Targeting chemotherapy-resistant tumour sub-populations using inorganic chemistry: Anti-cancer stem cell metal complexes

Cancer stem cells (CSC) are a sub-population of tumours linked to metastasis and relapse. Current chemotherapeutic drug options are ineffective against CSCs at their administered doses. New families of cytotoxic agents, and new, highly specific ways of delivering them to CSCs, are needed to provide durable clinical outcomes. Inorganic compounds have recently emerged as a promising class of anti-CSC agents with clinically relevant potencies. In this short review, we present the very latest efforts (post-2020) on the development of anti-CSC metal complexes. The activities of the metal complexes in monolayer and three-dimensional CSC cultures and animal models is documented. The mechanism of action of the metal complexes with respect to their chemical structures is also highlighted.     

Synthesis, structural studies and solubility properties of zinc(II), nickel(II) and copper(II) complexes of bulky tris(triazolyl)borate ligands

Tris(triazolyl)borate (Ttz) ligands are sterically similar to tris(pyrazolyl)borate (Tp) but complexes of Ttz show improved solubility in water and alcohols due to their propensity for forming hydrogen bonds. Recently developed bulky tris(triazolyl)borate ligands can produce four and five coordinate transition metal complexes and serve as models for enzyme active sites in an aqueous environment. Herein we report the synthesis of such complexes, i.e. (Ttz^tBu,Me)ZnCl, (Ttz^tBu,Me)ZnBr, (Ttz^tBu,Me)NiCl, and (Ttz^tBu,Me)CuCl, which were analyzed by X-ray crystallographic and spectroscopic methods [Ttz^tBu,Me = tris(3-t-butyl-5-methyl-1,2,4-triazolyl)borate]. (Ttz^tBu,Me)ZnCl crystallizes as two different polymorphs with cubic and monoclinic symmetry. Both polymorphs of (Ttz^tBu,Me)ZnCl and (Ttz^tBu,Me)ZnBr have tetrahedral zinc atoms whereas the geometries at the metal in (Ttz^tBu,Me)NiCl and (Ttz^tBu,Me)CuCl are distorted tetrahedral. All complexes are methanol soluble and they also dissolve in methanol/water mixtures with up to 60% water.     

Structural and spectroscopic comparison of five-coordinate cobalt(II) and nickel(II) thiolato complexes with the related four-coordinate complexes

Five-coordinate thiolato complexes, [L1M(SMeIm)] (M = Co and Ni) (L1 = hydrotris(3,5-diisopropyl-1-pyrazolyl)borate anion and HSMeIm = 2-mercapto-1-methylimidazole), were synthesized. These complexes were compared with the corresponding Cu(II) and Zn(II) complexes with the same ligands and were also compared with the related four-coordinate complexes [L1M(SC₆F₅)] (HSC₆F₅ = pentafluorobenzenthiol). All the complexes were characterized by X-ray crystallography and UV-Vis absorption, IR, ¹H NMR, and other spectroscopic techniques. All five-coordinate thiolato complexes, [L1M(SMeIm)] (M = Co, Ni, and Cu), form a distorted square pyramidal structure with a high spin state, and only [L1Zn(SMeIm)] takes a four-coordinate structure with a distorted tetrahedral configuration. The N21-M-S bond angles of the obtained five-coordinate complexes were proportional to the corresponding d value, which comes from between the equatorial basal plane with N4S ligand donor sets and metal ion. These observations and M-S bond distances affect on UV-Vis and far-IR spectral behavior.     

Copper(II) PMDTA and copper(II) TMEDA complexes: precursors for the synthesis of dinuclear dicationic copper(II) complexes

Copper(II) cations coordinated with PMDTA (pentamethyldiethylenetriamine) and TMEDA (tetramethylethylenediamine) possess a high synthetic potential. The synthesis of these cations was carried out by metathesis reactions with silver salts. The cationic copper(II) complexes, [Cu(PMDTA)(Me₂CO)Cl]⁺, [Cu(PMDTA)(H₂O)Cl]⁺, [Cu(PMDTA)(DMF)]⁺, [Cu(PMDTA)Cl]⁺, [Cu(PMDTA)OAc]⁺, [Cu(PMDTA)(MeCN)₂]²⁺, [Cu₂(TMEDA)₂Cl₃]⁺ and [Cu(TMEDA)(MeCN)₃]²⁺ were synthesised as PF₆ salts, crystallised and characterised by single-crystal X-ray diffraction.     

