Pt(II) Bis(pyrrole-imine) complexes: Luminescent probes and cytotoxicity in MCF-7 cells†.

Four Pt(II) bis(pyrrole-imine) Schiff base chelates (1-4) were synthesised by previously reported methods, through a condensation reaction, and the novel crystal structure of 2,2'-{propane-1,3-diylbis[nitrilo(E)methylylidene]}bis(pyrrol-1-ido)platinum(II) (1) was obtained. Pt(II) complexes 1-4 exhibited phosphorescence, with increased luminescence in anaerobic solvents or when bound to human serum albumin (HSA). One of the complexes shows a 15.6-fold increase in quantum yield when bound to HSA and could be used to detect HSA concentrations as low as 5 nM. Pt(II) complexes 1-3 was investigated as potential theranostic agents in MCF-7 breast cancer cells, but only complex 3 exhibited cytotoxicity when irradiated with UV light (λ355nmExcitation). Interestingly, the cytotoxicity of complex 1 was unresponsive to UV light irradiation. This indicates that only complex 3 can be considered a potential photosensitising agent.

Chiral Au(III) chelates exhibit unique NCI-60 cytotoxicity profiles and interactions with human serum albumin.

Au(III) bis(pyrrolide-imine) chelates are emerging as a class of versatile, efficacious metallodrug candidates. Here, we synthesised two enantiopure chiral ligands H2L1 and H2L2 (tetradentate cyclohexane-1,2-diamine-bridged bis(pyrrole-imine) derivatives). Metallation of the ligands with Au(III) afforded the chiral cationic complexes AuL1 and AuL2. The in vitro cytotoxicities of AuL1 and AuL2 determined in the NCI-60 single-dose drug screen were 56.5% and 89.1%, respectively. AuL1 was subsequently selected for a five-dose NCI-60 screen, attaining GI50, IC50, and LC50 values of 4.7, 9.3 and 39.8 µM, respectively. Hierarchical cluster analysis of the NCI-60 data indicated that the profile for AuL1 was similar to that of vinblastine sulfate, a microtubule-targeting vinca alkaloid. Reactions of AuL1 with glutathione (GSH) in vitro confirmed its susceptibility to reduction, Au(III) → Au(I), by intracellular thiols. Because human serum albumin (HSA) is responsible for transporting clinically deployed and investigational drugs, we studied the uptake of AuL1 and AuL2 by HSA to delineate how chirality impacts their protein-binding affinity. Steady-state fluorescence quenching data acquired on the native protein and data from site-specific probes showed that the compounds bind at sites close enough to Trp-214 (subdomain IIA) of HSA to quench the fluorophore. The bimolecular quenching rate constants, Kq, were ca. 102 times higher than the maximum diffusion-controlled collision constant of a biomolecule in water (1010 M-1 s-1), confirming that static fluorescence quenching was the dominant mechanism. The Stern-Volmer constants, KSV, were ∼104 M-1 at 37 °C, while the affinity constants, Ka (37 °C), measured ∼2.1 × 104 M-1 (AuL1) and ∼1.2 × 104 M-1 (AuL2) for enthalpy-driven ligand uptake targeting Sudlow's site I. Although far- and near-UV CD spectroscopy indicated that both complexes minimally perturb the secondary and tertiary structure of HSA, substantial shifts in the CD spectra were recorded for both protein-bound ligands. This study highlights the role of chirality in determining the cytotoxicity profiles and protein binding behaviour of enantiomeric Au(III) chelates.

A Survey of the Angular Distortion Landscape in the Coordination Geometries of High-Spin Iron(II) 2,6-Bis(pyrazolyl)pyridine Complexes.

