Michael Lloyd Williams

Metallocene-based inhibitors of cancer-associated carbonic anhydrase enzymes IX and XII.

In this study, 20 metallocene-based compounds comprising extensive structural diversity were synthesized and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. These compounds proved moderate to good CA inhibitors in vitro, with several compounds displaying selectivity for cancer-associated isozymes CA IX and CA XII compared to off-target CA I and CA II. Compound 6 was the most potent ferrocene-based inhibitor with K(i)s of 5.9 and 6.8 nM at CA IX and XII, respectively. A selection of key drug-like parameters comprising Log P, Log D, solubility, and in vitro metabolic stability and permeability were measured for two of the ferrocene-based compounds, regioisomers 1 and 5. Compounds 1 and 5 were found to have characteristics consistent with lipophilic compounds, however, our findings show that the lipophilicity of the ferrocene moiety is not well modeled by replacement with either a naphthyl or a phenyl moiety in software prediction tools.

Selective cytotoxic Ru(II) arene Cp* complex salts [R-PhRuCp*](+)X(-) for X = BF4(-), PF6(-), and BPh4(-).

A novel series of ionic Ru(II) arene Cp* sandwich complexes has been synthesized and characterized. Screening results for cytotoxicity against a range of human tumor cell lines and normal human cells indicate that the complexes show promising anticancer activity, which varies with changes in the arene ligand and the anionic counterion.

Protein crystal structures with ferrocene and ruthenocene-based enzyme inhibitors

We have determined the protein X-ray crystal structures of four organometallic inhibitors in complex with their target enzyme carbonic anhydrase II. The barrel-shaped hydrophobic ferrocene and ruthenocene moieties have provided a structure-based avenue to better occupy the hydrophobic binding patch within the enzyme active site.

Peripherally-metallated porphyrins: synthesis and spectra of meso-η1-palladio- and platinioporphyrins and the crystal structures of cis-{PtBr[10,20-diphenylporphyrinatonickel(II)-5-yl](PPh3)2} and trans-{PtBr[10,20-diphenylporphyrin-5-yl](PPh3)2}·0.25CH2Cl2

Abstract A series of meso-η1-palladio(II)- and platinio(II)porphyrins containing either monodentate Group 15 ligands (PPh3, AsPh3) or chelating diphosphines (dppe, dppp, dppf) has been prepared by oxidative addition of mono- and dibromo derivatives of 5,15-diphenylporphyrin (H2DPP) to Pd(0) and Pt(0) precursors. The products were characterized by their 1H- and 31P-NMR, visible absorption, and mass spectra and the X-ray crystal structures of trans-[PtBr(H2DPP)(PPh3)2] (14) (as a 0.25CH2Cl2 solvate) and cis-[PtBr(NiDPP)(PPh3)2] (15) were determined. The structures show approximately square planar geometry about the Pt atoms, although there are distortions due to crowding of the PPh3 ligands in 15. The NiDPP ring in 15 suffers ruffling typical of peripherally-crowded Ni(II) porphyrins, the pairs of opposite meso carbons being displaced alternately >±0.4 A out of the C20N4 mean plane The conformations of the phenyl groups of the PPh3 ligands indicate the presence of non-covalent phenyl–porphyrin π–π interactions. These derivatives are the first isolated examples of peripheral organometallic porphyrins with direct transition metal to porphyrin σ-bonds, and they represent a new class of superstructured porphyrins with one or both faces of the macrocycle heavily shielded by the phenyl groups on the auxiliary ligands.

Pentakis(methoxycarbonyl)cyclopentadiene chemistry. Part 1. Preparation and properties of the diene, and of derivatives containing the alkali metals or thallium(I): crystal and molecular structures of HC5(CO2Me)5, Li[C5(CO2Me)5]·H2O, K[C5(CO2Me)5]·MeOH, and Tl[C5CO2Me)5]

The alkali metal (Li, Na, K, Rb, and Cs) and thallium(I) derivatives of HC5(CO2Me)5 have been prepared and characterised; their i.r., u.v., 1H, and l3C n.m.r. spectra are reported and discussed. Single-crystal X-ray structure determinations have been carried out on the diene and its Li, K, and Tl salts at 295 K. In the solid, as in non-polar solvents, the diene has the fulvenoid configuration, with the acidic proton bridging two adjacent carbonyl groups. This configuration is preserved in univalent metal cation salts. Lithium is four-co-ordinate (from two carbonyl oxygens, the water molecule, and a carbonyl oxygen from a second anion). In the potassium salt, the metal is co-ordinated by methanol, and five carbonyl oxygens from three different anions; all carbonyl oxygens of each anion are likewise involved in co-ordination to three different metal atoms. In the thallium salt the metal has irregular five-co-ordination, with two chelating carbonyl groups from one anion and three from separate anions; all carbonyl oxygens of each anion co-ordinate to four different metal atoms.

