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Zinc(II), ruthenium(II), rhodium(III), palladium(II), silver(I), platinum(II) and complexes of 2-(2′-hydroxy-5′-methylphenyl)-benzotriazole as simple or primary ligand and 2,2′-bipyridyl, 9,10-phenanthroline or triphenylphosphine as secondary ligands: Structure and anticancer activity
JournalofMolecularStructure1059(2014)193–201
ContentslistsavailableatScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Zinc(II), ruthenium(II), rhodium(III), palladium(II), silver(I), platinum(II)
and MoO2þ complexes of 2-(20-hydroxy-50-methylphenyl)-benzotriazole
2
as simple or primary ligand and 2,20-bipyridyl, 9,10-phenanthroline
or triphenylphosphine as secondary ligands: Structure and anticancer
activity
Hala A. El-Asmya, Ian S. Butlera,⇑ , Zhor S. Mouhrib, Bertrand J. Jean-Claudeb, Mohamed S. Emmamc,
Sahar I.
Mostafac,⇑
aDepartmentofChemistry,McGillUniversity,Montreal,QCH3A2K6,Canada
bRoyalVictoriaHospital,DepartmentofMedicine,McGillUniversity,Montreal,QCH3A1A1,Canada
cChemistryDepartment,FacultyofScience,MansouraUniversity,Mansoura35516,Egypt
h i g h l i g h t s g r a p h i c a l a b s t r a c t
(cid:2)Newcomplexesof2-(20-hydroxy-50- Newcomplexesof2-(20-hydroxy-50-methylphenyl)-benzotriazolehavebeensynthesizedandstructur-
methylphenyl)-benzotriazole ally characterized. The reported complexes have been tested against human breast cancer (MDA-
(Hhmbt)arereported. MB231)andhumanovariancancer(OVCAR-8)celllines.
(cid:2)Hhmbtcoordinatesviadeprotonated
hydroxyandiminenitrogen. H3C CH3
(cid:2)FreeHhmbtanditscomplexeswere
testedagainstbreastcancer(MDA-
MB231)andovariancancer(OVCAR-
8)celllines. O hν O
(cid:2)[Ag(hmpbt)(PPh
3
)]and
N H Δ H N
[Pd(phen)(hmbt)]Clexhibitthe
N N N N
highestactivity.
a r t i c l e i n f o a b s t r a c t
Articlehistory: New complexes of 2-(20-hydroxy-50-methylphenyl)-benzotriazole (Hhmbt), [Zn(hmbt)(HO)],
2 2 2
Received1October2013 [Zn(hmbt)(OAc)(HO)], [Pd(hmbt)(HO)Cl], [Pd(hmbt)], [M(PPh)(hmbt)Cl], [M(L)(hmbt)]Cl (M(II)=Pd,
2 2 2 2 3
Receivedinrevisedform14November2013 Pt; L=bpy, phen), [Ag(hmbt)], [Ag(phen)(hmbt)], [Ag(PPh)(hmbt)], [Rh(hmbt)(HO)]Cl, [Ru(hmbt)
2 2 3 2 2 2 2
Accepted14November2013
(HO)],[Ru(PPh)(hmbt)Cl]andcis-[MoO(hmbt)]havebeensynthesized.Theyhavebeenstructurally
Availableonline23November2013 2 2 3 2 2 2
andspectroscopicallycharacterizedonthebasisofelementalanalysis,IR,NMR(1H,13C,31P),UV–vis.and
ESI-massspectroscopy,thermalandmolarconductivitymeasurements.2-(20-Hydroxy-50-methylphenyl)-
Keywords:
benzotriazolebehavesasamononegativebidentatethroughthedeprotonatedphenolicoxygenandimine
Hhmbt
nitrogenatoms.Thereportedcomplexeshavebeentestedagainsthumanbreastcancer(MDA-MB231)and
Zinc
human ovarian cancer (OVCAR-8) cell lines. The complexes, [Ag(hmpbt)(PPh)], [Rh(hmbt)(HO)]Cl,
Palladium 3 2 2 2
Platinum [Pt(phen)(hmbt)]Cland[Pd(phen)(hmbt)]ClexhibitthehighestgrowthinhibitoryactivitywithmeanIC 50 val-
Silver ues1.37,7.52,5.24and4.85lM(MDA-MB231)and1.75,8.50,3.00and2.99lM(OVACAR-8),respectively.
Anticancer CrownCopyright(cid:2)2013PublishedbyElsevierB.V.Allrightsreserved.
⇑
Correspondingauthors.Tel.:+201008502625;fax:+20502246781.
E-mail addresses: ian.butler@mcgill.ca (I.S. Butler), sihmostafa@yahoo.com
(S.I.Mostafa).
0022-2860/$-seefrontmatterCrownCopyright(cid:2)2013PublishedbyElsevierB.V.Allrightsreserved.
http://dx.doi.org/10.1016/j.molstruc.2013.11.039
194 H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201
1.Introduction ondaryligands.TheanticanceractivityofHhmbtanditscomplexes
havebeentestedagainsthumanbreastcancer(MDA-MB231)and
2-(20-Hydroxy-50-methylphenyl)-benzotriazole (Fig. 1) is com- humanovariancancer(OVCAR-8)celllines.
monly known as drometrizole. Drometrizole and its phenyl sub-
stituents are potent UV-light absorbers and constitute an 2.Experimental
importantclassofindustrialadditivesforpolymersandlight-stabi-
lized coatings. They are used in a variety of polymers including 2.1.Materialsandmeasurements
polycarbonates, unsaturated polyesters, polystyrenes, acrylics,
polyvinylchloride,thermoplasticpolyesters,andpolyacetals.They AllreagentsandsolventswerepurchasedfromAlfa/Aesarand
have the common photochemical feature of strong absorption of allmanipulationswereperformedunderaerobicconditionsusing
ultraviolet light (290–350nm). This feature, as an ultraviolet ab- materials and solvents as received. [M(bpy)Cl 2 ], [M(phen)Cl 2 ],
sorber (UVA), is utilized commercially to impart light stability [M(PPh 3 ) 2 Cl 2 ](M(II)=Pd,Pt)[18]and[Ru(PPh 3 ) 3 Cl 2 ][19].DMSO-
(protection against photo-degradation) to a wide variety of poly- d 6 wasusedfortheNMRmeasurementsreferencedagainstTMS.
mers (plastics, polyesters, celluloses, acrylates, dyes, rubber, syn- The human breast cancer (MDA-MB231) and human ovarian
thetic and natural fibers, waxes, detergent solutions, and cancer (OVCAR-8) cell lines were obtained from the American
orthodonticadhesives)againstdiscolorationanddeterioration[1]. Type Culture Collection (ATCC catalog number). Cells were
DugdaleandCotton[2]hasreportedthatbenzotriazoleformsa maintained in Dulbecco’s Modified Eagle Medium (Wisent Inc.,
strongly bonded chemisorbed two-dimensional barrier film less St-Bruno, Canada) supplemented with 10% FBS, 10mM HEPES,
than 50Å thick, which may be a monomolecular layer, protects 2mM L-gutamine and 100lg/mL penicillin/streptomycin
copperanditsalloysinaqueousmedia,variousatmospheres,lubri- (GibcoBRL, Gaithersburg, MD). In all assays cells were plated
cants, and hydraulic fluids [2]. Moreover, benzotriazole forms 24hbeforedrugtreatment.
insoluble precipitates with copper ions in solution, thereby pre- InfraredspectrawererecordedonaNicolet6700DiamondATR
venting the corrosion of aluminum and steel in other parts of a spectrometerinthe4000–200cm(cid:4)1range.NMRspectrawerere-
watersystem[2]. corded on VNMRS 200 and 500MHz spectrometer in DMSO-d 6
The UV-stabilizer 2-(20-hydroxy-50-methylphenyl)-benzotria- usingTMSasreference.Massspectra(ESI-MS)wererecordedusing
zole (Hhmbt) has been reported as a ligand for complexing VO2+ LCQDuoanddoublefocusingMS25RFAinstruments,respectively.
