Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host-guest chemistry.

A new [PdPtL4]4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL4]4+ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p-tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL4]4+ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host-guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD3CN. No HG interactions were observed in the more polar d6-DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC50) values in the range of 25-35 µM. Most [PdPtL4]4+-drug mixtures tested had higher IC50 values than the hosts. However, the [PdPtL4]4+ cages, and [PdPtL4]4+:drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil.

Quadruply Stranded Metallo-Supramolecular Helicate [Pd2(hextrz)4]4+ Acts as a Molecular Mimic of Cytolytic Peptides.

[Pd2(hextrz)4]4+ is a quadruply stranded helicate, a novel bioinorganic complex designed to mimic the structure and function of proteins due to its high stability and supramolecular size. We have previously reported that [Pd2(hextrz)4]4+ exhibited cytotoxicity toward a range of cell lines, with IC50 values ranging from 3 to 10 µM. Here we demonstrate that [Pd2(hextrz)4]4+ kills cells by forming pores within the cell membrane, a mechanism of cell death analogous to the naturally occurring cytolytic peptides. [Pd2(hextrz)4]4+ induced cell death is characterized by an initial influx of Ca2+, followed by nuclear condensation and mitochondrial swelling. This is accompanied by progressive cell membrane damage that results in the formation of large blebs at the cell surface. This allows the efflux of molecules from the cell leading to loss of cell viability. These data suggest that it may be possible to design metallo-supramolecular complexes to mimic the cytotoxic action of pore forming proteins and peptides and so provide a new class of drug to treat cancer, autoimmune disorders, and microbial infection.

Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd2L4]4+ Metallosupramolecular Cages.

New bis-quinoline (L q) and bis-isoquinoline-based (L iq) ligands have been synthesized, along with their respective homoleptic [Pd2(L q or L iq)4]4+ cages (C q and C iq). The ligands and cages were characterized by 1H, 13C and diffusion ordered (DOSY) NMR spectroscopies, high resolution electrospray ionization mass spectrometry (HR-ESIMS) and in the case of the bis-quinoline cage, X-ray crystallography. The crystal structure of the C q architecture showed that the [Pd2(L q)4]4+ cage formed a twisted meso isomer where the [Pd(quinoline)4]2+ units at either end of the cage architecture adopt the opposite twists (left and right handed). Conversely, Density Functional Theory (DFT) calculations on the C iq cage architecture indicated that a lantern shaped conformation, similar to what has been observed before for related [Pd2(L tripy)4]4+ systems (where L tripy = 2,6-bis(pyridin-3-ylethynyl)pyridine), was generated. The different cage conformations manifest different properties for the isomeric cages. The C iq cage is able to bind, weakly in acetonitrile, the anticancer drug cisplatin whereas the C q architecture shows no interaction with the guest under the same conditions. The kinetic robustness of the two cages in the presence of Cl- nucleophiles was also different. The C iq cage was completely decomposed into free L iq and [Pd(Cl)4]2- within 1 h. However, the C q cage was more long lived and was only fully decomposed after 7 h. The new ligands (L iq and L q) and the Pd(II) cage architectures (C iq and C q) were assessed for their cytotoxic properties against two cancerous cell lines (A549 lung cancer and MDA-MB-231 breast cancer) and one non-cancerous cell line (HDFa skin cells). It was found that L q and C q were both reasonably cytotoxic (IC50S ≈ 0.5 µM) against A549, while C iq was slightly less active (IC50 = 7.4 µM). L iq was not soluble enough to allow the IC50 to be determined against either of the two cancerous cell lines. However, none of the molecules showed any selectivity for the cancer cells, as they were all found to have similar cytotoxicities against HDFa skin cells (IC50 values ranged from 2.6 to 3.0 µM).

Self-Assembly with 2,6-Bis(1-(pyridin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)pyridine: Silver(I) and Iron(II) Complexes.

