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Inhibition of telomerase activity and SK-OV-3/DDP cell apoptosis by rhodium(III) and iron(III) complexes with 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine
Inorganic Chemistry Communications 102 (2019) 180–184
ContentslistsavailableatScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Short communication
Inhibition of telomerase activity and SK-OV-3/DDP cell apoptosis by
T
rhodium(III) and iron(III) complexes with 4′-(3-thiophenecarboxaldehyde)-
2,2′:6′,2″-terpyridine
Qing-Min Weia,1, Zhen-Feng Wanga,1, Qi-Pin Qina,⁎ , Shu-Long Wanga, Ming-Xiong Tana,⁎ ,
Bi-Qun Zoub,d,⁎⁎ , Peng-Fei Yaoc,⁎ , Hong Liangd
aGuangxiKeyLaboratoryofAgriculturalResources,ChemistryandBiotechnology,CollegeofChemistryandFoodScience,YulinNormalUniversity,1303Jiaoyudong
Road,Yulin537000,China
bDepartmentofChemistry,GuilinNormalCollege,9FeihuRoad,Gulin541001,China
cGuangxiCollegesandUniversitiesKeyLaboratoryofRegionalEcologicalEnvironmentAnalysisandPollutionControlofWestGuangxi,CollegeofChemistryand
EnvironmentalEngineering,BaiseUniversity,Baise,Guangxi533000,China
dStateKeyLaboratoryfortheChemistryandMolecularEngineeringofMedicinalResources,SchoolofChemistryandPharmacy,GuangxiNormalUniversity,15Yucai
Road,Guilin541004,China
GRAPHICAL ABSTRACT
tpatpy-Rhinhibitedtelomerasebydown-regulationofc-mycandhTERT,aswellasinducedSK-OV-3/DDPcellarrestintheSphase.
ARTICLE INFO ABSTRACT
Keywords: Tworhodium(III)andiron(III)complexesof4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine(tpatpy):[Rh
4′-(3-Thiophenecarboxaldehyde)-2,2′:6′,2″- (tpatpy)Cl3]·CH3OH (tpatpy-Rh) and [Fe(tpatpy)Cl3] (tpatpy-Fe) have been prepared and characterized.
terpyridine Tpatpy-Rh(5.03±1.15μM)andtpatpy-Fe(18.02±0.45μM)exhibitedgreatercytotoxicitythanthetpatpy
Rhodium(III)complex ligand(70.11±0.28μM)andcisplatin(61.21±1.39μM)againstSK-OV-3/DDPcells.Inaddition,tpatpy-Rh
Cellapoptosis
inhibitedtelomerasebydown-regulationofc-mycandhTERT,aswellasinducedSK-OV-3/DDPcellarrestinthe
Telomeraseactivity
Sphase.
In1978cisplatin(cis-[PtCl2(NH3)2])wasthefirstapprovedbythe applicabilitywaslimitedatsometimes[1–4].Therefore,thenon‑pla-
FDAasananti-tumormetaldrugforclinicaltreatment[1–3].However, tinum(II/IV)transitionmetalcomplexeshavereceivedrecentinterestat
cisplatinanditsderivativeshavealsoshownsideeffects/drawbacksin presentduetotheirhavehighspecificitytobindtoproteinmolecules,
the clinical treatment, including nephrotoxicity, ototoxicity, and ac- telomeraseandDNA,etc.[5–14]AlthoughlesswidelystudiedthanPt
quired resistance or cisplatin-resistant tumor cells, etc., thus their (II/IV) compounds, complexes based on Fe(III) and Rh(III) have
⁎Correspondingauthors.
⁎⁎Correspondenceto:B.-Q.Zou,DepartmentofChemistry,GuilinNormalCollege,9FeihuRoad,Gulin541001,China.
E-mailaddresses:qpqin2018@126.com(Q.-P.Qin),mxtan2018@126.com(M.-X.Tan),zoubiqun@163.com(B.-Q.Zou),yaopengfei1986@163.com(P.-F.Yao).
1Theseauthorscontributedequallytothiswork.
https://doi.org/10.1016/j.inoche.2019.02.030
Received9January2019;Receivedinrevisedform18February2019;Accepted18February2019
Available online 20 February 2019
1387-7003/ © 2019 Elsevier B.V. All rights reserved.
Q.-M.Wei,etal. Inorganic Chemistry Communications 102 (2019) 180–184
Scheme1.Syntheticrouteoftpatpyligandanditstpatpy-Rhandtpatpy-Fecompexes.Reagentsandsolventsareasfollows:(a)ethanol,25%NH3·H2O(aq),KOH;
(b)RhCl3·3H2OorFeCl3·6H2O(1.0mmol),3.5mLCH3OHand0.5mLCH2Cl2,85°C,2days.