and MoO2þ to give [{VO(acac) }(l-hbmt) ] and cis-[MoO ElectronicspectrawererecordedinDMFusingaHewlett-Packard
2 2 2 2
(acac)(hmbt)]. The X-ray crystal structures of both of complexes 8453 spectrophotometer. Thermal analysis measurements were
havebeenalsodiscussed[3].ThephotolabilityofHhmbtwasex- madeinthe20–800(cid:3)Crangeataheatingrateof20(cid:3)Cmin(cid:4)1using
plained due to an excited-state intramolecular proton transfer Ni and NiCo as references, on a TA instrument TGA model
throughtheintramolecularhydrogenbond(FormA,B;Scheme1) Q500Analyzer TGA-50. Molar conductivity measurements were
[4–6].Thus,thereplacementwithatransitionmetal(chelatesthe carried out at room temperature on a YSI Model 32 conductivity
oxygen and nitrogen) with the investigation of its effect on the bridge.
photochemical and photophysical properties have been reported
[3]. 2.2.Preparations
Thecomplexes,[ReOX (hmpbta)(APh )](cid:3)MeCN(X=Cl,Br;A=P,
2 3
As)and[ReBr 2 (hmpbta)(PPh 3 )](cid:3)MeCN(hmpbta=2-(20-hydoxy-50- 2.2.1.[Pd(hmbt)(H 2 O)Cl](cid:3)2H 2 O
methylphenyl)-benzotriazole),havebeenpreparedandcharacter- AnaqueoussolutionofK 2 [PdCl 4 ](0.16g,0.5mmol;5mL)was
ized.TheX-raystructureandDFTcalculationsforthedisubstituted addedtoHhmbt(0.113g,0.5mmol)inEtOH(15mL).Theresulting
[ReOCl(hmpbta) ]chelatehavealsobeenreported[7]. suspensionwasstirredat80(cid:3)Cfor2handayellowsolidwasob-
2
Over the past few years, our laboratory has been actively in- tained. It was filtered off, washed with water, ethanol and air-
volvedinthesynthesisofO,O;O,N;N,SandO,N,S-donorstransition dried. Yield: 0.195g, 71%. Elemental Anal.: Calcd. C, 37.1; H, 3.8;
metalcomplexes,whichhavebeenevaluatedasanticanceragents N,10.0;Pd,25.3(C 13 H 16 N 3 O 4 Pd);Found:C,37.2;H,3.9;N,10.3;
against either Ehrlich ascites tumor cells (EACs) [8–11] or human Pd,25.4%.Conductivitydata(10(cid:4)3MinDMF):K M =8.0ohm(cid:4)1.IR
cancercelllines[12–14].Asacontinuationofourinterestincom- (cm(cid:4)1):m(C@N),1600;m(CO),1250;m(N–N),1141;m(Pd–O),501;
plexeswithO,N-donors[8,12,15–17],herewedescribetheprepa- m(Pd–N), 461. Raman (cm(cid:4)1): m(C@N), 1573; m(CO), 1251; m(N–
ration and characterization of new Zn(II), MoO2þ, Ru(II), Rh(III), N), 1149; m(Pd–O), 538; m(Pd–N), 471; m(Pd–Cl), 194. 1H NMR
2
Pd(II), Ag(I), Pt(II) complexes with 2-(20-hydroxy-50-methyl- (ppm): 7.96 (H(3), d, J=3Hz, 1H); 7.65 (H(6), S, 1H); 7.23 (H(7),
phenyl)-benzotriazole (Hhmbt) as simple or primary ligand and d, J=4.5Hz, 1H); 7.40 (H(8), t, J=4.2Hz, 1H); 7.30 (H(9), t,
2,20-bipyridyl, 9,10-phenanthroline or triphenylphosphine as sec- J=4.2Hz, 1H); 7.08 (H(10), d, J=4.5Hz, 1H); 2.40 (CH3, S, 3H).
UV–visible (nm): 248, 386, 468. MS (m/z): 331 (Calcd. 330.4),
226(Calcd.226.4).
3
OH 2.2.2.[Pd(hmbt) 2 ]
4 2 AnaqueoussolutionofK [PdCl ](0.16g,0.5mmol;5mL)was
2 4
added to Hhmbt (0.225g, 1mmol) in MeOH containing KOH
5 1 (0.056g,1mmol;15mL).Thereactionmixturewasstirredat45(cid:3)
N Cfor2h.Theorangesolidwasfilteredoff,washedwithwater,eth-
H C N 11 10 anol and air-dried. Yield: 0.320g; 83%. Elemental Anal.: Calcd. C,
3 6
56.3;H,3.6;N,15.2;Pd,19.2(C H N O Pd);Found:C,56.1;H,
26 20 6 2
N 3.5; N, 15.3; Pd, 19.1%. Conductivity data (10(cid:4)3M in DMF):
12 9 K M =5.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1612; m(CO), 1251; m(N–N),
1141;m(Pd–O),501;m(Pd–N),473.Raman(cm(cid:4)1):m(C@N),1572;
7 8
m(CO),1251;m(N–N),1148;m(Pd–O),538;m(Pd–N),471.UV–visi-
ble (nm):278, 388. MS (m/z): 554.5 (Calcd. 554.4), 329.4 (Calcd.
Fig.1. Structureof2-(20-hydroxy-50-methylphenyl)-benzotriazole(Hhmbt). 330.4),226.7(Calcd.226.4).
H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201 195
H3C CH3
O
hν
O
N H Δ H N
N N N N
(A) (B)
Scheme1. Enol-ketotautomeric(AandB)formsofHhmbt.
2.2.3.[Pd(L)(hmbt)]Cl(cid:3)nH O(L=bpy,n=2;L=phen,n=1) 2.2.5.[Pt(L)(hmbt)]Cl(cid:3)nH O(L=bpy,n=1;L=phen,n=2)
2 2
To a stirred suspension of [Pd(bpy)Cl ] (0.03g, 0.1mmol) or A similar procedure as the palladium analogue was applied,
2
[Pd(phen)Cl ] (0.04g, 0.1mmol) in MeOH (10mL) a solution of [Pt(L)Cl ] (L=bpy, phen) were used to produce yellow-orange
2 2
Hhmbt (0.023g, 0.1mmol) in MeOH containing KOH (0.006g, precipitates.
0.1mmol;10mL)wasaddeddropbydropwithstirring.Thereac- For[Pt(bpy)(hmbt)]Cl(cid:3)H O:Yield:0.35g(60%).ElementalAnal.:
2
tion mixture was warmed for 48h, upon which a yellow-orange Calcd.:C,43.9;H,3.5;N,11.1;Pt,31.0(C ClH N O Pt);Found:C,
23 22 5 2
precipitate was filtered off, washed with MeOH, Et O and dried 43.7;H,3.7;N,11.0;Pt,31.2%.Conductivitydata(10(cid:4)3MinDMF):
2
invacuo. K =80.0ohm(cid:4)1.IR(cm(cid:4)1):m(C@N),1607;m(CO),1251;m(Pt–O),
M
For[Pd(bpy)(hmbt)]Cl(cid:3)2H O: Yield: 0.07g (51%). Elemental 549; m(Pt–N), 489. Raman (cm(cid:4)1): m(C@N), 1605; m(CO), 1251;
2
Anal.: Calcd. C, 49.5; H, 4.3; N, 12.6; Pd, 19.1 (C H N O Pd); m(Pt–O), 550; m(Pt–N), 486. 1H NMR (ppm): 8.34 (H(3), d,
23 24 5 3
Found: C, 49.7; H, 4.2; N, 12.7; Pd, 19.1%. Conductivity data J=5.1Hz, 1H); 7.68 (H(6), S, 1H); 7.49 (H(7), d, J=4.8Hz, 1H);
(10(cid:4)3M in DMF): K =84.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1621; 7.2 (H(8), t, J=6.3Hz,1H); 7.55 (H(9), t, J=5.4Hz, 1H); 6.76
M
m(CO), 1251; m(N–N), 1141; m(Pd–O), 500; m(Pd–N), 459. Raman (H(10),d,J=6Hz,1H);2.35(CH3,S,3H).MS(m/z):574.3(Calcd.
