Metal complexes in cancer therapy – an update from drug design perspective

Figures & data

Table 1 An update on the anticancer activities of metal-based complexes (2010–2016)

Metal complexes	Molecular formula	Proposed mechanism of action	Target enzymes/cell lines/therapeutic indications	IC50 range (µM)
Carbene–metal complexes and related ligands
Novel gold(I) and gold(III) NHC complexes^Citation62	C52H44Au2N12P2F12 C26H24AuCl2OF6N6P	Induction of apoptosis Inhibition of TrxR^Citation62 Induction of ROS^Citation62	TrxR A549, HCT116, HepG2, MCF7 Chemotherapy of solid tumors^Citation62	C52H44Au2N12P2F12 5.2±1.5 (A549) 3.6±4.1 (HCT-116) 3.7±2.3 (HepG2) 4.7±0.8 (MCF7)^Citation62 C26H24AuCl2OF6N6P 5.2±3.0 (A549) 5.9±3.6 (HCT-116) 5.1±3.8 (HepG2) 6.2±1.4 (MCF7)^Citation62
Caffeine-based gold(1) NHCs^Citation81	[Au(Caffeine-2-yielding)2] [BF4]^Citation81	Inhibition of protein PARP-1^Citation81	DNA A2780, A2780R, SKOV3, A549 and HEK-293T	0.54–28.4 (A2780) 17.1–49 (A2780/R) 0.75–62.7 (SKOV3) 5.9–90.0 (A549) 0.20–84 (HEK-293T)
Ester- and amide-functionalized imidazole of NHC complexes^Citation82	{[Im^A]AgCl} {[Im^A]AuCl} {[Im^B]2AgCl} {[Im^B]AuCl} HIm^ACl = [1,3-bis (2-ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride] HIm^BCl = {1,3-bis[2(diethylamino)-2-oxoethyl]-1H-imidazol-3-ium chloride}	Inhibition of tyrosine by gold(I) NHC ligands, thereby targeting TrxR^Citation82 CuNHC cell cycle arrest progression in GI phase^Citation82 Anticancer activity of Ag^1NHC is based on highly lipophilic aromatic-substituted carbenes^Citation82	TrxR^Citation82 A375, A549, HCT-15 and MCF7 Human colon adenocarcinoma,^Citation82 leukemia and breast cancer^Citation82	{[Im^A]AgCl} 24.65 (A375) 22.14 (A549) 20.32 (HCT-15) 21.14 (MCF7) {[Im^A]AuCl} 44.64 (A375) 42.37 (A549) 41.33 (HCT-15) 38.53 (MCF7) {[Im^B]2AgCl} 24.46 (A375) 16.23 (A549) 14.11 (HCT-15) 15.31 (MCF7)^Citation82
Novel Ru(II) NHCs^Citation83	[(η^6-p-cymene)2Ru2(Cl2)2] NHC	Mimic iron^Citation84 Interact with plasmidic DNA^Citation84	DNA as target Caki-1 and MCF7 Chemotherapy of solid tumor^Citation66	13–500 (Caki-1) 2.4–500 (MCF7)^Citation83
Caffeine-derived rhodium(I) NHC complexes^Citation85	[Rh(I)Cl(COD)(NHC)] complexes	Inhibition of TrxR^Citation85 Increase in ROS formation^Citation85 DNA damage^Citation85 Cell cycle arrest^Citation85 Decrease in mitochondria membrane potential^Citation85	TrXR^Citation85 MCF7, HepG2 MDA-MB-231, HCT-116, LNCaP, Panc-1 and JoPaca-1 Chemotherapy of solid tumor^Citation85	84 (HepG2) 20 (HCF-7) 23 (MDA-MB-231) 35 (JoPaca-1) 49 (Panc-1) 80 (LNCaP) 9.0 (HCT-116)^Citation85
NHC–amine Pt(II) complexes^Citation86	NHC (PtX2)–amine complexes^Citation86	Nuclear DNA platination^Citation86	Target DNA^Citation86 KB3-1, SK-OV3, OVCAR-8, MV-4-11, A2780 and A2780/DPP Chemotherapy of solid and non-solid tumors^Citation86	2.5 (KB3-1) 4.33 (SK-OV3) 1.84 (OVCAR-8) 0.60 (MV-4-11) 4.00 (A2780) 8.5 (A2780/DPP)^Citation86
2-Hydroxy-3-[(hydroxyimino)-4-oxopentan-2-ylidene] benzohydrazide derivatives^Citation87	[(HL)Cu(OAc)(H2O)2]·H2O C14H21N3O9Cu	Bind to DNA^Citation87	Target DNA^Citation87 HepG2 Chemotherapy of solid tumors^Citation87	2.24–6.49 (HepG2)^Citation87
Molybdenum(II) allyl dicarbonate complexes^Citation88	[Mo(allyl)(CO)2(N-N)(py)]PF6	DNA fragmentation^Citation88 Induction of apoptosis^Citation88	Target DNA^Citation88 NALM-6, MCF7 and HT-29 Chemotherapy of solid and non-solid tumors^Citation88	1.8–13 (NALM-6) 2.1–32 (MCF7) 1.8–32 (HT-29)^Citation88
Metal-arene complexes and other ligands