A new "click" ligand, 2,6-bis(1-(pyridin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)pyridine (L) featuring a tridentate 2,6-bis(1,2,3-triazol-4-yl)pyridine (tripy) pocket and two pyridyl (py) units was synthesized in modest yield (42%) using the copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The coordination chemistry of the ligand with silver(I) and iron(II) ions was examined using a battery of solution (¹H and DOSY (diffusion ordered spectroscopy) nuclear magnetic resonance (NMR), infrared and absorption spectroscopies, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)), and solid state (X-ray crystallography, elemental analysis) techniques. When treated with silver(I) ions, the ligand forms discrete [Ag(L)]⁺ (X-, where X- = BF4-, NO3- or SbF6-) complexes in dimethyl sulfoxide (DMSO) solution but these complexes crystallize as coordination polymers. The addition of [Fe(H2O)6](BF4)2 to an acetonitrile solution of the ligand forms the expected monomeric octahedral [Fe(L)2]2+ complex and treatment of the iron(II) complex with AgBF4 generates a heterometallic linear coordination polymer.

Solid-State Gas Adsorption Studies with Discrete Palladium(II) [Pd2 (L)4 ]4+ Cages.

The need for effective CO2 capture systems remains high, and due to their tunability, metallosupramolecular architectures are an attractive option for gas sorption. While the use of extended metal organic frameworks for gas adsorption has been extensively explored, the exploitation of discrete metallocage architectures to bind gases remains in its infancy. Herein the solid state gas adsorption properties of a series of [Pd2 (L)4 ]4+ lantern shaped coordination cages (L = variants of 2,6-bis(pyridin-3-ylethynyl)pyridine), which had solvent accessible internal cavities suitable for gas binding, have been investigated. The cages showed little interaction with dinitrogen gas but were able to take up CO2 . The best performing cage reversibly sorbed 1.4 mol CO2 per mol cage at 298 K, and 2.3 mol CO2 per mol cage at 258 K (1 bar). The enthalpy of binding was calculated to be 25-35 kJ mol-1 , across the number of equivalents bound, while DFT calculations on the CO2 binding in the cage gave ΔE for the cage-CO2 interaction of 23-28 kJ mol-1 , across the same range. DFT modelling suggested that the binding mode is a hydrogen bond between the carbonyl oxygen of CO2 and the internally directed hydrogen atoms of the cage.

Multicavity [PdnL4]2n+ Cages with Controlled Segregated Binding of Different Guests.

Multicavity [Pdn(L)4]2n+ metallosupramolecular cages based on long backboned ligands are an attractive approach to increasing molecular size without loss of the binding specificity conferred by small cavity [Pd2(L)4]4+ assemblies. We herein report the synthesis of two double cavity polypyridyl [Pd3(L)4]6+ cages that bind cisplatin [Pt(NH3)2Cl2] within their internal cavities and interact with triflate (TfO-) on their exohedral faces. We also report the first example of a triple cavity [Pd4(L)4]8+ cage. This cage differs in that the central cavity is phenyl-linked rather than having the pyridyl core as in the peripheral cavities. The difference in cavity character results in selective guest binding of cisplatin in the peripheral cavities, with triflate binding within the central cavity and on the exohedral faces of the peripheral palladium(II) ions. All the cavities could be simultaneously filled by introducing both cisplatin and triflate concurrently, providing the first example of a discrete metallosupramolecular architecture with segregated guest binding in different designed internal cavities. The ligands and cages were characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and, in one case, X-ray crystallography.

Functional metallosupramolecular architectures using 1,2,3-triazole ligands: it's as easy as 1,2,3 "click".

Self-assembled metallosupramolecular architectures have become an increasingly popular area of inorganic chemistry. These systems show a range interesting biological, electronic and photophysical properties. Additionally, they display extensive host-guest chemistry that could potentially be exploited for drug delivery and catalysis. To fully realise these types of applications the ability to generate more functionalised metallosupramolecular architectures is required. In this perspective review we examine the exploitation of 1,2,3-triazole ligands, generated using the Cu(i)-catalysed 1,3-cycloaddition of organic azides with terminal alkynes (the CuAAC "click" reaction), for the assembly of discrete functional metallosupramolecular architectures. These "click" ligands have been used to generate metallomacrocycles, cages and helicates. Some of the architectures have shown promise as anti-cancer and anti-bacterial agents while others have been exploited for small molecule activation and catalysis.