(cm(cid:4)1):m(C@N),1602;m(CO),1251;m(N–N),1141;m(Pd–O),501; 574.0).
m(Pd–N), 460. 1H NMR (ppm): 8.00 (H(3), d, J=6Hz, 1H); 7.75 For [Pt(phen)(hmbt)]Cl(cid:3)2H O: Yield: 0.1g (60%). Elemental
2
(H(6), S, 1H); 7.86 (H(7), d, J=5.4Hz, 1H); 7.73 (H(8), t, J=5Hz, Anal.: Calcd.: C, 46.0; H, 3.7; N, 10.7; Pt, 29.9 (C ClH N O Pt);
25 24 5 3
1H); 7.69 (H(9), t, J=5Hz, 1H); 7.22 (H(10), d, J=5.2Hz, 1H); Found: C, 46.1; H, 3.8; N, 10.5; Pt, 29.7%. IR (cm(cid:4)1): m(C@N),
2.50 (CH3, S, 3H). MS (m/z): 486.4 (Calcd. 486.4), 368.2 (Calcd. 1600;m(CO),1251;m(N–N),1134;m(Pt–O),549;m(Pt–N),473.Ra-
368.4), 292.4 (Calcd. 292.4), 262.4 (Calcd. 262.4), 156.3 (Calcd. man (cm(cid:4)1): m(C@N), 1605; m(CO), 1251; m(N–N), 1136; m(Pt–O),
156.0). 550;m(Pt–N),476.Conductivitydata(10(cid:4)3MinDMF):K =79.0-
M
For[Pd(phen)(hmbt)]Cl(cid:3)H O: Yield: 0.08g (54%). Elemental ohm(cid:4)1.1HNMR(ppm):7.96(H(3),d,J=3.9Hz,1H);7.59(H(6),S,
2
Anal.: Calcd. C, 53.2; H, 3.9; N, 12.4; Pd, 18.7 (C H N O Pd); 1H);7.06(H(7),d,J=1.8Hz,1H);7.45(H(8),t,J=3.3Hz,1H);7.42
25 22 5 2
Found: C, 53.3; H, 4.0; N, 12.3; Pd, 18.6%. Conductivity data (H(9),t,J=3.3Hz,1H);6.85(H(10),d,J=8.4Hz,1H);2.35(CH3,S,
(10(cid:4)3M in DMF): K =81.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1600; 3H).MS(m/z):599.5(Calcd.599.0).
M
m(CO), 1252; m(N–N), 1138; m(Pd–O), 564; m(Pd–N), 495. Raman
(cm(cid:4)1):m(C@N),1604;m(CO),1252;m(N–N),1139;m(Pd–O),565; 2.2.6.[Pt(PPh )(hmbt)Cl]
3
m(Pd–N), 495. 1H NMR (ppm): 7.96 (H(3), d, J=5.1Hz, 1H); 7.30 Thesynthesisof [Pt(PPh )(hmbt)Cl] wasachieved by a similar
3
(H(6), S, 1H); 7.60 (H(7), d, J=4.5Hz, 1H); 7.77 (H(8), t, procedure to that for Pd(II) analogue with [Pt(PPh ) Cl ] replac-
32 2
J=4.2Hz, 1H); 7.73 (H(9), t, J=4.5Hz, 1H); 7.22 (H(10), d, ing[Pd(PPh ) Cl ]. Yield: 0.21g (82%). Elemental Anal.: Calcd.: C,
32 2
J=4.2Hz, 1H); 2.50 (CH3, S, 3H). MS (m/z): 510.4 (Calcd. 510.4), 51.9; H, 3.5; N, 5.9; Cl, 5.0; Pt, 27.2 (C ClH N OPt); Found: C,
31 25 3
286.4(Calcd.286.4),180.6(Calcd.180.0). 51.4; H, 3.6; N, 6.0; Cl, 5.4; Pt, 27.5%. Conductivity data (10(cid:4)3M
in DMF): K =3.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1600; m(CO), 1300;
M
m(N–N), 1132; m(Pt–O), 514; m(Pt–N), 492. Raman (cm(cid:4)1):
2.2.4.[Pd(PPh )(hmbt)Cl] m(C@N),1598;m(CO),1301;m(N–N),1144;m(Pt–O),545;m(Pt–N),
3
[Pd(PPh ) Cl ] (0.175g, 0.25mmol) was added to Hhmbt 462;m(Pt–P),305;m(Pt–Cl),227.MS(m/z):716.5(Calcd.716.5).
32 2
(0.057g,0.25mmol)inCH Cl (20mL).Thereactionmixturewas
2 2
heated under reflux for 48h. The yellow precipitate was filtered 2.2.7.[Ag (hmbt) ]
2 2
off,washedwithCH Cl anddriedinvacuo.Yield:0.20g;86%.Ele- Silvernitrate(0.085g,0.5mmol)inwater(1mL)wasaddedto
2 2
mental Anal.: Calcd.: C, 59.2; H, 4.0; N, 6.7; Cl, 5.7; Pd, 16.9 (C Hhmbt (0.113g, 0.5mmol) in MeOH containing KOH (0.028g,
31-
ClH N OPd); Found: C, 59.4; H, 4.1; N, 6.6; Cl, 5.6; Pd, 16.8%. 0.5mmol; 15mL). The reaction mixture was stirred at 40(cid:3)C in
25 3
Conductivity data (10(cid:4)3M in DMF): K =7.0ohm(cid:4)1. IR (cm(cid:4)1): thedarkfor5h.Thepale-greensolidwasfilteredoff,washedwith
M
m(C@N), 1586; m(CO), 1307; m(N–N), 1158; m(Pd–O), 532; m(Pd– water,MeOH,Et Oanddriedinvacuo.Yield:0.15g(75%).Elemen-
2
N), 438. Raman (cm(cid:4)1): m(C@N), 1585; m(CO), 1309; m(N–N), talAnal.:Calcd.C,47.0;H,3.0;N,12.6%(C H N O Ag );Found:C,
26 20 6 2 2
1160; m(Pd–O), 530; m(Pd–N), 434; m(Pd–P), 301; m(Pd–Cl), 199. 47.3; H, 3.2; N, 12.4%. Conductivity data (10(cid:4)3M in DMF):
UV–visible(nm):280,358,388.MS(m/z):628.2(Calcd.627.9). K =6.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1600; m(CO), 1250; m(N–N),
M
196 H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201
1144;m(Ag–O),500;m(Ag–N),465.Raman(cm(cid:4)1):m(C@N),1598; (10mL).Thereactionmixturewasheatedunderrefluxfor2hdur-
m(CO), 1250; m(N–N), 1147; m(Ag–O), 502; m(Ag–N), 464. MS (m/ ing which shiny green microcrystals were isolated, washed with
z):332.22(Calcd.331.8). MeOH,Et Oanddriedinvacuo.Yield:0.26g(83%).ElementalAnal.:
2
Calcd.:C,62.4;Cl,4.2;H,4.1;N,9.9(C ClH N O PRu);Found:C,
44 35 6 2
2.2.8.[Ag(phen)(hmbt)] 62.5;Cl,4.1;H,4.4;N,10.0%.Conductivitydata(10(cid:4)3MinDMF):
Silver perchlorate (0.101g, 0.5mmol) in water (1mL) was K =4.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1633; m(CO), 1255; m(N–N),
M
addedtophen(0.090g,0.5mmol)inMeOH(10mL).Totheyellow 1131;m(Ru–O),519;m(Ru–N),438.Raman(cm(cid:4)1):m(C@N),1619;
solution, Hhmbt (0.113g, 0.5mmol) in MeOH containing KOH m(CO),1262;m(N–N),1133;m(Ru–O),531;m(Ru–N),420.UV–visi-
(0.028g, 0.5mmol; 10mL) was added. The reaction mixture was ble (nm): 305, 362, 629. MS (m/z): 811.2 (Calcd. 811.1), 588.0
stirred in the dark for 3h and the pale-yellow solid was filtered (Calcd.587.1).