Ru(II)–arene complex^Citation89	[(η^6-arene)Ru(II)(en)Cl]^+	DNA damage^Citation89 Cell cycle arrest^Citation89 Induction of apoptosis^Citation89	Target DNA AH54 and AH63 Chemotherapy of colorectal cancer^Citation89	C15H18C1F6N2PRu 16.6 (AH54)^Citation89 C16H2OC1F6N2PRu 10.9 (AH63)^Citation89
Novel ruthenium–arene pyridinyl methylene complexes^Citation90	[(η^6-p-cymene)RuCl (pyridinylmethylene)]	DNA binding^Citation90	Target DNA^Citation90 MCF7 and HeLa Chemotherapy of solid tumor^Citation90	07.76–25.42 (MCF7) 07.10–29.22 (HeLa)^Citation90
Multi-targeted organometallic Ru(II)–arene^Citation91	[(η^6-p-cymene)RuCl2]2-PARP and PARP-1 inhibitors^Citation91	DNA binding^Citation91 PARP-1 inhibition^Citation91 Transcription inhibition^Citation91	Target DNA^Citation91 A549, A2780, HCT-116, HCC1937 and MRC-5 Chemotherapy of solid tumors^Citation91	85.1–500 (A549) 38.8–500 (A2780) 46.0–500 (HCT-116) 93.3–500 (HCC1937) 143–500 (MRC-5)^Citation91
Ru(II)–arene complexes with 2-aryldiazole ligands^Citation92	[(η^6-arene)RuX(k^2-N,N-L)]Y	DNA binding^Citation92 Inhibition of CDK1	Target DNA^Citation92 A2780, A2780cis, MCF7 and MRC-5 Chemotherapy of solid tumors	11–300 (A2780) 11–34 (A2780cis) 26–300 (MCF7) 25–224 (MRC-5)^Citation92
Osmiun(II)–arene carbohydrate base anticancer compound^Citation93	Osmium(II)-bis [dichloride(η^6-p-cymene)]	DNA binding^Citation93	Target DNA^Citation93 CH1, SW480 and A549	50–746 (CH1) 215–640 (SW480) 640 (A549)^Citation93
Ru(II)–arene complexes with carbosilane metallodendrimers^Citation94	Gn-[NH2Ru(η^6-p-cymene)Cl2]m	Interaction with DNA^Citation94 Interaction with HSA^Citation94 Inhibition of cathepsin B^Citation94	Target DNA^Citation94 HeLa, MCF7, HT-29 MDA-MB-231 and HEK-239T Chemotherapy of solid and non-solid tumors^Citation94	6.3–89 (HeLa) 2.5–56.0 (MCF7) 3.3–41.7 (HT-29) 4–74 (MDA-MB-231) 5.0–51.9 (HEK-239T)^Citation94
Ru(II) complexes with aroylhydrazone ligand^Citation95	[Ru(η^6-C6H6)Cl(L)]	Induction of apoptosis^Citation95 Fragmentation of DNA^Citation95	Target DNA^Citation95 MCF7, HeLa, NIH-3T3 Chemotherapy of solid tumor^Citation95	10.9–15.8 (MCF7)^Citation95 34.3–48.7 (HeLa) 152.6–192 (NIH-3T3)
Cyclopentadienyl complexes and other ligands
Iridium(III) complexes with 2-phenylpyridine ligand^Citation96	[(η^5-Cp*)Ir(2-(R′-phenyl)-R-pyridine)Cl]	Interaction with DNA nucleobases^Citation96 Catalysis of NADH oxidation^Citation96	Target DNA^Citation96 A2780, HCT-116, MCF7 and A549 Chemotherapy of solid tumor^Citation96	1.18–60 (A2780) 3.7–57.3 (HCT-116) 4.8–28.6 (MCF7) 2.1–56.67 (A549)^Citation96
New iron(II) cyclopentadienyl derivative complexes^Citation97	[Fe(η^5-C5H5)(dppe)L][X]	Interaction with DNA^Citation97 Induction of apoptosis^Citation97	Target DNA HL-60 Chemotherapy of non-solid tumors^Citation97	0.67–5.89 (HL-60)
Ru(II) cyclopentadienyl complexes with carbohydrate ligand^Citation98	[Ru(η^5-C5H5)(PP)(L)][X]	Induction of apoptosis^Citation98 Activation of caspase-3 and -7 activity^Citation98	HCT116CC, HeLa Chemotherapy of solid tumors^Citation98	0.45 (HCT116CC) 3.58 (HeLa)^Citation98
Ru(II) cyclopentadienyl complexes with phosphane co-ligand^Citation98	[Ru(η^5-C5H5)(PP)(L)][X]	Induction of apoptosis^Citation98	HeLa Chemotherapy of solid tumor^Citation98	2.63 (HeLa)^Citation98
Organoiridium cyclopentadienyl complexes^Citation99	[(η^5-Cpx)Ir(L^L′)Z]	Intercalation of DNA^Citation99 Coordination with DNA guanine^Citation99	HeLa Chemotherapy of solid tumor^Citation99	0.23 (HeLa)^Citation99