Reaction of 2,4,6-trifluoropyridine with sodium 3,4-dimethoxybenzenethiolate and 2 equiv of sodium pyrazolate in tetrahydrofuran at room temperature affords 4-(3,4-dimethoxyphenylsulfanyl)-2,6-di(pyrazol-1-yl)pyridine (L), in 30% yield. The iron(II) complexes [FeL2][BF4]2 (1a) and [FeL2][ClO4]2 (1b) are high-spin with a highly distorted six-coordinate geometry. This structural deviation from ideal D2d symmetry is common in high-spin [Fe(bpp)2]2+ (bpp = di{pyrazol-1-yl}pyridine) derivatives, which are important in spin-crossover materials research. The magnitude of the distortion in 1a and 1b is the largest yet discovered for a mononuclear complex. Gas-phase DFT calculations at the ω-B97X-D/6-311G** level of theory identified four minimum or local minimum structural pathways across the distortion landscape, all of which are observed experimentally in different complexes. Small distortions from D2d symmetry are energetically favorable in complexes with electron-donating ligand substituents, including sulfanyl groups, which also have smaller energy penalties associated with the lowest energy distortion pathway. Natural population analysis showed that these differences reflect greater changes to the Fe-N{pyridyl} σ-bonding as the distortion proceeds, in the presence of more electron-rich pyridyl donors. The results imply that [Fe(bpp)2]2+ derivatives with electron-donating pyridyl substituents are more likely to undergo cooperative spin transitions in the solid state. The high-spin salt [Fe(bpp)2][CF3SO3]2, which also has a strong angular distortion, is also briefly described and included in the analysis.

Spectroscopic and computational study of the interaction of Pt(II) pyrrole-imine chelates with human serum albumin.

Three bis(pyrrolide-imine) Pt(II) chelates were synthesised and characterized with different bridging alkyl groups, specifically 2-hydroxypropyl (1), 2,2-dimethylpropyl (2), and 1,2-(S,S)-(+)-cyclohexyl (3). Novel compounds 1 and 2 were analysed by single-crystal X-ray diffraction (space group P1̄). The asymmetric unit of 1 comprises three independent molecules linked by hydrogen bonds involving the OH groups, forming a trimeric supramolecular structure. The Pt(II) chelates were reacted with human serum albumin (HSA) to investigate how the ligand bound to the Pt(II) ion influences the compound's affinity for HSA. Fluorescence quenching data obtained for native HSA and HSA bound to site-specific probes (warfarin, subdomain IIA; ibuprofen, subdomain IIIA) indicated that the three Pt(II) chelates bind close enough (within ∼30 Å) to Trp-214 to quench its intrinsic fluorescence. The bimolecular quenching constant (kq) was 103-104 -fold higher than the maximum diffusion-controlled collision constant in water (1010 M s-1) at 310 K, while the affinity constants, Ka, ranged from ∼5 × 103 to ∼5 × 105 at 310 K, and followed the order 1 > 3 > 2. The reactions of 1 and 3 with HSA were enthalpically driven, while that for 2 was entropically driven. Macromolecular docking simulations (Glide XP) and binding site specificity assays employing site-specific probes and UV-vis CD spectroscopy indicated that 1 and 2 target Sudlow's site II in subdomain IIIA, minimally perturbing the tertiary structure of the protein. Well-resolved induced CD signals from 1 and 2 bound to HSA in subdomain IIIA were adequately simulated by hybrid QM:MM TD-DFT methods. We conclude that the structure of the bis(pyrrolide-imine) Pt(II) chelate measurably affects its uptake by HSA without detectable decomposition or demetallation. Such compounds could thus serve as metallodrug candidates capable of utilising an HSA-mediated cellular uptake pathway.

Ionic mononuclear [Fe] and heterodinuclear [Fe,Ru] bis(diphenylphosphino)alkane complexes: Synthesis, spectroscopy, DFT structures, cytotoxicity, and biomolecular interactions.

