James E. M. Lewis

Stimuli-responsive Pd2L4 metallosupramolecular cages: towards targeted cisplatin drug delivery

Metallosupramolecular cages are an emerging, but as of yet relativity unexplored, drug delivery vector. Herein we show that discrete dipalladium(II) molecular cages of the formula [Pd2L4](X)4 can be quantatively self-assembled from a simple tripyridyl ligand (2,6-bis(pyridin-3-ylethynyl)pyridine) and [Pd(CH3CN)4](X)2 (X = BF4− or SbF6−). The cages have been fully characterised using 1H, 13C and DOSY NMR spectroscopy, elemental analysis, IR spectroscopy, and high resolution electrospray mass spectrometry (HR-ESMS). Additionally, the molecular structure of the [Pd2L4](SbF6)4 cage was confirmed unequivocally using X-ray diffraction. These [Pd2L4](X)4 cages are stimuli-responsive and can be reversibly disassembled/reassembled upon the addition/removal of suitable competing ligands. The central cavities of the [Pd2L4](X)4 cages are lined with four hydrogen bond accepting pyridine units which enable the encapsulation of two cisplatin molecules within the metallosupramolecular architecture through hydrogen bonding interactions between the cage and the amine ligands of the cisplatin guest. The structure of the [Pd2L4⊃(cisplatin)2](BF4)4 host–guest adduct has been confirmed by 1H NMR spectroscopy, HR-ESMS and X-ray crystallography. Additionally we have demonstrated that the cage–cisplatin host–guest adduct can be quantatively disassembled upon the addition of a competing ligand, releasing the cisplatin guest. This is the first crystallographically characterised example of a discrete metallosupramolecular cage encapsulating an FDA-approved inorganic drug molecule. This host–guest chemistry could open the way to relatively unexplored methods of drug delivery, which circumvent the malicious side effects and drug resistance associated with cisplatin and other anticancer therapeutics.

A facile “click” approach to functionalised metallosupramolecular architectures

Herein we describe a CuAAC click methodology for exo-functionalisation of Pd2L4 metallosupramolecular architectures. The potentially coordinating 1,2,3-triazole does not affect formation of the desired discrete complexes, nor does this external functional decoration affect the cisplatin-binding ability of the interior cavity of the assembly.

A Stimuli-Responsive Rotaxane-Gold Catalyst: Regulation of Activity and Diastereoselectivity.

A rotaxane-based Au catalyst was developed and the effect of the mechanical bond on its behavior was studied. Unlike the non-interlocked thread, the rotaxane requires a catalytically innocent cofactor, the identity of which significantly influences both the yield and diastereoselectivity of the reaction. Under optimized conditions, AuI (the catalyst), AgI (to abstract the Cl− ligand), and CuI (the cofactor) combine to produce a catalyst with excellent activity and selectivity.

‘Click’ to functionalise: synthesis, characterisation and enhancement of the physical properties of a series of exo- and endo-functionalised Pd2L4 nanocages

The synthesis of self-assembled metallosupramolecular architectures has been of steadily growing interest in recent years due to their diverse applications. Appending additional functionality to the ligands of these architectures has been limited as this often involves incorporation of coordinating groups that can potentially disrupt formation of the desired structure. Herein we report the use of the facile, functional group tolerant and high yielding CuAAC ‘click’ reaction to attach a variety of functional moieties to a tripyridyl ligand system. Despite the presence of the potentially coordinating 1,2,3-triazole rings, self-assembly of quadruply-stranded dipalladium(II) cage architectures in the presence of Pd(II) ions was almost universally observed for the functionalised “click” ligands. The only system which did not assemble into the expected cage featured a 2-(1,2,3-triazol-4-yl)pyridine binding pocket which sequestered the Pd(II) ions. Blocking this chelating pocket with an inert [Re(CO)3Cl] moiety restored the ability of the ligand to self-assemble into the desired quadruply-stranded dipalladium(II) cage, generating a heterometallic cage architecture. All ligands and cage architectures have been characterised using 1H, 13C and DOSY NMR, IR, UV-Vis and emission spectroscopies, mass spectrometry and in some cases by X-ray crystallography. Whilst the parent cage system is devoid of useful physical properties and displays a limited range of solubility, the CuAAC methodology provides a facile method to enhance the cages properties. A variety of fluorescent, redox active and biologically relevant species have been appended to the external surface of these cages. These groups enabled the generation of a series of aqueous soluble, fluorescent and electrochemically active Pd2L4 cages in a modular fashion.