off, washed with water, MeOH, Et O and dried in vacuo. Yield:
2
0.21g (72%). Elemental Anal.: Calcd. C, 58.6; H, 3.9; N, 13.7% 2.2.13.[Zn(hmbt)(OAc)(H O) ]
2 2
(C H N OAg);Found:C,58.9;H,3.8;N,13.6%.Conductivitydata Zn(OAc) (0.109g, 0.5mmol) in EtOH (5mL) was added to
25 20 5 2
(10(cid:4)3MinDMF):K =4.0ohm(cid:4)1.IR(cm(cid:4)1):m(C@N),1590,m(CO), Hhmbt(0.113g,0.5mmol)inEtOH(20mL).Thereactionmixture
M
1250;m(N–N),1141;m(Ag–O),514;m(Ag–N),440.Raman(cm(cid:4)1): washeatedunderrefluxfor8h.Apale-yellowprecipitatewasob-
m(C@N), 1589, m(CO), 1250; m(N–N), 1143; m(Ag–O), 553; tained,washedwithEtOHanddriedinvacuo.Yield:0.18g(81%).
m(Ag–N), 418. UV–visible (nm): 225, 269, 288, 441. MS (m/z): Elemental Anal.: Calcd.: C, 46.9; H, 4.0; N, 10.9 (C H N O Zn);
15 17 3 5
511.3(Calcd.511.8),287.3(Calcd.287.8). Found: C, 47.1; H, 4.2; N, 11.0%. Conductivity data (10(cid:4)3 M in
DMF): K =9.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1615; m(CO), 1250;
M
2.2.9.[Ag(PPh )(hmbt)] m(N–N), 1132; m(Zn–O), 520; m(Zn–N), 441. Raman (cm(cid:4)1):
3
Asimilarprocedureas[Ag(phen)(hmbt)]wasapplied,PPh was m(C@N), 1612; m(CO), 1258; m(N–N), 1131; m(Zn–O), 548; m(Zn–
3
replacingphentoproduceagreenprecipitate.Yield:0.29g(86%). N),459. 1H NMR(ppm): 8.06(H(3),d, J=3.3Hz,1H);7.56 (H(6),
Elemental Anal.: Calcd. C, 61.0; H, 4.4; N, 6.9% (C H N O PAg); S, 1H); 7.31 (H(7), d, J=6Hz, 1H); 7.55 (H(8), t, J=6Hz, 1H);
31 27 3 2
Found: C, 60.7; H, 4.4; N, 7.0%. Conductivity data (10(cid:4)3M in 7.52 (H(9), t, J=5.7Hz, 1H); 6.73 (H(10), d, J=7.5Hz, 1H); 2.47
DMF): K =2.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1609; m(CO), 1250; (CH3,S,3H).MS(m/z):384.3(Calcd.384.5),366.2(Calcd.366.5).
M
m(N–N), 1141; m(Ag–O), 501; m(Ag–N), 461. Raman (cm(cid:4)1):
m(C@N), 1607; m(CO), 1250; m(N–N), 1147; m(Ag–O), 509; m(Ag– 2.2.14.[Zn(hmbt) (H O) ]
2 2 2
N),464.1HNMR(ppm):7.96(H(3),d,J=4Hz,1H);7.65(H(6),S, ZnCl (0.11g, 0.5mmol)in water(5mL)wasadded toHhmbt
2
1H); 7.31 (H(7), d, J=3.5Hz, 1H); 7.40 (H(8), t, J=8.5Hz, 1H); (0.225g,1mmol) inEtOHcontaining(0.028g,0.5mmol;20mL).
7.30 (H(9), t, J=4.5Hz, 1H); 6.73 (H(10), d, J=8.5Hz, 1H); 2.47 Thereactionmixturewasheatedunderrefluxfor4h.Anoff-white
(CH3, S, 3H). UV–visible (nm): 257, 280, 339, 416. MS (m/z): precipitate was obtained. It was filtered off, washed with water,
593.4(Calcd.593.8),369.4(Calcd.369.8). EtOH and dried in vacuo. Yield: 0.29g (87%). Elemental Anal.:
Calcd.:C,60.8;H,3.9;N,16.4(C H N O Zn);Found:C,61.0;H,
26 20 6 2
2.2.10.[Rh(hmbt) (H O) ]Cl(cid:3)5H O 3.8; N, 16.3%. Conductivity data (10(cid:4)3M in DMF): K =11.0-
2 2 2 2 M
Hydratedrhodiumtrichloride(0.13g,0.5mmol)wasaddedtoa ohm(cid:4)1. IR (cm(cid:4)1): m(C@N), 1613; m(CO), 1252; m(N–N), 1132;
solution of AcONa (0.62g, 7.5mmol) in water (30mL) and m(Zn–O), 500; m(Zn–N), 463. Raman (cm(cid:4)1): m(C@N), 1612;
Hhmbt(0.226g, 1.0mmol) was added. The mixture was refluxed m(CO),1250;m(N–N),1130;m(Zn–O),504;m(Zn–N),464.1HNMR
for10handayellowprecipitatewasobtaineduponreducingthe (ppm): 8.00 (H(3), d, J=2.8Hz, 1H); 7.64 (H(6), S, 1H); 7.64
volume. It was filtered off, washed with ice-cold water and air (H(7),d,J=4.4Hz,1H);7.21(H(8),t,J=4.4Hz,1H);7.52(H(9),t,
dried. Yield: 0.35g (60%). Elemental Anal.: Calcd.: C, 43.8; H, 4.3; J=6.4Hz, 1H); 7.50 (H(10), d, J=3.6Hz, 1H); 2.47 (CH3, S, 3H).
N,11.8(C H N O Rh);Found;C,43.8;H,4.2;N,11.7%.Conduc- MS(m/z):513.1(Calcd.513.5),289.1(Calcd.289.5).
26 35 6 7
tivity data (10(cid:4)3M in DMF): K =79.0ohm(cid:4)1. IR (cm(cid:4)1):
M
m(C@N), 1604; m(CO), 1251; m(N–N), 1146; m(Rh–O), 506; m(Rh– 2.2.15.Cis-[MoO (hmpt) ]
2 2
N), 471. Raman (cm(cid:4)1): m(C@N), 1602; m(CO), 1251; m(N–N), [MoO (acac) ] (0.164g, 0.5mmol) in methanol (2mL) was
2 2
1148;m(Rh–O),497;m(Rh–N),476.1HNMR(ppm):8.01(H(3),d, added HL (0.225g, 1mmol) in methanol containing KOH
1
J=2.8Hz, 1H); 7.62 (H(6), S, 1H); 7.21 (H(7), d, J=2Hz, 1H); (0.028g,0.5mmol;10mL).Thereactionmixturewas heatedun-
7.52 (H(8), t, J=6Hz, 1H); 7.50 (H(9), t, J=5.6Hz, 1H); 7.06 der reflux for 3h. The pale yellow precipitate was filtered off,
(H(10),d,J=4.4Hz,1H);2.48(CH3,S,3H).UV–visible(nm):280, washed with water and methanol, and finally air-dried.
310,358,408,430.MS(m/z):551.2(Calcd.551.0). Yield:0.089g (23%). Elemental Anal.: Calcd.: C, 54.2; H, 3.5; N,
14.6(C H N O Mo);Found:C,54.5;H,3.6;N,14.7%.Conductiv-
26 20 6 4
2.2.11.[Ru(hmbt) (H O) ] ity data (10(cid:4)3M in DMF): K =4.0ohm(cid:4)1. IR (cm(cid:4)1): m(C@N),
2 2 2 M
Hydrated ruthenium trichloride (0.102g, 0.5mmol) in water 1604; m(CO), 1253; m(N–N), 1145; m(O–Mo–O), 939; m(Mo–O),
(5mL) was added to Hhmbt (0.34g, 1.5mmol) in EtOH (15mL). 560; m(Mo–N), 470. Raman (cm(cid:4)1): m(C@N), 1606; m(CO), 1250;
Themixturewasheatedunderrefluxfor6htilladarkgreenpre- m(N–N),1149;m(O–Mo–O),942;m(Mo–O),570;m(Mo–N),473.1H
cipitate formed. It was filtered off during hot, washed with hot NMR (ppm): 7.98 (H(3), d, J=7Hz, 1H); 7.02 (H(6), S, 1H); 7.54
water, EtOH and air dried. Yield: 0.35g (80%). Elemental Anal.: (H(7),d,J=7.5Hz,1H);7.16(H(8),t,J=3.5Hz,1H);7.52(H(9),t,
Calcd.:C,53.3;H,4.3;N,14.2(C H N O Ru);Found;C,53.5;H, J=5Hz,1H);7.19(H(10),d,J=3.5Hz,1H);2.47(CH3,S,3H).MS
26 24 6 3
4.1;N,14.4%.Conductivitydata(10(cid:4)3MinDMF):K =5.0ohm(cid:4)1. (m/z):575.8(Calcd.575.9),352.1(Calcd.351.9).
