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Review
. 2019 Jan 24;9(6):3239-3278.
doi: 10.1039/c8ra07926a. eCollection 2019 Jan 22.

Scope of organometallic compounds based on transition metal-arene systems as anticancer agents: starting from the classical paradigm to targeting multiple strategies

Mehvash Zaki  1 , Suboot Hairat  2 , Elham S Aazam  1
Affiliations
Review

Scope of organometallic compounds based on transition metal-arene systems as anticancer agents: starting from the classical paradigm to targeting multiple strategies

Mehvash Zaki et al. RSC Adv. .

Abstract

The advent of the clinically approved drug cisplatin started a new era in the design of metallodrugs for cancer chemotherapy. However, to date, there has not been much success in this field due to the persistence of some side effects and multi-drug resistance of cancer cells. In recent years, there has been increasing interest in the design of metal chemotherapeutics using organometallic complexes due to their good stability and unique properties in comparison to normal coordination complexes. Their intermediate properties between that of traditional inorganic and organic materials provide researchers with a new platform for the development of more promising cancer therapeutics. Classical metal-based drugs exert their therapeutic potential by targeting only DNA, but in the case of organometallic complexes, their molecular target is quite distinct to avoid drug resistance by cancer cells. Some organometallic drugs act by targeting a protein or inhibition of enzymes such as thioredoxin reductase (TrRx), while some target mitochondria and endoplasmic reticulum. In this review, we mainly discuss organometallic complexes of Ru, Ti, Au, Fe and Os and their mechanisms of action and how new approaches improve their therapeutic potential towards various cancer phenotypes. Herein, we discuss the role of structure-reactivity relationships in enhancing the anticancer potential of drugs for the benefit of humans both in vitro and in vivo. Besides, we also include in vivo tumor models that mimic human physiology to accelerate the development of more efficient clinical organometallic chemotherapeutics.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Chemical structures of (a) RAED-C and (b) RAPTA-C.
Fig. 2
Fig. 2. Chemical structures of complexes (a) [Ru(η6-p-cymene)(NQ)Cl], (b) [Ru(η6-p-cymene)(PT)Cl] and (c) [Ru(η6-p-cymene)(CHM)Cl] synthesized for macromolecular conjugation.
Fig. 3
Fig. 3. Chemical structure of (a) dinuclear [Ru2(η6-p-cymene)2(DIXD)Cl2] and (b) trinuclear [Ru3(η6-p-cymene)3(BTPE)Cl6] ruthenium complexes of polypyridyl ester.
Fig. 4
Fig. 4. Chemical structure of ruthenium(ii) arene benzhydrazone complexes.
Fig. 5
Fig. 5. MDA-MB-231 cells were treated with complexes [Ru(η6-C6H6)(Cl)(L3)] and [Ru(η6-p-cymene)(Cl)(L3) for 24 h. The scale bar is 20 mm. This figure was reproduced from ref. 65 with permission from the Royal Society of Chemistry.
Fig. 6
Fig. 6. Design of ligand framework and chemical structure of organometallic ruthenium Ru(ii) arene 9-anthraldehyde benzhydrazone complexes. This figure was reproduced from ref. 66 with permission from the Royal Society of Chemistry (Great Britain).
Fig. 7
Fig. 7. Chemical structure of ruthenium(ii) Schiff-base (RAS) complexes [Ru(η6-HMB)(MQMA)Cl]Cl and [Ru(η6-TBP)(MQMA)Cl]Cl.
Fig. 8