[Fe2L3]4+ cylinders derived from bis(bidentate) 2-pyridyl-1,2,3- triazole "click" ligands: Synthesis, structures and exploration of biological activity

A series of metallosupramolecular [Fe2L3](BF4)4 “click” cylinders have been synthesized in excellent yields (90%–95%) from [Fe(H2O)6](BF4)2 and bis(bidentate) pyridyl-1,2,3-triazole ligands. All complexes were characterized by elemental analysis, IR, UV-vis, 1H-, 13C- and DOSY-NMR spectroscopies and, in four cases, the structures confirmed by X-ray crystallography. Molecular modeling indicated that some of these “click” complexes were of similar size and shape to related biologically active pyridylimine-based iron(II) helicates and suggested that the “click” complexes may bind both duplex and triplex DNA. Cell-based agarose diffusion assays showed that the metallosupramolecular [Fe2L3](BF4)4 “click” cylinders display no antifungal activity against S. cerevisiae. This observed lack of antifungal activity appears to be due to the poor stability of the “click” complexes in DMSO and biological media.

fac-Re(CO)3 complexes of 2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine “click” ligands: synthesis, characterisation and photophysical properties

The syntheses of the 4-n-propyl and 4-phenyl substituted fac-Re(CO)(3) complexes of the tridentate click ligand (2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine) are described. The complexes were obtained by refluxing methanol solutions of [Re(CO)(5)Cl], AgPF(6) and either the 4-propyl or 4-phenyl substituted ligand for 16 h. The ligands and the two rhenium(I) complexes were characterised by elemental analysis, HR-ESMS, ATR-IR, (1)H and (13)C NMR spectroscopy and the molecular structures of both complexes were confirmed by X-ray crystallography. The electronic structure of the fac-Re(CO)(3) click complexes was probed using UV-Vis, Raman and emission spectroscopy, cyclic voltammetry and DFT calculations. Altering the electronic nature of the ligands substituent, from aromatic to alkyl, had little effect on the absorption/emission maxima and electrochemical properties of the complexes indicating that the 1,2,3-triazole unit may insulate the metal centre from the electronic modification at the ligands periphery. Both Re(I) complexes were found to be weakly emitting with short excited state lifetimes. The electrochemistry of the complexes is defined by quasi-reversible Re oxidation and irreversible triazole-based ligand reduction processes.

Iterative Synthesis of Oligo[n]Rotaxanes in Excellent Yield

We present an operationally simple iterative coupling strategy for the synthesis of oligomeric homo- and hetero[n]rotaxanes with precise control over the position of each macrocycle. The exceptional yield of the AT-CuAAC reaction, combined with optimized conditions that allow the rapid synthesis of the target oligomers, opens the door to the study of precision-engineered oligomeric interlocked molecules.

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.

Exo- and endo-hedral interactions of counteranions with tetracationic Pd2L4 metallosupramolecular architectures

A series of [Pd2L4]4+(X− )4 metallosupramolecular architectures have been synthesised where X− = , , OTf− , OMs− or OTs− and L = 2,6-bis(pyridin-3-ylethynyl)pyridine. These systems have been characterised by NMR, IR and UV–vis spectroscopies, mass spectrometry, elemental analysis and, in several cases, by X-ray crystallography. Using these solution- and solid-state methods, we have investigated the exohedral and endohedral interactions of various anions with these cationic assemblies.

Luminescent Cages: Pendant Emissive Units on [Pd2L4]4+ “Click” Cages

The photophysics of a family of exo-functionalized [Pd2L4](4+) metallo-supramolecular cage architectures constructed from a tripyridyl 1,2,3-triazole backbone are reported. Several spectroscopic techniques are employed including both electronic (steady-state and transient absorption and emission) and vibrational (resonant and nonresonant Raman) methods. These experimental results are interpreted alongside simulated results from density functional theory calculations of the systems vibrational and electronic properties. The ligands and cages are shown to be essentially insulated from the exo-functionalization. They exhibit electronic transitions in the UV region and excited-state properties that are little affected by formation of the cage. Upon functionalization, characteristic Raman bands, electronic transitions, and emission bands associated with, and confined to, the substituent are observed.