Iron(II) and Ru(II) half-sandwich compounds encompass some promising pre-clinical anticancer agents whose efficacy may be tuned by structural modification of the coordinated ligands. Here, we combine two such bioactive metal centres in cationic bis(diphenylphosphino)alkane-bridged heterodinuclear [Fe2+, Ru2+] complexes to delineate how ligand structural variations modulate compound cytotoxicity. Specifically, Fe(II) complexes of the type [(η5-C5H5)Fe(CO)2(κ1-PPh2(CH2)nPPh2)]{PF6} (n = 1-5), compounds 1-5, and heterodinuclear [Fe2+, Ru2+] complexes, [(η5-C5H5)Fe(CO)2(µ-PPh2(CH2)nPPh2))(η6-p-cymene)RuCl2]{PF6} (n = 2-5) (compounds 7-10), were synthesized and characterised. The mononuclear complexes were moderately cytotoxic against two ovarian cancer cell lines (A2780 and cisplatin resistant A2780cis) with IC50 values ranging from 2.3 ± 0.5 µM to 9.0 ± 1.4 µM. For 7-10, the cytotoxicity increased with increasing Fe⋅⋅⋅Ru distance, consistent with their DNA affinity. UV-visible spectroscopy suggested the chloride ligands in heterodinuclear 8-10 undergo stepwise substitution by water on the timescale of the DNA interaction experiments, probably affording the species [RuCl(OH2)(η6-p-cymene)(PRPh2)]2+ and [Ru(OH)(OH2)(η6-p-cymene)(PRPh2)]2+ (where PRPh2 has R = [-(CH2)5PPh2-Fe(C5H5)(CO)2]+). One interpretation of the combined DNA-interaction and kinetic data is that the mono(aqua) complex may interact with dsDNA through nucleobase coordination. Heterodinuclear 10 reacts with glutathione (GSH) to form stable mono- and bis(thiolate) adducts, 10-SG and 10-SG2, with no evidence of metal ion reduction (k1 = 1.07 ± 0.17 × 10-1 min-1 and k2 = 6.04 ± 0.59 × 10-3 min-1 at 37 °C). This work highlights the synergistic effect of the Fe2+/Ru2+ centres on both the cytotoxicity and biomolecular interactions of the present heterodinuclear complexes.

Discovery of novel heterocyclic amide-based inhibitors: an integrative in-silico approach to targeting soluble epoxide hydrolase.

Inhibition of soluble epoxide hydrolase (sEH) is considered as an emerging druggable target to reduce blood pressure, improve insulin sensitivity, and decrease inflammation. Despite the availability of different classes of sEH small molecule inhibitors for the potential treatment of hypertension, only a few candidates have reached clinical trials, making the optimal control of blood pressure presently unattainable. This necessity motivated us to explore a series of novel quinazoline-4(3H)-one and 4,6-disubstituted pyridin-2(1H)-one derivatives targeting sEH enzyme. Herein, comprehensive computational investigations were performed to probe the inhibition efficacy of these potent compounds in terms of inhibitor-enzyme interactions against sEH. In this study, the 39 in-house with a focused library comprising 39 in-house synthesized compounds were selected. The structure-based pharmacophore modeling was developed based on the crystal structure of sEH with its co-crystallized biologically active inhibitor. The generated hypotheses were applied for virtual screening-based PHASE fitness scores. Docking-based virtual screening workflows were used to generate lead compounds using HTVS, SP and XP based GLIDE G-score values. The candidate leads were filtered using ADMET pharmacological and physicochemical properties screening. A 100-ns of molecular dynamics simulations with Molecular dynamics simulations (100 ns) were performed to explore the binding affinities of the considered compounds. Our study identified four best candidates from quinazoline-4(3H)-one derivatives, which indicated that a quinazolinone ring serves as a suitable scaffold to develop novel small molecule sEH inhibitors.

Cancer molecular biology and strategies for the design of cytotoxic gold(I) and gold(III) complexes: a tutorial review.