M
IR (cm(cid:4)1): m(C@N), 1611; m(CO), 1251; m(N–N), 1137; m(Ru–O),
501; m(Ru–N), 468. Raman (cm(cid:4)1): m(C@N), 1611; m(CO), 1251; 2.3.Biologicalassay
m(N–N), 1143; m(Ru–O), 502; m(Ru–N), 467. UV–visible (nm):
300,340,631.MS(m/z):549.9(Calcd.549.1). Growth inhibition assay; human breast cancer (MDA-MB231)
and human ovarian cancer (OVCAR-8) cells were plated at 3000
2.2.12.[Ru(PPh )(hmbt) Cl] cells/wellin96-well(100lL/well)flat-bottomedmicroliterplates
3 2
A stirred suspension of [Ru(PPh ) Cl ] (0.25g, 0.25mmol) in (Costar,Corning,NY).After24hincubation,thecellswereexposed
33 2
MeOH(10mL)wasaddedtoaHhmbt(0.09g,0.4mmol)inMeOH to different concentrations of each compound continuously for
H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201 197
5days.Briefly,followingdrugtreatment,thecellswerefixedusing vibrations of the coordinated phen or bpy [15,28]. These bands
50lLofcoldtrichloroaceticacid(50%)for2hat4(cid:3)C,washedwith areathigherwavenumberscomparedwiththoseforthefreephen
water,stainedwithsulforhodamineB(SRB0.4%)overnightatroom orbpyligandindicatingchelation[29].
temperature, rinsedwith1%aceticacidandallowedtodryover- In the 1000–750cm(cid:4)1 region, the spectra of [MoO (hmbt) ]
2 2
night [20]. The resulting colored residue was dissolved in 200lL (Fig.3)showsbandscharacteristicofthecis-MoO2þ units[30,31].
2
Tris base (10mM,pH 10.0) and the opticaldensity was recorded TheIRbandsat939(943inRaman)and897(911inRaman)cm(cid:4)1
at490nmusingamicroplatereaderELx808(BioTekInstruments). are assigned to the v(MoO ) and v (MoO ) modes, respectively
s 2 as 2
TheresultswereanalyzedbyGraphPadPrism(GraphPadSoftware, [30,31].Asexpected,thesymmetricmodeisweakintheIRspectra
Inc., San Diego, CA) and the sigmoidal dose response curve was andstronginRaman,whiletheoppositeappliesfortheasymmet-
used to determine 50% cell growth inhibitory concentration ricone.Theappearanceoftwostretchingbandsisindicativeofthe
(IC ). Each point represents the average of two independent cis-configuration[15,32,33].
50
experimentsperformedintriplicate[20]. TheIRandRamanspectraofthecomplexesshowseveralbands
in 500–200cm(cid:4)1 due to m(M–O), m(M–N), m(M–P) and m(M–Cl)
stretches[26,33].
3.Resultanddiscussion
Section2describesthesynthesisofthenewcomplexesof2-(20- 3.2.NMRspectra
hydroxy-50-methylphenyl)-benzotriazole (Hhmbt) and lists their
The1HNMRspectroscopicdataforHhmbtcomplexesinDMSO-
elementalanalysesandspectroscopicdata,whichareinexcellent
d arereportedintheexperimentalsection.
agreement with the assigned formulae. The molar conductivities 6
The spectrum of the free Hhmbt (see Fig. 1 for numbering
(K ) in DMF at room temperature suggest all complexes to be
M
scheme) exhibits three singlets at d 3.34, 7.69 and 10.35ppm
non-electrolytesexceptfor,[M(L)(hmbt)]Cl(M(II)=Pd,Pt;L=bpy,
attributedtoCH ,H(6)andOH,respectively.Therearetwotriplets
phen) and [Rh(hmbt) (H O) ]Cl, which show as 1:1 electrolytes 3
2 2 2
atd7.55and7.52ppmandfourdoubletsatd8.03,8.00,7.24and
[21]. All the new complexes are microcrystalline or powder-like,
7.05ppm assigned to H(8), H(9), H(3), H(4), H(7) and H(10),
stable under normal laboratory conditions and soluble in DMF
respectively.ThesharpsingletduetoOHproton,ismissedinthe
andDMSO.
complexes, indicating the replacement of the hydroxy proton by
the metal ions [34]. On the other hand, the signals for H(7) and
3.1.Vibrationalspectra H(10)areshifteddownfield,indicatingthecomplexationofhmbt(cid:4)
through the deprotonated hydroxy oxygen and imine nitrogen
The solid-state properties of 2-(20-hydroxy-50-methylphenyl)- atoms[35,36].
benzotriazole (Hhmbt; Fig. 1) were examined by IR and Raman The1HNMRspectrumof[Rh(hmbt) (H O) ]Clshouldshowthe
2 2 2
spectroscopy. The spectrum of Hhmbt was compared with those presenceoffacandmerisomerssincehmbt(cid:4)isanunsymmetrical
of the complexes. Tentative assignments of selected IR bands are bidentateligand(imineanddeprotonatedhydroxyoxygenatoms
reported in the experimental section. The IR spectrum of Hhmbt are non-equivalent). In the fac isomer, the hmbt(cid:4) are equivalent
exhibitsastrongbroadatbandat3400cm(cid:4)1duetom(OH),support
whileinthemertheyaredifferent[10,37].Twopeaksareobserved
theexistenceofHhmbtintheenolform(Scheme1)[3,7],thisband for each proton assigned to cis-hmbt(cid:4) and cis-H O configuration
2
is missedon the complexes. These data are further supported by (Fig.4).Thisfeaturewasfurthersupportedby13CNMRspectrum,
theshiftoftheintensebandnear1250cm(cid:4)1inthespectraoffree andexpectedduetothebulkyhmbt(cid:4)moieties.
ligandto higher frequency,indicating the coordination of Hhmbt The1HNMRspectraofthe[M(hmbt)(PPh )Cl],[M(hmbt)(L)]Cl
throughthedeprotonatedphenolic(C(2)–O(cid:4))[22,23].Theseobser-
(M(II)=Pd, Pt; L=bpy, phen), [Ag(PPh
3
)(hmbt)(H O)] and
3 2
vationsindicatethereplacementoftheacidichydrogenbytheme- [Ru(PPh )(hmbt) Cl] complexes show complicated multiplets in
talion[13].Thestrongbandat1600(IR)and1601(Raman)cm(cid:4)1
thed7.6
3
–8.4and
2
7.2–7.8ppmregions,whichareassignedtobpy
infreeligandischaracteristicofm(C@N)group.Itisexpectedthat
or phen and PPh protons, respectively. The bpy or phen and
3
coordination of the nitrogen to the metal ion would reduce the PPh protons show upfield shifts in comparison to those of
electron density in the azomethine link and thus shifted m(C@N) [M(L 3 )Cl ] (M(II)=Pd, Pt; L=bpy, phen) and [Ru(PPh ) Cl ]. This
2 33 2
stretch [24]. In the spectra of the complexes, this band is shifted observation is interpreted in term of strong binding of hmbt(cid:4) to
to the region at 1604–1630cm(cid:4)1 [25]. The band near 1131cm(cid:4)1 metalionsascomparedtobindingofchlorideion[9].
infreeHhmbtisassignedtothem(N–N)stretch.Inthecomplexes,
thisbandisshiftedtolowerwavenumber[26].Thesemeansthat
hmbt(cid:4)acts asamononegativebidentateligand,coordinatingthe H3C
metalionsthroughtheazomithinenitrogenandthedeprotonated
hydroxyoxygencenters formingsix-memberedring.In thecom-
plex,[Zn(hmbt)(AcO)(H O) ](Fig.2),twoextrabandsareobserved
2 2
at 1532 and 1408cm(cid:4)1 assigned to m as (COO(cid:4)) and m s (COO(cid:4)) H 2 O
stretching vibration of the acetate group, respectively [15]. O O
The separation between these two bands {D=m (COO(cid:4)) and
as
m s (COO(cid:4))=124cm(cid:4)1}, indicatingasymmetricbidentatecoordina- N Zn C CH 3
tionofthecarboxylicgroup[15,16].