Fig. 8. Differential ER stress pathway activation by the [Ru(η6-HMB)(MQMA)Cl]Cl and [Ru(η6-TBP)(MQMA)Cl]Cl complexes leads to an alternative (non-apoptotic) PCD, which bypasses drug resistance mechanisms. This figure was reproduced from ref. 68 [M. J. Chow, C. Licona, G. Pastorin, G. Mellitzer, W. H. Ang and C. Gaiddon, Chem. Sci., 2016, 7, 4117–4124.] with permission from The Royal Society of Chemistry.
Fig. 9
Fig. 9. Design of a novel ligand for metallodrugs. This figure was reproduced from ref. 71a with permission from the Royal Society of Chemistry (Great Britain).
Fig. 10
Fig. 10. Synthesis of cyclometalated ruthenium complexes (a) [Ru(η6-p-cymene)(Bnz-Bu)Cl], (b) [Ru(η6-p-cymene)(Bnz-Bz)Cl] and (c) [Ru(η6-p-cymene)(Bnz-Bu·R)Cl].
Fig. 11
Fig. 11. (a) Curcuma longa- (turmeric) and (b) ruthenium(ii) arene RAPTA-type complexes [Ru(η6-p-cymene)(curc)-(PTA)]X and [Ru(hmb)(curc)(PTA)]X derived from curcumin. (a) was reproduced from its original paper after taking the copyright from ACS. This figure was taken from ref. 72, which is an open access article published under an ACS Author Choice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Fig. 12
Fig. 12. Design of RAPTA-type ruthenium(ii) complexes [Ru(η6-p-cymene)(F3C-acac-Ar)Cl] and [Ru(η6-p-cymene)(F3C-acac-Ar)pta]PF6 containing the F3C-acac-Ar ligand. This figure was reproduced from ref. 73 with permission from the American Chemical Society.
Fig. 13
Fig. 13. Chemical structure of titanocene dichloride.
Fig. 14
Fig. 14. Chemical structure of substituted titanocene salts (a) [Cp(CH2)2N(CH2)5]2TiBr2·2HBr, (b) [Cp][Cp(CH2)2N(CH2)5]TiBr2·HBr and (c) [Cp-(SiMe3)2][Cp(CH2)2N(CH2)5]TiCl2·HCl.
Fig. 15
Fig. 15. Chemical structure of a series of titanocene derivatives, [(η5-Cp-R1)(η5-Cp-R2)TiCl2], containing alkylammonium pendant groups on both or one ring.
Fig. 16
Fig. 16. Chemical structure of a series of substituted ansa-titanocenes.
Fig. 17
Fig. 17. Chemical structure of dimethylamino-functionalised titanocene {η5-Cp-CH[NMe2][C5H3Z]}2TiCl2.
Fig. 18
Fig. 18. Chemical structure of titanocene–gold complexes [Ti{η5-Cp(CH2)nPPh2(AuCl)}2]·2THF.
Fig. 19
Fig. 19. Chemical structure of titanocene–gold complexes (a) [(η5-Cp)2Ti{OC(O)CH2PPh2AuCl}2 and (b) [(η5-Cp)2Ti{OC(O)-C6H4PPh2AuCl}2.
Fig. 20
Fig. 20. Chemical structure of titanocene–gold complex containing gold(i)-phosphane [(η5-Cp)2TiMe(μ-mba)Au(PPh3)].
Fig. 21
Fig. 21. Chemical structure of heterobimetallic titanocene–gold complexes [(η5-Cp)2Ti(CH3){OC(O)-p-C6H4SAu(NHC)}].
Fig. 22
Fig. 22. Chemical structure of Au(iii) complexes of 2-(dimethylaminomethyl)phenyl (dmamp). (a) [Au(dmamp)Cl2] and (b) [Au(dmamp)(OAc)2].
Fig. 23
Fig. 23. Chemical structure of a series of a series of cycloaurated complexes (a) [Au(dmamp)(X–X)], (b) [Au(R-C^N)(X–X)] and (c) [Au(R-N^E^C-R′)X2].
Fig. 24
Fig. 24. Chemical structure of gold(iii) biguanide complexes (a) [AuIII(R-C^N)(BG)]Cl and (b) [AuIII(R-C^N)(BU)].
Fig. 25
Fig. 25. Fluorescence images of HeLa cells co-expressing mRFP and YFP-ER after treatment with or without [AuIII(nBu-C^N)(BG)]Cl (24 mM, 24 h). This figure was reproduced from ref. 145 with permission from the Royal Society of Chemistry (Great Britain).
Fig. 26
Fig. 26. Chemical structure of organogold(iii) complexes (a) [Au{κ2-C,N-C6H4(PPh2N(C6H5)-2}Cl2], (b) [Au{κ2-C,N-C6H4(PPh2N(C6H5)-2}(S2CN-R2)]PF6, (c) [Au{κ2-C,N-C6H4(PPh2N(C6H5)-2}(P{Cp(m-C6H4-SO3Na)2}3)Cl] and (d) [Au{κ2-C,N-C6H4(PPh2N(C6H5)-2}(PR3)2Cl]PF6.