This tutorial review highlights key principles underpinning the design of selected metallodrugs to target specific biological macromolecules (DNA and proteins). The review commences with a descriptive overview of the eukaryotic cell cycle and the molecular biology of cancer, particularly apoptosis, which is provided as a necessary foundation for the discovery, design, and targeting of metal-based anticancer agents. Drugs which target DNA have been highlighted and clinically approved metallodrugs discussed. A brief history of the development of mainly gold-based metallodrugs is presented prior to addressing ligand systems for stabilizing and adding functionality to bio-active gold(I) and gold(III) complexes, particularly in the burgeoning field of anticancer metallodrugs. Concepts such as multi-modal and selective cytotoxic agents are covered where necessary for selected compounds. The emerging role of carbenes as the ligand system of choice to achieve these goals for gold-based metallodrug candidates is highlighted prior to closing the review with comments on some future directions that this research field might follow. The latter section ultimately emphasizes the importance of understanding the fate of metal complexes in cells to garner key mechanistic insights.

A Cytotoxic Bis(1,2,3-triazol-5-ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation.

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) AuI -CNC pincer complex suitable for oxidation to the redox-stable [AuIII (CNC)Cl]+ cation. Although the ligand salt and the [AuIII (CNC)Cl]+ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [AuIII (CNC)Cl]+ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII (CNC)Cl]+ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic π-type interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.

Self-assembled supramolecular structures of O,N,N' tridentate imidazole-phenol Schiff base compounds.

Three imidazole-derived Schiff base compounds comprising an N-methyl imidazole group coupled to a phenol ring through an imine bond were synthesised. The structures differ by the substituent on the phenol ring at the 4-position: methyl (1), tert-butyl (2) and hydrogen (3). The compounds were synthesised using both a traditional reflux in solvent as well as an environmentally friendly solid-state reaction. Compounds (1)-(3) as well as the hemihydrate of (3) were all studied by single crystal X-ray diffraction. The asymmetric unit of compound (1) consists of two nominally planar molecules linked by hydrogen bonds to form a dimeric supramolecular structure. This dimeric structure was ubiquitous for the anhydrous forms of (1)-(3). The complementary hydrogen bonding motif between the imidazole N atoms and the phenol OH results in a stable 16-membered hydrogen-bonded ring. The asymmetric unit of (3) comprises two symmetry-independent molecules one of which has co-planar imidazole and phenol rings while the other shows a significantly oblique orientation. The hemihydrate of (3) similarly forms extensive hydrogen bonds, though in the form of a water-bridged dimeric structure. The hydrogen bond lengths (D⋯A) for compounds (1)-(3) are relatively short, ranging from 2.662(1) to 2.688(1) Å. DFT was used to understand the relative stability of the monomeric and dimeric species. These showed the hydrogen-bonded supramolecular structures were ca. 101 kJ mol-1 lower in energy than the non-interacting monomers. Scan simulations were used to calculate the total energy of the molecule as a function of phenyl ring rotation and showed why the expected planar configuration for a conjugated π-system was not observed experimentally. The barrier to rotation was found to be relatively low, 7.97(6) kJ mol-1, with the lowest energy conformations subtending dihedral angles of 22.319, 24.265 and 25.319° for molecules (1), (2) and (3), respectively. The electrostatic potential maps are able to succinctly explain the stability of the hydrogen bonds through the partial charges of the interacting atoms. TD-DFT simulations and analysis of the simulated and experimental UV/visible spectra suggest that the dimeric supramolecular structure is a stable species in solution. This was confirmed through 1H NMR titrations and an equilibrium constant of 0.16(5) M-1 was estimated.

Supramolecular solvatochromism: mechanistic insight from crystallography, spectroscopy and theory.

A solvatochromic dinuclear copper(ii) metallocycle effectively traps tetrahydrofuran, diethyl ether and pentane significantly above their boiling points. X-ray crystallography, EPR and UV-visible spectroscopy were used to delineate an empirical relationship between the guest-induced structural perturbation of the metallocycle, the ligand field splitting parameter Δ (νmax), and the EPR g-values of the inclusion compounds, thereby elucidating the solvatochromic mechanism.

Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus.

Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

Cobalt Porphyrin-Thiazyl Radical Coordination Polymers: Toward Metal-Organic Electronics.