Tryptophan anion complexes of β-cyclodextrin (cyclomaltaheptaose), an aminopropylamino-β-cyclodextrin and its enantioselective nickel(II) complex

6I-(3-Aminopropylamino)-6I-deoxy-cyclomaltaheptaose (βCDpn) exhibits enhanced complexation of tryptophan anion, by comparison with βCD, while the nickel(II) complex of βCDpn complexes tryptophan anion even more strongly and exhibits a tenfold enantioselectivity in favour of the (S)-tryptophan anion.

Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition

Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgens 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21-23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.

Novel organometallic cationic ruthenium(II) pentamethylcyclopentadienyl benzenesulfonamide complexes targeted to inhibit carbonic anhydrase

Cationic ruthenium(II) pentamethylcyclopentadienyl benzenesulfonamide sandwich complexes have been synthesized and screened for enzymatic inhibition of the physiologically dominant carbonic anhydrase (CA) isozymes: human CA I and II, mitochondrial isozymes VA and VB, and the cancer-associated isozyme IX. The complexes demonstrated weaker binding to CAs compared with typical aromatic sulfonamides, inhibiting the enzyme at high nanomolar concentrations. An in vitro cytotoxic evaluation of the complexes was also undertaken against a range of tumorigenic cell lines and a healthy human cell line. Complexes inhibited the growth of cancerous cells at low micromolar concentrations while expressing lower levels of toxicity towards the normal human cell line. Factors influencing the synthesis, cytotoxicity, and enzyme affinity for this series of organometallic complexes are discussed.

Cluster chemistry. Part 45. Synthesis and some reactions of [Ru3(µ3-PPhCH2PPh2)(CO)9]– : X-ray crystal structures of [MRu3(µ3-PPhCH2PPh2)(CO)9(PPh3)](M = Cu, Ag, or Au)

Reactions between K[BHBus3] and [Ru3(CO)10(µ-EPh2CH2EPh2)](E = P or As) afford solutions of the dephenylated anions, [Ru3(µ3-EPhCH2EPh2)(CO)9]–, which can be reversibly protonated to give [Ru3(µ-H)(µ3-EPhCH2EPh2)(CO)9]. The latter complexes may also be obtained directly from [Ru3(CO)10(µ-EPh2CH2EPh2)] and H2(20 atm, 80 °C, 2h) in cyclohexane (yields 65–75%). Similar complexes were obtained in poor yield from [Ru3(CO)10(µ-PPh2CH2CH2PPh2)]. The group 1 B metal-containing clusters [MRu3(µ3-EPhCH2EPh2)(CO)9(PPh3)](E = P, M = Cu, Ag, or Au; E = As, M = Au) were prepared from [Ru3(µ3-EPhCH2EPh2)(CO)9]– and sources of [M(PPh3)]+; the analogous [AuRu3(µ3-PPhCH2CH2PPh2)(CO)9(PPh3)] was also obtained. Single-crystal X-ray studies on the first three, title complexes showed that they are isostructural, the M(PPh3) fragment bridging the same Ru–Ru bond as that bridged by the PPh group of the face-capping phosphidophosphine ligand. Detailed examination of bond parameters in the Ru2MP moiety suggests that the three M(PPh3) fragments are not strictly isolobal, although it is the Ag(PPh3) fragment which interacts least strongly with the Ru3 core. The structures were refined by least-squares methods to residuals of 0.039, 0.044, and 0.041 for 4 560, 4 917, and 9 275 independent ‘observed’ reflections, respectively.

Selective, Cytotoxic Organoruthenium(II) Full‐Sandwich Complexes: A Structural, Computational and In Vitro Biological Study

A structurally diverse range of lipophilic, cationic η(6)-arene η(5)-cyclopentadienyl (η(5)-Cp*) full-sandwich complexes of ruthenium(II) have been prepared and structurally characterized by Fourier-transform IR and NMR spectroscopy, electrospray mass spectrometry, and elemental microanalyses. Computational experiments incorporating the Hartree-Fock theory and the second-order Møller-Plesset perturbation theory predict each complex to possess a uniform δ+ electrostatic potential, with the cationic charge of the [RuCp*](+) moiety completely delocalizing throughout the molecular structure of each metallocene. In vitro cytotoxicity studies demonstrate these delocalized lipophilic cations to be potent growth inhibitors of eleven unique tumorigenic cell lines, while exhibiting significantly lower levels of toxicity towards both a normal human fibroblast and a mouse macrophage cell line. Single-crystal X-ray structural determinations are additionally reported for five complexes, [Ru(η(6)-C(6)H(5)(CH(2))(2)CH(3))(η(5)-C(5)(CH(3))(5))]BPh(4), [Ru(η(6)-C(6)H(5)CO(2)CH(2)CH(3))(η(5)-C(5)(CH(3))(5))]BF(4), [Ru(η(6)-C(10)H(8))(η(5)-(5) (CH(3))(5))]BPh(4), [Ru(η(6)-C(14)H(10))(η(5)-C(5)(CH(3))(5))]BPh(4), and [Ru(η(6)-C(16)H(10))(η(5)-C(5)(CH(3))(5))]BPh(4).