Fig. 27
Fig. 27. Chemical structure of gold(iii)-phosphine complex [Au2(C^N^C)2(μ-dppp)](CF3SO3)2.
Fig. 28
Fig. 28. (A) The sizes of tumor nodules of the vehicle-control (NT, left) or [Au2(C^N^C)2(μ-dppp)](CF3SO3)2-treated (0.5 mg kg−1) rat examined by Xenogen Imaging System (upper) and dissect ion (lower). (B) H&E, vWF, and TUNEL staining of the tumor tissue of vehicle control (NT) and [Au2(C^N^C)2(μ-dppp)](CF3SO3)2-treated (0.5 mg kg–1) rats. This figure is reproduced from ref. 150 with permission from the Royal Society of Chemistry (Great Britain).
Fig. 29
Fig. 29. Chemical structure of novel (C^N)gold(iii) cyclometallated compounds (a) [Au(pyb-H)Cl2], (b) [Au(pyb-H)(PTA)Cl]PF6, (c) [Au(pyb-H)(GST)Cl] and (d) [Au(pyb-H)(GST)2].
Fig. 30
Fig. 30. Chemical structures of the clinically used antirheumatic gold(i) complexes with promising anticancer potential.
Fig. 31
Fig. 31. Chemical structures of (a) [Au(NHC)Cl], (b) [Au(NHC)2]I (c) [Au(NHC)PR3]I and (d) [Au(NHC)(NAP)Cl] complexes.
Fig. 32
Fig. 32. Chemical structure of the dinuclear gold(i) complex [Au(B-NHC)(B-DP)](PF6)2.
Fig. 33
Fig. 33. Antitumor effect of [Au(B-NHC)(B-DP)](PF6)2 on mice bearing HeLa xenografts. (a) Changes in tumor volume (V) after treatment with [Au(B-NHC)(B-DP)](PF6)2,*p < 0.05. (b) Representative mouse photos after 9 days of treatment. This figure was reproduced from ref. 167 with permission from John Wiley and Sons.
Fig. 34
Fig. 34. Chemical structure of the alkyne gold(i) complex [Au(CCCH2Spyridine)(PTA)].
Fig. 35
Fig. 35. (A) Bioluminescence images after injection of luciferin to mice infected with HCT-116-luc2. (B) Results showing the changes in the HCT-116-luc2 tumor volume against number of days in mice treated with [Au(CCCH2Spyridine)(PTA)] in comparison with the control mice. *P < 0.05 vs. control. This figure was reproduced from ref. 168 with permission from the Royal Society of Chemistry (Great Britain).
Fig. 36
Fig. 36. Chemical structure of (a) [Au(CCPh)(DAPTA)], (b) [Au(CC-3-SC4H3)(DAPTA)] and (c) N[Au(CCCH2)(DAPTA)]3.
Fig. 37
Fig. 37. Chemical structure of alkynyl gold(i) complexes (a) [Au(CC-BnZO)PPh3] and (b) [Au(CC-MeOPh)PPh3].
Fig. 38
Fig. 38. Blood vessel formation in developing zebrafish embryos (transgenic zebrafish line, Tg:fli1/eGFP) was monitored three days after fertilization; top: ligand HCC-BnZO (0.1 μm) and bottom: [Au(CC-MeOPh)PPh3] (0.1 μm). Examples of effects on vessel formation are marked with arrows. This figure was reproduced from ref. 171 with permission from John Wiley and Sons.
Fig. 39
Fig. 39. Chemical structure of Au(i) triphenylphosphine complexes (a) [Au(1-DOQ)PPh3], (b) [Au(1,4-DOQ)PPh3] and (c) [Au(1,8-DOQ)PPh3].
Fig. 40
Fig. 40. Images of MCF-7 cells incubated with [Au(1,4-DOQ)PPh3] (100 μg mL−1, 4 °C, 30 min), excited at 405 nm, acquired at 530–580 nm showing: (A) cytoplasmic distribution (overlaid luminescence and transmitted light), (B) appearance of vacuoles upon irradiation (transmitted light only) and (C and D) photobleaching (luminescence only). This figure was reproduced from ref. 171 with permission from the American Chemical Society.
Fig. 41
Fig. 41. Chemical structures of (a) ferrocenium picrate and (b) ferrocenium trichloroacetate salts.
Fig. 42
Fig. 42. Chemical structure of 2-ferrocenyl-1,1-diphenylbut-1-ene complex [Fe(η5-cp)2(TAM)].
Fig. 43