Copper(II) and palladium(II) complexes of a terdentate pyrrolidine diester ligand

The synthesis and characterisation of three copper(II) complexes, [CuLCl] (4), [CuLBr] (5) and [CuL(NCS)] (6), and a palladium(II) complex, [PdLCl] (7), of the monoanionic terdentate ligand L⁻ [L⁻ is the deprotonated form of diethyl 2,2′-(pyrrolidine-2,5-diylidene)diacetate (HL) (3)] are reported. The X-ray crystal structure determinations show that both 4 and 6 feature square planar copper(II) centres. The cis bond angles are close to 90° (85-93°) thanks in large part to the introduction of an additional carbon atom between the pyrrole ring and each of the ester moieties. These results indicate that the failure of the 2,5-diiminopyrrole head unit to coordinate in a terdentate manner to first row transition metal ions can, in principle, be resolved by introducing an extra carbon atom between the pyrrole ring and each of the imine moieties. A comparison of structural parameters between the two structurally characterised complexes (4 and 6) and the non-deprotonated free ligand HL (3) indicates that there is an increase in delocalisation of the electron density throughout the π system of the deprotonated ligand on coordination, as the CC and CO double bonds are longer and C-C and C-O single bonds are shorter than the corresponding bond distances in 3.     

Nickel(II) complexes with Schiff-base ligands derived from epimeric pyranose backbones as 2,3-chelators: modeling the coordination chemistry of chitosan

Two mononuclear nickel(II) complexes with Schiff-base ligands derived from the epimeric sugars glucosamine and mannosamine have been synthesized. The X-ray crystal structure reveals a distorted octahedral geometry at the nickel(II) ions with an N4O2 donor set and the rare 2,3-chelation of the donor atoms of the carbohydrate backbone. Upon complexation only the glucopyranose ring maintains the 4C1 chair conformation, whereas the mannopyranose ring adopts the OS5 screw-boat conformation. Dimeric units of complex cations are formed by intermolecular hydrogen bonding which are further assembled by pi-stacking affording one-dimensional chains with a twofold screw symmetry.     

Formation of oligonuclear complexes between copper(II) and 1-hydroxyethane-1,1-diphosphonic acid

The complex formation between Cu(II) and 1-hydroxyethane-1,1-diphosphonic acid was studied by means of pH-potentiometry and spectroscopy (UV-Vis and EPR). Speciation revealed the formation of a trinuclear complex [Cu₃A₃]⁶⁻ besides the mononuclear 1:1 and 1:2 species. In the complex [Cu₃A₃]⁶⁻ , which is not formed with other diphosphonic derivatives, the ligands adopt chelating and bridging modes via the four O atoms of the two phosphonates, the alcoholic-OH groups remaining in the protonated form.     

Reaction of platinum(II) diamine and triamine complexes with selenomethionine

Four new coordination polymers namely {[Mn₂(BT)(DPS)₂(H₂O)₆]·10H₂O}_n (MnBTDPS), {[Co₂(BT)(DPS)₂(H₂O)₆]·10H₂O}_n (CoBTDPS), {[Cu₂(BT)(DPS)(H₂O)₄]·5H₂O}_n (CuBTDPS) and {[Zn₂(BT)(DPS)₂]·6H₂O}_n (ZnBTDPS), where BT = 1,2,4,5-benzenetetracarboxylate and DPS = di(4-pyridyl) sulfide, were synthesized and characterized by thermal analysis, vibrational spectroscopy (Raman and infrared) and single crystal X-ray diffraction analysis. In all compounds, the DPS ligands are coordinated to metal sites in a bridging mode and the carboxylate moiety of BT ligands adopts a monodentate coordination mode, as indicated by the Raman spectra data through the Δν (ν_asym(COO) − ν_sym(COO)) value. According to X-ray diffraction analysis, MnBTDPS and CoBTDPS are isostructural and in these cases, the metal centers exhibit a distorted octahedral geometry. In CuBTBPP, the Cu²⁺ centers geometries are best described as square-pyramids, according to the trigonality index τ = 0.14 for Cu1 and τ = 0.10 for Cu2. On the other hand, in ZnBTDPS, the Zn²⁺ sites adopt a tetrahedral geometry. Finally, the four compounds formed two-dimensional sheets that are connected to each other through hydrogen bonding giving rise to three-dimensional supramolecular arrays.     