Investigating the cytotoxicity of platinum(II) complexes incorporating bidentate pyridyl-1,2,3-triazole "click" ligands.

Six platinum(II) complexes of the type [Pt(PL)(AL)]2+, where PL is a bidentate pyridyl-1,2,3-triazole "click" ligand and AL is the R,R or S,S isomer of 1.2-diaminocyclohexane, have been synthesised and characterised by several methods including elemental microanalysis, proton NMR spectroscopy and X-ray crystallography. The in vitro cytotoxicity of each complex was assessed in eleven cell lines, revealing moderate to good activity for complexes incorporating 2-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine.

Enhanced kinetic stability of [Pd2L4](4+) cages through ligand substitution.

There is considerable interest in exploiting metallosupramolecular cages as drug delivery vectors. Recently, we developed a [Pd2L4](4+) cage capable of binding two molecules of cisplatin. Unfortunately, this first generation cage was rapidly decomposed by common biologically relevant nucleophiles. In an effort to improve the kinetic stability of these cage architectures here we report the synthesis of two amino substituted tripyridyl 2,6-bis(pyridin-3-ylethynyl)pyridine () ligands (with amino groups either in the 2-() or 3-() positions of the terminal pyridines) and their respective [Pd2()4](4+) cages. These systems have been characterised by (1)H, (13)C and DOSY NMR spectroscopies, high resolution electrospray mass spectrometry, elemental analysis and, in one case, by X-ray crystallography. It was established, using model palladium(ii) N-heterocyclic carbene (NHC) probe complexes, that the amino substituted compounds were stronger donor ligands than the parent system ( > > ). Competition experiments with a range of nucleophiles showed that these substitutions lead to more kinetically robust cage architectures, with [Pd2()4](4+) proving the most stable. Biological testing on the three ligands and cages against A549 and MDA-MB-231 cell lines showed that only [Pd2()4](4+) exhibited any appreciable cytotoxicity, with a modest IC50 of 36.4 ± 1.9 µM against the MDA-MB-231 cell line. Unfortunately, the increase in kinetic stability of the [Pd2()4](4+) cages was accompanied by loss of cisplatin-binding ability.

A Dinuclear Platinum(II) N4Py Complex: An Unexpected Coordination Mode For N4Py.

The polypyridyl compound N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py) acts as a bridging ligand and coordinates to two Pt(II) ions giving an unexpected diplatinum(II) complex, whose photophysical and anticancer properties were investigated.

Biologically active [Pd2L4](4+) quadruply-stranded helicates: stability and cytotoxicity.

There is emerging interest in the anti-proliferative effects of metallosupramolecular systems due to the different size and shape of these metallo-architectures compared to traditional small molecule drugs. Palladium(II)-containing systems are the most abundant class of metallosupramolecular complexes, yet their biological activity has hardly been examined. Here a small series of [Pd2(L)4](BF4)4 quadruply-stranded, dipalladium(II) architectures were screened for their cytotoxic effects against three cancer cell lines and one non-malignant line. The helicates exhibited a range of cytotoxic properties, with the most cytotoxic complex [Pd2(hextrz)4](BF4)4 possessing low micromolar IC50 values against all of the cell lines tested, while the other helicates displayed moderate or no cytotoxicity. Against the MDA-MB-231 cell line, which is resistant to platinum-based drugs, [Pd2(hextrz)4](BF4)4 was 7-fold more active than cisplatin. Preliminary mechanistic studies indicate that the [Pd2(hextrz)4](BF4)4 helicate does not induce cell death in the same way as clinically used metal complexes such as cisplatin. Rather than interacting with DNA, the helicate appears to disrupt the cell membrane. These studies represent the first biological characterisation of quadruply-stranded helicate architectures, and provide insight into the design requirements for the development of biologically active and stable palladium(II)-containing metallosupramolecular architectures.