attractedrecentinterestfortheir interestinganti-tumoractivityprop- CH3OH/CH2Cl2 (2.5mL: 0.1mL) generated [Rh(tpatpy)Cl3]·CH3OH
erties [11,15,16], such as phenanthroline Rh(III) complex [Rh (tpatpy-Rh, Yield: 85.12%) and [Fe(tpatpy)Cl3] (tpatpy-Fe, Yield:
(phq)2(MOPIP)]+ (phq=2-phenylquinoline and MOPIP=2-(4-meth- 77.03%),respectively.Thestructuresoftpatpy-Rhandtpatpy-Fewere
oxyphenyl)-1H-imidazo[4,5-f][1, 10]phenanthroline) [11], octahedral determined by elemental analysis and X-ray crystallography (Table
Rh(III) complexes [16], the antibiotic platensimycin Fe(III) complex S1–S6,Figs.1and2).AsshownintheFigs.1and2,theRh(III)andFe
[15,17], 4-chloro-2-phenylquinoline rhodium(III) complexes [18], (III)centerintpatpy-Rhandtpatpy-Feadoptedasix-coordinatedoc-
piano-stool dipyrrinato Rh(III) complex [19], 2-phenylbenzimidazole tahedralgeometry.Inaddition,theRheNandNeFebondlengthswere
rhodium(III)complex[20],andmore. intherangeof1.935(3)–2.045(3)Åand2.108(7)–2.151(7)Å,respec-
Ontheotherhand,alargenumberoftribipyridinederivativesand
tively.Inaddition,thehighestpeakswith2.38eÅ−3oftpatpy-Feinthe
theirmetalcomplexes,suchasPdII,ZnII,IrIII,FeII,PtII,CuII,RuII,AuIII, residualelectrondensityarelocated0.02ÅfromatomCl(1).Thedee-
VIIIandOsIIIcomplexes[21–51],havebeenreportedtostudyfortheir pestholewith−2.59eÅ−3oftpatpy-Feintheresidualelectronden-
DNAbindingability[21–40],inhibittelomerasebydown-regulationof sityarelocated0.04ÅfromatomS(1).
c-mycandhTERT[41–51],inducetumorcellcyclearrestandstabilize To gain information about the anti-tumor activity of the tpatpy
thetelomere(HTG21)andproto-oncogene(c-Myc)G-quadruplexDNA ligand,tpatpy-Rh,tpatpy-Fe,cisplatin,RhCl3·3H2OandFeCl3·6H2O,
[21–51].However,therhodium(III)andiron(III)complexeswith4′-(3- MTTassaywasperformedandtheIC50valuesweredeterminedforSK-
thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpatpy) have not OV-3, SK-OV-3/DDP, T-24, HeLa cancer cells and HL-7702 normal
been reported in the literature [50,51], and the detailed anti-tumor cellsexposedtoeachofcompound(Table1).Theresultsshowedthat
activitymechanismsofitsRh(III)andFe(III)complexesstillneedtobe tpatpy-Rh was the most active complex against SK-OV-3/DDP cells,
explored. with the lowest IC50 value was 5.03 ± 1.15μM, which it was
Herein,wereportedtworhodium(III)andiron(III)complexesof4′- 3.6–14.0foldsmoreactivethanthetpatpyligand(70.11 ± 0.28μM),
(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpatpy): [Rh tpatpy-Fe (18.02 ± 0.45μM), and cisplatin (61.21 ± 1.39μM), re-
(tpatpy)Cl3]·CH3OH (tpatpy-Rh) and [Fe(tpatpy)Cl3] (tpatpy-Fe). In spectively. Compared with the selected four tumor cells, tpatpy-Rh
addition, we explored tpatpy-Rh in vitro anti-tumor activity and in- andtpatpy-FedisplayedlowinhibitoryratesagainstHL-7702normal
vestigateditsactionmechanisms. cells,indicatingtheselectivityoftpatpy-Rhandtpatpy-FeonSK-OV-
The 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpatpy) 3/DDPcells.Becauseoftheweakantitumoractivityoftpatpy-Fein
was synthesized via the synthetic routes shown in Scheme 1, starting MTT assay, thus, only tpatpy-Rh (5.03μM) was selected for further
from 2-acetylpyridine and 2-thenaldehyde, which was synthesized by assays.
using modified method reported procedures [48,50,51]. In addition, Telomerase is transcriptionally repressed in most human normal
the reactions of RhCl3·3H2O and FeCl3·6H2O with 4′-(3-thiophene- cellswhilebeingover-expressedinabout85%oftumorcells[56,57].
carboxaldehyde)-2,2′:6′,2″-terpyridine (tpatpy) in the presence of This activity by chemical complexes or compounds leads to the
Fig.1.Molecularstructureoftpatpy-Rh(A)andtpatpy-Fe(B),respectively.
181
Q.-M.Wei,etal. Inorganic Chemistry Communications 102 (2019) 180–184
Fig.2.Modulationoftelomeraseactivitybytpatpy-Rh(5.03μM)inSK-OV-3/DDPcellsfor24h.(A)Analysisofthetelomeraseactivity.(BandC)c-mycandhTRET
proteinsintpatpy-Rh(5.03μM)treatedcellsweredetectedbywesternblot.