Synthesis and structural diversity of 2-pyridylmethylideneamine complexes of zinc(II) chloride

The addition reactions of zinc(II) chloride to N-substituted pyridine-2-carbaldimines [Py-CHNR, R = Me (1a), Ph (1b), Bz (1c), allyl (1d)] lead to different complexes dependent on the N-bound substituent R. The 1:1 complexes show molecular structures of the type [(Py-CHNR)ZnCl₂] for R = methyl (2a), phenyl (2b), and allyl (2d) with a distorted tetrahedral environment for the zinc atom. The zinc complex with the N-methylated pyridine-2-carbaldimine also forms a dimer of the type [(Py-CHNR)ZnCl₂]₂ (2a)₂ with a square pyramidal coordination sphere of zinc. A 3:2 stoichiometry is observed for R = benzyl and an ion pair of the type [Zn(Py-CHNR)₃]²⁺ [ZnCl₄]²⁻ (2c) is found in the solid state.     

The synthesis and characterisation of phenolate complexes of Cu(II) and Ni(II) that are capable of supporting a phenoxyl radical ligand

New Cu^II and Ni^II complexes of potentially tridentate N₂O Schiff base ligands 1 and 2 have been synthesised and characterised. [Cu(2)(OH₂)]⁺ possesses a square planar geometry in the solid state whereas [Ni(1)₂] possesses a distorted octahedral geometry in which the amine donors of 1 coordinate weakly to the Ni^II centre. EPR spectroscopy demonstrates that the N₂O₂ coordination sphere of [Cu(2)(OH₂)]⁺ is retained in CH₂Cl₂ solution. [Cu(2)(OH₂)]⁺ exhibits a reversible one electron oxidation at E_1/2 = 0.54 V versus [Fc]⁺/[Fc], the product of which has been characterised by UV-Vis absorption and EPR spectroscopies. The spectroscopic signature of the oxidised product is consistent with the formation of a stable phenoxyl radical ligand bound to a Cu^II centre. [Ni(1)₂] possesses a reversible metal-based oxidation process at E_1/2 = 0.03 V versus [Fc]⁺/[Fc] and a further oxidation, attributed to the generation of a phenoxyl radical centre, at  = 0.44 V versus [Fc]⁺/[Fc]. UV-Vis absorption and EPR spectroscopic studies indicate that the lower potential process is a formal Ni^III/II couple. In contrast, the pro-ligands 1H and 2H exhibit chemically irreversible oxidation processes at  = 0.42 and 0.40 V versus Fc⁺/Fc, respectively, and do not support the formation of stable phenoxyl radical species.     

Neutral and cationic rare-earth metal alkyl complexes that contain bis(2-methoxyethyl)(trimethylsilyl)amine, a neutral [ONO]-type ligand

Neutral tris(trimethylsilylmethyl) complexes [Ln(CH₂SiMe₃)₃(L)] (Ln = Sc (1), Lu (2)) and cationic bis(trimethylsilylmethyl) complexes [Ln(CH₂SiMe₃)₂(L)(THF)]⁺[BPh₄]⁻, (Ln = Sc (3), Lu (4)) that contain bis(2-methoxyethyl)(trimethylsilyl)amine (L = Me₃SiN(CH₂CH₂OMe)₂) as a neutral, tridentate ligand were synthesized and characterized by NMR spectroscopy. X-ray structural analysis was performed for the scandium complex 1 and exhibited a distorted octahedral coordination geometry with a facially arranged ligand at the neutral scandium center. NMR spectroscopy corroborated the coordination of the tertiary amine function of the ligand to the metal. Complexes 3 and 4 expand the still limited range of cationic rare-earth metal alkyl complexes with known neutral, multidentate ligands.     