N N
The presence of the coordinated PPh 3 groups in O
[M(hmbt)(PPh 3 )Cl] (M(II)=Pd, Pt), [Ru(PPh 3 )(hmbt) 2 Cl] and H 2 O
[Ag(PPh )(hmbt)(H O)]ismanifestedbythestrongIRbandsnear
3 2
1099and751cm(cid:4)1,attributedtothem(P–C )andd(C–CH)vibra-
ph
tions,respectively[27].
The spectra of the complexes, [M(L)(hmbt)]Cl (M(II)=Pd, Pt;
L=bpy, phen) show bands near 1580, 1515, 1495, 1420 (phen)
and854,841,750and725(bpy)cm(cid:4)1areattributedtothec(CH) Fig.2. Structureof[Zn(hmbt)2(H2O)2].
198 H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201
[40].Transitionsbelow400nmareassignedtointra-ligandcharge
transfer(n?p⁄andp?p⁄).
The electronic spectrum of the diamagnetic complex,
[Rh(hmbt) (H O) ]Cl,displaybandsat589,497and408nm,which
2 2 2
O O resemblethoseofotheroctahedralRh(III)complexesandmaybe
assigned to 1A ?3T , 1A ?1T and 1A ?1T transitions,
1g 1g 1g 1g 1g 2g
Mo
N N N N respectively[10,32,41].
Theelectronicspectraofthe diamagnetic ruthenium(II) com-
N N plexes show intense transitions near 636 (1A ?1T ), 340
1g 1g
(1A ?1T )and300(ligand(p–dp))nm[10].Theseareattributed
1g 2g
O O toalow-spinoctahedralgeometryaroundRu(II)[8,10].Theelec-
tronic spectra of the diamagnetic Pd(II), Pt(II) complexes exhibit
bandsnear470and320nmdueto1A ?1B and1A ?1E tran-
1g g 1g g
sitions, respectively, in a square-planar configuration [42,43]. In
thecomplexes,[M(hmbt)(PPh )Cl],[M(hmbt)(L)]Cl(M(II)=Pd,Pt;
H 3 C CH 3 L=bpy, phen), the absorption 3 band at 370nm is assigned to a
mixtureofchargetransferfromM(II)tothep⁄orbitalofbpy,phen
Fig.3. Structureofcis-[MoO2(hmbt)2].
orPPh andd–dbands[10,42,43].
3
In the electronic spectrum of complex cis-[MoO (hmbt) ] dis-
2 2
The 31P NMR spectra of the complexes, [M(hmbt)(PPh )Cl] playsbandsat 456and 358(shoulder)nm;thelatterisassigned
3
(M(II)=Pd, Pt), [Ag(PPh )(hmbt)] and[Ru(hmbt) (PPh )Cl] in to O2(cid:4)?Mo(VI) p–d transition and is characteristic of the
3 2 3
DMSO-d 6 showsharpsingletneard20.0ppm,suggestingthepres- MoO2 2 (cid:4) moietyinoctahedralgeometry[10].
enceofonecoordinatedPPh moietyinthecomplex[38].
3
The 13C NMR spectrum of Hhmbt in DMSO-d has been mea- 3.4.Massspectra
6
sured and assigned. The spectrum shows ten resonances at d
20.28, 118.24, 118.37, 125.36, 127.14, 127.80, 129.11, 132.04, The mass spectral data of the complexes are reported in the
143.88 and 148.88ppm, may be assigned to CH (5), C(3), C(8,9), Experimental section and theirmolecularion peaks are in agree-
3
C(4), C(6), C(7,10), C(1), C(5), C(11,12) and C(2), respectively. In mentwiththeirassignedformulae.
the complexes, the resonances for the carbon atoms adjacent to Themassspectrumof[Pd(hmbt)(H 2 O)Cl]showsfragmentation
thecoordinationsites,C(1),C(2),C(3),C(11)andC(12),areshifted patternscorrespondingtosuccessivedegradationsofthemolecule.
downfield relative to their positions in the free ligand (Table 1) Thefirstsignalatm/z331(Calcd.330.4)with50%abundancerep-
[39]. Thisfeaturemay bedueto anincreasein thebenzotriazole
resentsthemolecularion,[Pd(hmbt)]+.Thespectrumexhibitsone
ringcurrentinC(11)andC(12)broughtaboutbycoordinationto more peak at 226.0 (Calcd. 226.4) corresponding to [Pd(hmbt-
triazole nitrogen center [18]. In the spectrum of [Rh(hmbt) 2 (H 2- C 6 H 4 N 2 )]+.Themassspectrumof[Pd(hmbt) 2 ]showsthefirstpeak
O) ]Cl,twosignalswereobservedforeachcarbonatom,supporting atm/z554.5(Calcd.554.4)with100%abundancecorrespondingto
2
thecis-configuration,whichobservedinthe1HNMRspectrum. [Pd(hmbt) 2 ]+. The spectrum exhibits two more peaks at 329.4,
226.7 corresponding to [Pd(hmbt)]+, [Pd(hmbt-C H N )]+ frag-
6 4 2
ments, respectively. The mass spectra of [Pd(bpy)(hmbt)]Cl and
[Pd(phen)(hmbt)]Cl showpeaks at m/z 486.4, 510.4,respectively,
3.3.Electronicspectra representthemolecularions[Pd(bpy)(hmbt)]+(Calcd.486.4)and
[Pd(phen)(hmbt)]+(Calcd.510.4),respectively.Themassspectrum
TheelectronicspectraofHhmbtinEtOHandDMSOshowthree of [M(hmbt)(PPh )Cl] (M(II)=Pd, Pt) show signals at m/z 628.2
3
bands near 250, 300 and 358nm. The electronic spectra of the (Calcd.627.9),Pdand716.5(Calcd.716.5),Pt,inagreementwith
complexesin H 2 O, MeOH,DMSO or Nujolin the 200–900nm re- themolecularions[M(hmbt)(PPh 3 )Cl]+.Thefragmentationpattern
gionscontainintensebandsduetoligandtometalcharge-transfer ofPt(II)complexindicatesthestepwiseligandlossto[Pt(PPh )]2+
3
(LMCT)transitionsand weaker bands assignedto d–dtransitions (457) [8]. The mass spectra of [Pt(bpy)(hmbt)]Cl and [Pt(phen)
(hmbt)]Clshowpeaksatm/z574.3and599.5,representthemolec-
ular ions [Pt(bpy)(hmbt)]+ (Calcd. 575.0) and [Pd(phen)(hmbt)]+
(Calcd.599.0),respectively.
H3C The mass spectrum of the complex, [Zn(hmbt) 2 (H 2 O) 2 ] shows
the first signal at m/z 513.1 (Calcd. 513.5) with 100% abundance
correspondingtothemolecularion[Zn(hmbt) ]+.Onemoresignal
2
at 289.1 (Calcd. 289.5) is associated with [Zn(hmbt)]+ fragment,
indicatingstepwiseligandloss[43].
O Ag N N The spectrum of [Rh(hmbt) (H O) ]Cl shows signal at 551.2
2 2 2
N (Calcd. 551.1) corresponding to the molecular ion [Rh(hmbt) 2 ]+.
N The spectrum of [Ru(hmbt) 2 (H 2 O) 2 ] shows a signal at m/z 549.9
(Calcd. 549.1) corresponding to [Ru(hmbt) ]+ [8] while that of
N N Ag O 2
[Ru(PPh )(hmbt) Cl] shows peaks at m/z 812.2 and 588.0, which
3 2
correspond to [Ru(PPh )(hmbt) ]+ (Calcd. 811.1) and [Ru(PPh )
3 2 3
(hmbt)]+(Calcd.587.1),respectively,inagreementwithstepwise
ligandloss[10].