Table1
IC50values(μM±SD)forthetpatpyligand,tpatpy-Rh,tpatpy-Fe,cisplatin,RhCl3·3H2OandFeCl3·6H2OagainstSK-OV-3,SK-OV-3/DDP,T-24,HeLacancercells
andHL-7702normalcellsfor48hat37°C.
Compounds SK-OV-3 SK-OV-3/DDP T-24 HeLa HL-7702
tpatpy 35.96±0.15 70.11±0.28 18.23±1.59 25.06±1.78 35.02±1.85
tpatpy-Rh 29.62±1.14 5.03±1.15 15.31±0.22 >100 40.11±1.91
tpatpy-Fe 32.06±0.72 18.02±0.45 27.03±1.09 >100 38.15±0.22
RhCl3·3H2O >150 >150 >150 >150 >100
FeCl3·6H2O >150 >150 >150 >150 >100
Cisplatina 15.02±1.43 61.21±1.39 12.36±1.11 16.25±0.31 15.58±1.56
a Cisplatin(1.0mM)wasdissolvedinNaClsolution(0.154M)[52–55].
decrease in the level of hTERT and c-myc proteins [58–66], conse- (Fig. 3B and C). Thus, those prompt us to study the percentages of
quently inducing tumor cell cycle arrest and down-regulating the re- apoptosis cells (Q2+Q4), as shown in Fig. 4, SK-OV-3/DDP cells
lated-proteins [58–66]. Remarkably, Western blot assay testified that treated with tpatpy-Rh (5.03μM), the populations of apoptosis cells
tpatpy-Rh(5.03μM)inhibitedthetwoproteinslevelsofthehTERTand (Q2+Q4) was 54.40%, which suggested that tpatpy-Rh (5.03μM)
c-mycexpressionsinSK-OV-3/DDPcells(Fig.2BandC).Becauseofthe couldcauseapoptosis.
weak anti-tumor activity of tpatpy-Fe in MTT assay, only tpatpy-Rh In conclusion, we synthesized two Rh(III) and Fe(III) complexes,
(5.03μM) was selected for TRAP‑silver staining assay. Consequently, [Rh(tpatpy)Cl3]·CH3OH (tpatpy-Rh) and [Fe(tpatpy)Cl3] (tpatpy-Fe),
the inhibitory ratio (IR) forthe telomerase activity in cancercells in- with 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpatpy),
duced by tpatpy-Rh (5.03μM) reached 47.71% (Fig. 2A), comparing respectively. By MTT assay, it was confirmed that tpatpy-Rh
withthecontrol(5%DMSO),whichwasagreedwellwiththeresultsof (5.03 ± 1.15μM)andtpatpy-Fe(18.02 ± 0.45μM)exhibitedgreater
Westernblotanalysis(Fig.2).AsshowninFig.3,treatedwithtpatpy- cytotoxicity than the tpatpy ligand (70.11 ± 0.28μM) and cisplatin
Rh (5.03μM) for 24h, the populations of S-phase was approximately (61.21 ± 1.39μM)againstSK-OV-3/DDPcells.Inaddition,thesewere
35.89%,compared withthecontrol(21.74%), thesecan bedescribed thefirststudiestodemonstratethattpatpy-Rhinhibitedtelomeraseby
thattpatpy-Rh(5.03μM)causedSphasearrest(Fig.3A),andledtothe down-regulationofc-mycandhTERT,aswellasinducedSK-OV-3/DDP
decrease on the level of CDK2 and cyclin A by Western blot assay cellarrestintheSphase.
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Q.-M.Wei,etal. Inorganic Chemistry Communications 102 (2019) 180–184
Fig.3.Thechangeofcellcycleandrelated-
proteinsinSK-OV-3/DDPcellsaftertreated
withtpatpy-Rh(5.03μM)for24h.(A)The
cell cycle in SK-OV-3/DDP cells after
treated with tpatpy-Rh (5.03μM) was
analyzedbyflowcytometry.(BandC)The
cell cycle related-proteins in tpatpy-Rh
(5.03μM) treated cells were detected by
westernblot.
Fig.4.ApoptosisofSK-OV-3/DDPcellsaftertreatedwithtpatpy-Rh(5.03μM)for24h.
Acknowledgements AppendixA. Supplementarymaterial
This work was supported by the National Natural Science Inaddition,supplementarycrystallographicdatafortpatpy-Rhand
Foundation of China (Nos. 21867017 and 21761033), the Natural tpatpy-Fe collected in this study can be found under CCDC Nos.
Science Foundation of Guangxi (No. 2018GXNSFBA138021), the Key 1889618 and 1889619. These data include synthesis, materials and
Foundation Project of Colleges and Universities in Guangxi (No. methods of the most important compounds described in this article.
ZD2014108), the Innovative Team & Outstanding Talent Program of Supplementarydatatothisarticlecanbefoundonlineatdoi:https://
CollegesandUniversitiesinGuangxi(2014-49and2017-38),thePhD doi.org/10.1016/j.inoche.2019.02.030.
ResearchStartupProgramofYulinNormalUniversity(No.G2017009),
theprojectofGuibeicharacteristicmedicineresourcesresearchcenter References
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