8076277




70

80

90

100

110

0 5 10 15 20

1205732(∘

)

n = 2

n = 5 n = 11

d4 (Aring)

(a)

0

4

8

12

16

0 5 10 15 20

n = 2

n = 5

n = 11

d6 (Aring)

120583(D

)

120583 + C60 (D)120583 (D)

(b)


60]


Compounds 1198896 (A) 1198897 (A) 120583 (D)119899 = 2 404684 1395476 70695119899 = 5 748692 1771344 102224119899 = 11 1520008 2716047 43283

C60


60via a spacer


4 Conclusion


60-based drug-



d7

d6









60





References


















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




OO

TQThe spacer armC60

(a)

d1

(b)


3 5 7 9 11 13 15 17


E (u

a)

minus800

minus700

minus600

minus500

minus400

minus300

d1 (Aring)








0

2

4

6

0 3 6 9 12 15 18

HFDFT

120583(D

)

n = 3 n = 5 n = 7 n = 9 n = 11

n = 2 n = 4 n = 6 n = 8 n = 10

d1 (Aring)






2is included



rarr1205831 rarr

1205832 rarr120583

(a)

Alcohol

Carboxylic acid

rarr1205831

rarr1205832

rarr1205833

rarr120583

(b)


d3

d2

(a)

1205731

(b)




997888rarr1205831

997888rarr1205832



119911 0 0 0 0 0

120583 (D) 1728 2355 2411 334 042395a 041a


















119899 1198892 (A) 1198893 (A) 120583 (D) 1205731 (∘)2 3736 10293 537 119213 4974 12143 385 119334 6254 14583 558 119965 7538 16567 394 120036 8853 18941 563 119917 10105 21011 397 120258 11414 23371 566 120279 12677 25453 400 1202010 13977 27783 566 1202311 15245 29891 402 12019

3

4

5

6

0 3 6 9 12 15 18

120583(D

)

n = 2 n = 4 n = 6 n = 8 n = 10

n = 3 n = 5 n = 7 n = 9 n = 11

d2 (Aring)


d4

d5

1205732



Compounds119899

1198894 (A) 1198895 (A) 120583 (D) 1205732 (∘)

2 374351 1325676 1165 101559295 748692 1767825 648 902277211 1491388 3209813 798 8076277




70

80

90

100

110

0 5 10 15 20

1205732(∘

)

n = 2

n = 5 n = 11

d4 (Aring)

(a)

0

4

8

12

16

0 5 10 15 20

n = 2

n = 5

n = 11

d6 (Aring)

120583(D

)

120583 + C60 (D)120583 (D)

(b)


60]


Compounds 1198896 (A) 1198897 (A) 120583 (D)119899 = 2 404684 1395476 70695119899 = 5 748692 1771344 102224119899 = 11 1520008 2716047 43283

C60


60via a spacer


4 Conclusion


60-based drug-



d7

d6









60





References


















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





rarr1205831 rarr

1205832 rarr120583

(a)

Alcohol

Carboxylic acid

rarr1205831

rarr1205832

rarr1205833

rarr120583

(b)


d3

d2

(a)

1205731

(b)




997888rarr1205831

997888rarr1205832



119911 0 0 0 0 0

120583 (D) 1728 2355 2411 334 042395a 041a


















119899 1198892 (A) 1198893 (A) 120583 (D) 1205731 (∘)2 3736 10293 537 119213 4974 12143 385 119334 6254 14583 558 119965 7538 16567 394 120036 8853 18941 563 119917 10105 21011 397 120258 11414 23371 566 120279 12677 25453 400 1202010 13977 27783 566 1202311 15245 29891 402 12019

3

4

5

6

0 3 6 9 12 15 18

120583(D

)

n = 2 n = 4 n = 6 n = 8 n = 10

n = 3 n = 5 n = 7 n = 9 n = 11

d2 (Aring)


d4

d5

1205732



Compounds119899

1198894 (A) 1198895 (A) 120583 (D) 1205732 (∘)

2 374351 1325676 1165 101559295 748692 1767825 648 902277211 1491388 3209813 798 8076277




70

80

90

100

110

0 5 10 15 20

1205732(∘

)

n = 2

n = 5 n = 11

d4 (Aring)

(a)

0

4

8

12

16

0 5 10 15 20

n = 2

n = 5

n = 11

d6 (Aring)

120583(D

)

120583 + C60 (D)120583 (D)

(b)


60]


Compounds 1198896 (A) 1198897 (A) 120583 (D)119899 = 2 404684 1395476 70695119899 = 5 748692 1771344 102224119899 = 11 1520008 2716047 43283

C60


60via a spacer


4 Conclusion


60-based drug-



d7

d6









60





References


















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





119899 1198892 (A) 1198893 (A) 120583 (D) 1205731 (∘)2 3736 10293 537 119213 4974 12143 385 119334 6254 14583 558 119965 7538 16567 394 120036 8853 18941 563 119917 10105 21011 397 120258 11414 23371 566 120279 12677 25453 400 1202010 13977 27783 566 1202311 15245 29891 402 12019

3

4

5

6

0 3 6 9 12 15 18

120583(D

)

n = 2 n = 4 n = 6 n = 8 n = 10

n = 3 n = 5 n = 7 n = 9 n = 11

d2 (Aring)


d4

d5

1205732



Compounds119899

1198894 (A) 1198895 (A) 120583 (D) 1205732 (∘)

2 374351 1325676 1165 101559295 748692 1767825 648 902277211 1491388 3209813 798 8076277




70

80

90

100

110

0 5 10 15 20

1205732(∘

)

n = 2

n = 5 n = 11

d4 (Aring)

(a)

0

4

8

12

16

0 5 10 15 20

n = 2

n = 5

n = 11

d6 (Aring)

120583(D

)

120583 + C60 (D)120583 (D)

(b)


60]


Compounds 1198896 (A) 1198897 (A) 120583 (D)119899 = 2 404684 1395476 70695119899 = 5 748692 1771344 102224119899 = 11 1520008 2716047 43283

C60


60via a spacer


4 Conclusion


60-based drug-



d7

d6









60





References


















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




d7

d6









60





References


















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



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Research Article Study of Spacer Arm Length Influence on ...downloads.hindawi.com/journals/jnm/2015/374218.pdf · Research Article In Silico Study of Spacer Arm Length Influence on