CH3 Thespectrumof[Ag 2 (hmbt) 2 ](Fig.4)showssignalm/zat332.2
(Calcd. 331.8) with 8% abundance corresponding to [Ag(hmbt)]+.
The signal at 291.2 (Calcd. 289.8) is associated with [Ag(hmbt-
Fig.4. Structureof[Ag2(hmbt)2]. N 3 )]+ fragment. The spectrum of [Ag(PPh 3 )(hmbt)] shows peaks
H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201 199
Table1
13CNMRspectraldataofHhmbtanditscomplexes.
Compounds C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 CH3
d ppm
Hhmbt 129.11 148.88 118.24 125.36 132.04 127.14 127.80 118.37 118.37 127.80 143.88 143.88 20.28
[Pd(hmbt)(H2O)Cl] 132.00 152.00 118.98 125.67 132.32 127.43 127.98 119.04 119.18 129.30 148.43 148.56 21.09
[Rh(hmbt)2(H2O)2]Cla 131.54 152.90 118.56 125.89 132.33 127.40 127.99 119.32 119.55 129.32 147.90 148.29 21.11
131.80 153.06 118.81 126.06 132.61 127.56 128.24 119.49 119.84 129.73 148.12 148.55 21.36
[Zn(hmbt)(OAc)(H2O)2] 131.82 153.00 118.43 125.68 132.21 127.78 128.80 119.00 119.87 129.06 148.76 149.04 22.01
[Zn(hmbt)2(H2O)2] 132.41 154.04 118.61 125.54 132.25 127.65 128.41 119.73 119.79 128.98 147.99 148.87 21.98
Cis-[MoO2(hmpt)2] 131.23 153.81 118.78 125.59 132.09 127.88 128.00 119.09 119.68 129.07 148.31 148.97 20.98
a TwosignalsforeachCindicatingcis-(hmbt(cid:4))2configuration.
atm/z593.4and369.3,correspondingto[Ag(PPh )(hmbt)]+(Calcd. [Pt(phen)(hmbt)]Cl.2H O, is characterized by three steps in 30–
3 2
593.8)and[Ag(PPh )]+(Calcd.369.8)fragments,respectively. 100, 101–300 and 301–650(cid:3)C regions. These are assigned to the
3
elimination of lattice water (Calcd. 5.3, Found 5.1%), ½ Cl , phen
2
and C H (Calcd. 39.9, Found 40.1%), C H N (Calcd. 23.3, Found
4 4 9 6 3
3.5.Thermalmeasurements
22.9%), fragments, respectively, leaving PtO residue at 700(cid:3)C
(31.4%)[10,27].Thethermogramof[Pt(bpy)(hmbt)]Cl(cid:3)H Oshows
2
Thethermalstabilityanddegradationbehaviourofsomeofthere-
the first endothermic weight loss between 35 and 150(cid:3)C, which
ported complexes, [Zn(hmbt)(OAc)(H O) ], [Zn(hmbt) ], [Pd(hmbt)
2 2 2 may correspond to the release of crystal lattice water and ½ Cl
2
(H O)Cl](cid:3)3H O, [Pd(hmbt) ], [Pd(hmbt)(PPh )Cl], [M(bpy)(hmbt)]Cl
2 2 2 3 (Cacld.8.5,Found8.2%).Theseconddecompositionstepoccursbe-
(M=Pd, n=2; M=Pt, n=1), [M(phen)(hmbt)]Cl (M=Pd, n=1;
tween 151 and 320(cid:3)C, attributed to the loss of C H N fragment
6 4
M=Pt, n=2), cis-[MoO (hmbt) ], [Ag (hmbt) ], [Ag(PPh )(hmbt)],
2 2 2 2 3 (Calcd. 14.3, Found 14.6%) while the third one between 321 and
[Ru(hmbt) (H O) ], [Ru(PPh )(hmbt) Cl] and [Rh(hmbt) (H O) ]-
2 2 2 3 2 2 2 2 589(cid:3)C arise from the elimination of N and phen species (Calcd.
2
Cl(cid:3)5H O,werestudiedusingthethermogravimetric(TG)technique.
2 33.1, Found 33.1%). The fourth TG inflection lies in the 590–
Theweightlossobservedbelow130(cid:3)Cisduetodehydrationasthe
700(cid:3)C range, arise from the release of C H fragment (Calcd.
7 6
colourschangedfrompaletodeeper[37,41].
14.3,found13.9%),leavingPtO(Calcd.33.6,Found34.6%).
The thermogram of [Zn(hmbt)(OAc)(H O) ], shows the first-
2 2 The TGA data for the complex, [Rh(hmbt) (H O) ]Cl(cid:3)5H O,
2 2 2 2
step weight loss of 28.9% between 196 and 272(cid:3)C, which corre-
shows three TG inflections in the ranges 65–213, 214–301 and
sponds to the release of two coordinated waters molecules per
302–431(cid:3)C.Thefirstweightlossmayarisefromthereleaseoffive
molecule of complex, AcO and ½N (Calcd. 29.1%). The second
2 waterofcrystallization,twomoleculewaterofcoordination,½Cl
2
decompositionoccursbetween272and359(cid:3)C,whichisattributed
andC H N fragments(Calcd.39.2,Found39.5%),C H fragments
6 4 3 6 4
to the loss of C H and C H N fragments (Calcd. 50.5, Found
7 6 6 4 2 (Calcd. 10.6, found 10.3%) and C H N O (Calcd. 19.7, Found
7 6 3 ½
50.9%),leavingZnO(21.2%).Thethermogramof[Zn(hmbt) (H O) ]
2 2 2 19.8%),respectively,leavingRh O asaresidueat700(cid:3)C(17.8%).
2 3
shows TG inflection in the ranges 150–470(cid:3)C, arise from the re-
Forthecomplex,[Ru(hmbt) (H O) ](cid:3)2H O,fourTGinflectionsin
2 2 2 2
lease of two coordinated water, 2C H N and C H O fragments
7 6 3 6 4 the ranges 60–180, 181–350, 351–450 and 451–600(cid:3)C were ob-
(Calcd.71.3,Found70.7%),leavingZnOasaresidue.
served.Thefirstonearisefromthereleaseoftwowaterofcrystal-
The thermogram of [Pd(hmbt)(H O)Cl](cid:3)3H O, shows the first-
2 2 lizationandtwowaterofcoordination(Calcd.11.6,Found11.8%),
step weight loss of 13.3% between 63 and 110(cid:3)C, which corre-
2N molecules(Calcd.9.0,Found8.7%),C H NandC H fragments
2 6 4 6 4
sponds to the release of three waters molecules (Calcd. 12.3%);
(Calcd.26.7,Found27.0%),andC H NandC H fragments(Calcd.
7 6 7 6
therelativelylowtemperatureshowsthatthesewatermolecules
32.5, Found 32.4%), respectively, leaving Ru O as a residue at
2 3
arecrystallatticeheld[9,10,41].Anotherendothermicdecomposi-
700(cid:3)C (20.1%). The thermogram of [Ru(PPh )(hmbt) Cl], show
3 2
tionoccursbetween111and350(cid:3)C,whichisattributedtotheloss
three TG inflections in the ranges 217–304, 305–389 and 390–
ofcoordinatedH O, ½Cl and C H fragment(Calcd.29.6,Found
2 2 6 4 588(cid:3)C, arise from the release of ½ Cl (Calcd. 4.2, Found 4.3%),
2
29.4%) [27]. There is other TG inflection in 350–610(cid:3)C region,
C H N fragment(Calcd.15.6,found15.5%),3Phfragments(Calcd.
7 6 3
may arise from the elimination of C H N (Calcd. 30.2, Found
7 6 3 27.3, found 26.9%), and C H and C H N fragments (Calcd. 22.9,
6 4 7 6 2
30.5%) fragment, leaving PdO (28.0%). The thermogram of
found 22.6%) respectively [33], leaving Ru O as a residue at
2 3
[Pd(hmbt) ], is characterized by two steps in 225–425 and 426–
2 700(cid:3)C(15.7%).