Coordination chemistry on the surface of single-walled carbon nanotubes

A facile method to coordinate transition metal complexes (TMCs) on single-walled carbon nanotubes (SWNTs) has been developed. Reaction of Zn(OAc)₂ with carboxylic acid functionalized SWNTs (SWNT-COOH) affords SWNT complexes ‘zipped-together’ by zinc carboxylate units (termed SWNT-TMC-1 herein). Reactions of SWNT-TMC-1 with 2,2′-bipyridine or 4,4′-bipyridine gave two new SWNT-TMCs, the former being ‘unzipped’ (SWNT-TMC-2), and the latter involving an additional ligand bridge between the zinc ions (SWNT-TMC-3). Inclusion of 2,2′-bipyridine and 4,4′-bipyridine into the SWNT-TMCs was confirmed by IR spectroscopy. The microstructures of SWNT-TMC-2 and SWNT-TMC-3 were investigated by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (Xps), elemental mapping and linear profiles analysis.     

Chelation of ThIV, EuIII and NdIII by dianionic N,N'-bis(pyridoxylideneiminato)ethylene, (Pyr2en)2-. On the search of feasible modelings for heavy metals damage inhibition in living beings

The neutral Schiff base N,N'-bis(pyridoxylideneiminato)ethylene {H(2)pyr(2)en} reacts with Th(NO(3))4.4H2O, NdCl3.6H2O and EuCl3.6H2O to give [Th(pyr(2)en)2(H2O)] (1), [Nd(pyr(2)en)(Hpyr(2)en)].12H2O (2) and [Eu(pyr(2)en)(Hpyr(2)en)] (3). In the three not yet reported bimolecular chelate systems the endo hydroxyl groups of the rings undergo deprotonation confirming the remarkable ability of the pyridoxal-containing ligand H(2)pyr(2)en to yield stable heavy metal chelates with unusual coordination polyhedra. Complexes 2 and 3 show a coordination number 8 for Nd and Eu, achieving a distorted quadratic antiprism. In complex 1 the additional water molecule increases the coordination number of Th to 9 producing a capped square antiprism. The synthesis and structural elucidation of the title complexes starting from a probably non-toxic metabolite like H(2)pyr(2)en should represent a useful contribution to the research on models of prevention and therapy of damage caused by radioactive and heavy elements.     

Systematic characterization on electronic structures and spectra for a series of complexes, M(IDB)Cl2 (M = Mn, Fe, Co, Ni, Cu and Zn): a theoretical study

Theoretical studies on the coordination stabilities, spectra and DNA-binding trend for the series of metal-varied complexes, M(IDB)Cl₂ (M = Mn, Fe, Co, Ni, Cu and Zn; IDB = N, N -bis(2-benzimidazolylmethyl) amine), have been carried out by using the DFT/B3LYP method and PCM model. The calculated coordination stabilities (S) for these complexes present a trend of S(Ni) > S(Co) > S(Fe) > S(Cu) > S(Zn) > S(Mn). It has been estimated from the molecular orbital energies of the complexes that the DNA-binding affinities (A) of the complexes are in the order of A(Zn) < A(Mn) < A(Fe) ≈ A(Co) < A(Ni) < A(Cu). The studied results indicate that the Cu, Ni and Co complexes with large coordination stabilities present the low virtual orbitals, consequently yielding to the favorable DNA-binding affinities. The spectral properties of excitation energies and oscillator strengths for M(IDB)Cl₂ in the ultraviolet region were calculated by TD-DFT/B3LYP method.     