Abbreviations: IC₅₀, half maximal inhibitory concentration; NHC, N-heterocyclic carbene; TrxR, thioredoxin reductase; ROS, reactive oxygen species; PARP-1, Poly(ADP-ribose) polymerase-1; CDK1, cyclin-dependent kinase 1; HSA, human serum albumin; ADP, adenosine diphosphate.

Figure 1 Evolution of organometallic complexes in cancer therapy.

Abbreviation: FDA, US Food and Drug Administration.

Table 2 Summary of metal-based compounds undergoing clinical trials in human

Drug name	Developers	Phase of clinical trial	Indications
Picoplatin^Citation68 (JM473)	Pionard	Phase II	Treatment of colorectal cancer^Citation68 in combination with 5-FU and leucovorin
Lipoplatin™ (Nanoplatin™, Oncoplatin)	Regulon	Phase II^Citation68 and phase III clinical trial in different cancer cells	Treatment of locally advanced gastric cancer/squamous cell carcinoma of head and neck^Citation68
ProLindac™ (AP5046)	Access Pharm	Phase I, II and III trials	Advanced ovarian cancer^Citation68 and head and neck cancers
Satraplatin (JM216)	Spectrum Pharm and Agennix AG	Phase I, II and III trials	Treatment of colorectal cancer in combination with 5-FU and leucovorin,^Citation68 treatment of prostate cancer in combination with docetaxel and treatment of a patient with progressive or relapse NSCLC^Citation68
NAMIA-A	–	Phase I	Metastatic tumor (lung, colorecta, melanoma, ovarian and pancreatic)^Citation100
KP1019	–	Phase II	Advanced colorecta cancer^Citation100
^64Cu-ATSM	–	Phase II	PET/CT monitoring therapeutic progress in patient with cervica^Citation101

Abbreviations: FU, fluorouracil; NSCLC, non-small-cell lung cancer; ⁶⁴Cu-ATSM, ⁶⁴Cu-diacetyl-bis(N⁴-methylthiosemicarbazone); PET, positron emission tomography; CT, computed tomography.

Figure 2 Sugar-conjugated triazole ligands.

Notes: AcGlc-pyta (conjugate a) R = Ac. Glc-pyta (conjugate b) R = H.

Figure 3 Structure of phenanthriplatin.

Figure 4 Structure of platinum(IV) complexes under investigation: (A) [PtCl₄(bipy)], (B) [PtCl₄(dach)] and (C) cis-[PtCl₂(NH₃)₂].

Figure 5 The structure of KP1019 (A) and NAMI-A (B).

Abbreviation: DMSO, dimethyl sulfoxide.

Figure 6 RAPTA-C (A) and RAPTA-T (B).

Figure 7 A 3D structure of the TrxR reductase homodimer (PDB entry 2J3N), with two chains in green and purple.

Note: The active site residues CYS 59.B, CYS 64.B, HIS 472.A and GLU 477.A represent the possible binding site for the gold(III) compounds.
Abbreviations: TrxR, thioredoxin reductase; PDB, Protein Data Bank; CYS, cysteine; HIS, histidine; GLU, glutamate.

Figure 8 A and B are silver complexes with 2,6-disubstituted pyridine ligands.

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