575(cid:3)C region. They are assigned to the elimination of C H N ,
13 11 3 The thermogram of [Ag (hmbt) ], shows the first-step weight
2 2
C H N (Calcd.58.8,Found59.1%) and C H O(Calcd.19.1,Found
6 4 3 7 6 lossof24.9%between175and275(cid:3)C,maybeattributedtothere-
18.8%), fragments, respectively, leaving PdO residue at 700(cid:3) C
lease of 2C H , ½ N (Calcd. 25.0%). The second step occurs be-
6 4 2
(22.1%) [27]. The thermogram of [Pd(bpy)(hmbt)]Cl(cid:3)2H O shows
2 tween 276 and 430(cid:3)C, attributed to the loss of C H , N and ½
6 4 2
thefirstendothermicweightlossbetween23and150(cid:3)C,maybe
N (Calcd.17.7,Found17.1%).Thelastdecompositionstepoccurs
2
due to the release of crystal lattice water and ½ Cl molecule
2 between 431–510(cid:3)C, attributed to the loss of C H N O (Calcd.
7 6 2
(Calcd.12.8,Found12.8%).Theseconddecompositionstepoccurs
20.1,Found19.7%),leavingAg O(34.9%).Thecomplex,[Ag(PPh )
2 3
between 151 and 350(cid:3)C, attributed to the loss of bpy species
(hmbt)], shows two TG inflections in the ranges 175–310 and
(Calcd.28.0,Found28.2%).ThesecondTGinflectionbetween351
311–900(cid:3)C,arisedfromthereleaseofPPh andC H N fragments
3 6 4 3
and 450(cid:3)C may arise from the elimination of C H N fragment
6 4 3 (Calcd. 63.9, Found 63.9%), and C H O fragment (Calcd. 16.5,
7 6 ½
(Calcd.21.2,Found21.3%),leavingPdO(Calcd.21.9%).Thethermo-
Found16.8%),leavingAg Oasaresidue(19.5%)[12].
2
gram of [Pd(phen)(hmbt)]Cl(cid:3)H O shows weight losses in the 23–
2
150, 151–270, 271–580 and 581–900(cid:3) C, which may correspond
to the release of crystal lattice water (Cacld. 3.2, Found 3.5%), ½ 3.6.Anticanceractivity
Cl and C H N species (Calcd. 27.2, Found 27.5%), ½ N and
2 7 6 2 2
C H N(Calcd. 21.0, Found 21.1%) and C H (Calcd. 27.0, Found Cis-platin is considered to be one of the best known small
6 4 12 10
26.5%) fragments, leaving PdO (18.21%). The thermogram of metal-containing drug molecules. It acts as anticancer agent for
200 H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201
Fig.5A. IC50valuesof[Ag(hmpbt)(PPh3)],[Rh(hmbt)2(H2O)2]Cl,[Pt(phen)(hmbt)]Cland[Pd(phen)(hmbt)]Cltestedagainstthehumanbreastcancer(MDA-MB231)celllines.
Fig.5B. IC50valuesof[Ag(hmpbt)(PPh3)],[Rh(hmbt)2(H2O)2]Cl,[Pt(phen)(hmbt)]Cland[Pd(phen)(hmbt)]Cltestedagainstthehumanovariancancer(OVCAR-8)celllines.
severalhumancancers,particularly,testicularandovariancancers Table2
[8–14].Generally,thesideeffects,especiallynephrotoxicity,limit Anticanceractivityof Hhmbtanditscomplexes againstthehuman breastcancer
(MDA-MB231)andhumanovariancancer(OVCAR-8)celllines.
its widespread use in high doses [44]. The need to develop new
complexes with reduced nephrotoxicity and higher activity has Compounds IC50(lM) IC50(lM)
stimulated the synthesis of many new complexes. Over the past Humanbreastcancer Humanovariancancer
(MDA-MB231)celllines (OVCAR-8)celllines
years,arenewedinterestinZn(II),Ag(I),Pd(II)andPt(II)complexes
aspotentialanticanceragentshasdevelopedinourlaboratory[8– Hhmbt >100 87.55
14].
[Zn(hmbt)2(H2O)2] >100 84.69
We have recently examined the in vitro anticancer activity of
[
[
Z
P
n
d(
(
b
h
p
m
y
b
)(
t
h
)(
m
OA
bt
c
)
)
]
(
C
H
l
2O)2] 3
4
7
5
.
.
7
9
5
6
3
3
3
7
.
.
2
3
0
7
DL-piperidine-2-carboxylic acid (DL-H 2 pa) and its complexes, [Pt(bpy)(hmbt)]Cl 18.89 23.54
trans-[Zn (l-Ca) (Hpa) Cl ], [Pd(bpy)(Hpa)]Cl and [M(pa)(PPh ) ] [Pd(phen)(hmbt)]Cl 4.85 2.99
2 2 2 6 32
against serous ovarian cancer ascites, OV 90 cell line [12]. The [Pt(phen)(hmbt)]Cl 5.24 3.00
ultimate goal of this research is to develop new complexes with
[Ag2(hmbt)2] 14.13 13.54
[Ag(PPh3)(hmbt)] 1.37 1.75
high efficacy against cancer cells. The in vitro anticancer activity [Rh(hmbt)2(H2O)2]Cl 7.52 8.50
of the free Hhmbt and its complexes, [Zn(hmbt) (H O) ], [Zn Cis-platin 32.0 30.86
2 2 2
(hmbt)(OAc)(H O) ],[M(bpy)(hmbt)]Cl,[M(phen)(hmbt)]Cl(M(II)
2 2
=Pd,Pt),[Ag (hmbt) ],[Ag(PPh )(hmbt)]and[Rh(hmbt) (H O) ]Cl
2 2 3 2 2 2
were tested against the human breast cancer (MDA-MB231) and namic strength of a typical coordination bond, are much weaker
human ovarian cancer (OVCAR-8) cell lines in comparison to cis- than C–C, C–N or C–O covalent bonds; the data obtained from
platinasareference(Fig.5;Table2).Thecomplexes,[Ag (hmbt) ], TGA analysis, discussed above, confirming this feature. However,
2 2
[Ag(hmpbt)(PPh )], [Rh(hmbt) (H O) ]Cl, [Pt(phen)(hmbt)]Cl and theligandexchangebehaviorinPtcomplexesisquiteslow,which
3 2 2 2
[Pd(phen)(hmbt)]Clexhibitthehighestgrowthinhibitoryactivity givesthemhighkineticstability.Thus,theligandexchangereac-
withmeanIC values14.13,1.37,7.52,5.24and4.85lM(MDA- tions take place in minutes to days, rather than microseconds to
50
MB231) and 13.54, 1.75, 8.50, 3.00 and 2.99lM (OVACAR-8), seconds as in case of Pd(II) complexes [46]. The high activity of
respectively; the IC50 values of cis-platin being 32.00 and the complexes, [Ag (hmbt) ] and [Ag(hmpbt)(PPh )], is expected,
2 2 3
30.86lM. since Ag(I) complexes have been reported as active anti-cancer
Generally, it is accepted that binding of cis-platin to genomic agents and wound healing stimulators [13,47]. In addition, the
DNA (g-DNA) in the cell nucleus is the main event responsible pulkPPh group and itsslowhydrolysismayexplain theactivity
3
foritsantitumorproperties[45].Thus,thedamageinducedupon ofthelatercomplexwithrespecttothefirstone[9,10].Moreover,
binding of cisplatin to g-DNA may inhibit transcription, and/or thekinetictranseffectisresponsibleforligandexchangereactions;
DNA replication mechanisms. Subsequently, these alterations in i.e.,donoratomslocatedtranstootherdonorswithstrongtransef-
DNAprocessingwouldtriggercytotoxicprocessesthatleadtocan- fectaremorerapidlysubstitutedthanligandsincis-positions[46].
cercelldeath.AnimportantpropertyofPt(II)complexesisthefact These features may explain the activity of [Pt(phen)(hmbt)]Cl
thatPt–ligandbonds(Pt–N,Pt–O,Pt–P),whichhavethethermody- (Fig. 6) and [Pd(phen)(hmbt)]Cl complexes, which may attribute
H.A.El-Asmyetal./JournalofMolecularStructure1059(2014)193–201 201
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