Preparation and characterization of dinuclear palladium tetraamin-thiophenolate complexes coligated by bridging acetate and acetamidate units

The aromatic thioether (2,6-bis((2-(dimethylamino)ethylamino)methyl)phenyl)(tert-butyl)sulfane (6) reacts with [Pd(NCCH₃)₂Cl₂] under S-C bond cleavage to give the dinuclear palladium(II) complex [L³Pd₂(μ-Cl)]²⁺ (7), where (L³)⁻ = 2,6-bis((2-(dimethylamino)ethylamino)methyl)-thiophenolate. Complex 7 reacts readily with sodium acetate and sodium acetamide by the displacement of the bridging chloride group forming [L³Pd₂(μ-OAc)]²⁺ (8) and [L³Pd₂(μ-ONHCCH₃)]²⁺ (9), respectively. Complex 8 can also be prepared by the reaction of 6 with [Pd(OAc)₂]. All complexes were isolated as perchlorate salts and fully characterized by ESI-MS, IR, ¹H, and ¹³C NMR spectroscopy. The structures of 7[ClO₄] and 9[ClO₄]₂ have been determined by X-ray crystallography. The latter structure reveals a μ_1,3-bridging acetamidate unit showing that (L³)⁻ can alter its conformation sufficiently to accommodate a multi-atom bridging species between the two Pd atoms.     

The complexes of adenosine and organocobalamins with palladium (II)

The complexes of adenosine, methylcobalamin, adenosylcobalamin and the derivatives of adenosylcobalamin with tetrachloropalladate (II) are described. The compositions of the complexes were established by means of spectrophotometric titration. Depending on the structure of organocobalamins, three types of complexes with tetrachloropalladate (II) are formed. In the case of methylcobalamin, the palladium (II) is coordinated at the “lower” benzimidazole ligand. In adenosylcobalamin, palladium (II) coordinates the “upper” adenosyl ligand. The N-7-position in adenosine ligand and N-3-position in 5,6-dimethylbenzimidazolylribotide are the most probable coordination sites of palladium (II).     

Cationic (tripyrrinato)palladium(II) complexes

The formation of cationic palladium(II)complexes [TrpyPd^II]⁺X⁻ by salt metathesis of the respective trifluoroacetates with different salts of weakly coordinating anions X⁻ was investigated. With non-hydrolizable counterions, cationic mono- and dinuclear complexes are observed depending on the nature of the anion X⁻ and the solvent. The mononuclear cations, which are only formed with X = BAr^F, most probably carry a weakly bound molecule of dichloromethane at the fourth coordination site of Pd^II. When treated with diazoalkanes, only these are sufficiently reactive to form carbene complexes. Four- and five coordinate Lewis base adducts [TrpyPd^IIL]⁺ with L = CH₃NC, tBuNH₂, PMe₃, PEt₃ and PiPr₃ and [TrpyPd^IIL₂]⁺ with L = PMe₃ were prepared from the mononuclear cations [TrpyPd^II]⁺BAr^F−. From structural studies it becomes apparent, that the formation of stable five coordinate Pd^II species is restricted to medium size ligands and depends on the delicate balance between the steric influence of L and the strain, which is induced on the TrpyPd^II unit.     

Copper(II) nitrato and chloro complexes with sterically hindered tridentate ligands: Influence of ligand framework and charge on their structure and physicochemical properties

Copper(II) coordination complexes of the neutral ligand, tris(3-tert-butyl-5-methyl-1-pyrazolyl)methane (L2′), i.e. the copper(II) nitrato complexes [Cu(L2′)(NO₃)][Cu(NO₃)₄]_1/2 (1) and [Cu(L2′)(NO₃)](ClO₄) (2) and the copper(II) chloro complex [Cu(L2′)(Cl)](ClO₄) (3), and its anionic borate analogue, hydrotris(3-tert-butyl-5-methyl-1-pyrazolyl)borate (L2⁻), i.e. the copper(II) nitrato complex [Cu(L2)(NO₃)] (4) and the copper(II) chloro complex [Cu(L2)(Cl)] (5), were synthesized in order to investigate the influence of ligand framework and charge on their structure and physicochemical properties. While X-ray crystallography did not show any definitive trends in terms of copper(II) atom geometry in four-coordinate copper(II) chloro complexes 3 and 5, different structural trends were observed in five-coordinate copper(II) nitrato complexes 1, 2, and 4. These complexes were also characterized by spectroscopic techniques, namely, UV-Vis, ESR, IR/far-IR, and X-ray absorption spectroscopy.