Fig. 43. Chemical structure of (a) hydroxyferrocifens [Fe(η5-cp)2(TAM-OH)], [Fe(η5-cp)2(TAM-OH·R)] and their (b) ferrocenyl quinone methides [Fe(η5-cp)2(QM)] and [Fe(η5-cp)2(QM·R)].
Fig. 44
Fig. 44. Chemical structure of ferrocenyl tamoxifen derivatives [Fe(η5-cp)2(CTAM)] and [Fe(η5-cp)2-μ-C3H5(CTAM)].
Fig. 45
Fig. 45. Chemical structure of ferrocene (a) [Fe(η5-cp)2(DPME)] and (b) [3]ferrocenophane [Fe(η5-cp)2-μ-C3H5(DPME)] and tetrasubstituted olefin derivatives.
Fig. 46
Fig. 46. Chemical structure of ansa-FcdiOH molecule [Fe(η5-cp)2-μ-C3H5(DPME-OH)].
Fig. 47
Fig. 47. Chemical structure of (a) [Fe(η5-cp)2(NL)] and (b) [Fe(η5-cp)2(TAM-OH·R)].
Fig. 48
Fig. 48. Chemical structure of the ferrocene-derived HUNI 068 [Fe(η5-cp)2(Fmoc-AA)].
Fig. 49
Fig. 49. Chemical structure of the carbocyclic nucleoside analogues (a) [Fe(η5-cp)2(Nuc-tBu)] and (b) [Fe(η5-cp)2(Nuc-DTS)].
Fig. 50
Fig. 50. Chemical structure of the (a) [Fe(η5-cp)(dppe)(1-BuIm)]CF3SO3, (b) [Fe(η5-cp)(dppe)(1-BI)]CF3SO3, (c) [Fe(η5-cp)(dppe)(ImH)]CF3SO3 and (d) [Fe(η5-cp)(dppe)(1-HmIm)]CF3SO3 complexes.
Fig. 51
Fig. 51. Chemical structure of N-(ferrocenylmethyl)thymine [Fe(η5-cp)2(THY)].
Fig. 52
Fig. 52. Chemical structures of the ferrocene-carborane conjugates (a) [Fe(η5-cp)2(SB1)], (b) [Fe(η5-cp)2(SB2)] and (c) [Fe(η5-cp)2(SBCO)].
Fig. 53
Fig. 53. Chemical structures of the osmium complexes (a) Os-RAPTA-C, (b) Os-RM175 and (c) Os-NAMI-A.
Fig. 54
Fig. 54. Chemical structures of the osmium-arene complexes [Os(η6-p-cymene)(BIG-R)Cl2] containing P-derived sugar ligands.
Fig. 55
Fig. 55. Chemical structures of the osmium-arene complexes (a) [Os(η6-bip)(pico)Cl] and (b) [Os(η6-p-cym)(NPP)Cl].
Fig. 56
Fig. 56. Chemical structure of the osmium-arene complexes (a) [M(η6-p-cym)(mal)Cl] and (b) [Os(η6-p-cymene)(NEHP)Cl] containing an anionic O,O-chelating ligand.
Fig. 57
Fig. 57. Chemical structure of the cyclometalated osmium-arene complexes [Ru(η6-p-cym)(κ2-C^N-R)Cl].
Fig. 58
Fig. 58. Chemical structure of the S, N-coordinated osmium-arene complexes of the type [Os(η6-p-cym)(PCA)Cl]Cl.
Fig. 59
Fig. 59. Chemical structure of the N,N-coordinated osmium-arene complexes of the type [Os(η6-p-cym)(Impy-R)Cl]PF6.
Fig. 60
Fig. 60. Chemical structure of the N,N-coordinated osmium-arene complexes bearing 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one with the general formula [Os(η6-p-cym)(BOQ)Cl]Cl and [Os(η6-p-cym)(BTQ)Cl]Cl.
Fig. 61
Fig. 61. Chemical structure of the N,N-coordinated osmium-arene complexes containing a bioactive paullone-based ligand of the general formula (a) [Os(η6-p-cymene)L1Cl]Cl and (b) [Os(η6-p-cymene)L2Cl]Cl.
None
Mehvash Zaki
None
Suboot Hairat
None
Elham S. Aazam
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References

    1. Jaouen G., Bioorganometallics, Wiley-VCH, Weinheim (Germany), 2006
    1. Jaouen G. and Dyson P., in Comprehensive Organometallic Chemistry III, ed. R. H. Crabtree and D. M. P. Mingos, Elsevier Ltd., Oxford, 2007, vol. 12, p. 445
    1. Hartinger C. G. Metzler-Nolte N. Dyson P. J. Organometallics. 2012;31:5677–5685. doi: 10.1021/om300373t. - DOI
    1. Allardyce C. S. Dorcier A. Scolaro C. Dyson P. J. Appl. Organomet. Chem. 2005;19:1–10. doi: 10.1002/aoc.725. - DOI
    1. Kopf-Maier P. J. Struct. Biol. 1990;105:35–45. doi: 10.1016/1047-8477(90)90096-U. - DOI - PubMed
    2. Kopf-Maier P. and Kopf H., in Metal compounds in cancer therapy, ed. S. P. Fricker, Chapman and Hall, London, 1994, p. 109