Herein we delineate an unusual one-dimensional coordination polymer (CP), 3, prepared from S = 1/2 Co(TPP), 1 (TPP = 5,10,15,20-tetraphenylporphyrin dianion), and S = 1/2 4-(4'-pyridyl)-1,2,3,5-dithiadiazolyl (py-DTDA) radical, 2. The atypically long S-S distance for CP 3 (2.12 Å) reflects fractional electron transfer from the formally Co(II) ion into the antibonding π-SOMO of the metal-bound py-DTDA bridging ligand. The bonding in solid CP 3 involves noninteger redox states in a resonance hybrid repeat unit best formulated as [Co(TPP)]0.5+ hemication (Co2.5+) bound to a dithiadiazolide hemianion (py-DTDA0.5-). DFT calculations confirm the metal to ligand charge transfer (MLCT) character of the low-lying electronic states (641, 732, and 735 nm) observed for CP 3 and show that oligomer chains of length ≥14 repeat units tend toward a band structure with a limiting band gap energy of 0.669(6) eV. In dichloromethane, the reaction between radicals 1 and 2 involves coordination of the Co(II) ion by a py-DTDA ring sulfur atom, orbitally favored spin-pairing, and the formation of the thermodynamically favored diamagnetic five-coordinate S-bound adduct, Co(TPP)(S-py-DTDA), 3a. Polymerization and crystallization of 3a affords diamagnetic CP 3. Dissolution of CP 3 in DMSO favors Co-S bond heterolysis, yielding the diamagnetic six-coordinate purple N-bound CoIII(TPP)(N-py-DTDA-)(O═SMe2) complex (λmax, 436 nm). However, monomerization of CP 3 in dry 1,2-dichloroethane affords bright green diamagnetic CoIII(TPP)(N-py-DTDA-), 3b, with multiple MLCT bands in the 800-1100 nm NIR region and a red-shifted Soret band (λmax, 443 nm). Implications for the use of CP 3 in electronic devices are discussed based on its density of states.

Heterocyclic Bismuth(III) Dithiocarbamato Complexes as Single-Source Precursors for the Synthesis of Anisotropic Bi2 S3 Nanoparticles.

New complexes catena-(µ2 -nitrato-O,O')bis(piperidinedithiocarbamato)bismuth(III) (1) and tetrakis(µ-nitrato)tetrakis[bis(tetrahydroquinolinedithiocarbamato)bismuth(III)] (2) were synthesised and characterised by elemental analysis, FTIR spectroscopy and thermogravimetric analysis. The single-crystal X-ray structures of 1 and 2 were determined. The coordination numbers of the Bi(III) ion are 8 for 1 and ≥6 for 2 when the experimental electron density for the nominal 6s(2) lone pair of electrons is included. Both complexes were used as single-source precursors for the synthesis of dodecylamine-, hexadecylamine-, oleylamine and tri-n-octylphosphine oxide-capped Bi2 S3 nanoparticles at different temperatures. UV/Vis spectra showed a blueshift in the absorbance band edge characteristic of a quantum size effect. High-quality, crystalline, long and short Bi2 S3 nanorods were obtained depending on the thermolysis temperature, which was varied from 190 to 270 °C. A general trend of increasing particle breadth with increasing reaction temperature and increasing length of the carbon chain of the amine (capping agent) was observed. Powder XRD patterns revealed the orthorhombic crystal structure of Bi2 S3 .

Gold(III) macrocycles: nucleotide-specific unconventional catalytic inhibitors of human topoisomerase I.

Topoisomerase IB (Top1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au(3+) macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase IIα (Top2α) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au(3+) is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5'-TA-3' dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include π-π stacking and an Au···O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.

Redox behaviour of cymantrene Fischer carbene complexes in designing organometallic multi-tags.

A series of Group 7 Fischer carbene complexes, [Cp(CO)2 Mn(I) =C(OEt)Ar] (Cp=cyclopentadienyl, Ar=Th=thienyl (1 a), Ar=Fu=furyl (2 a), Ar=Fc=ferrocenyl (3 a)) and biscarbene complexes, [Cp(CO)2 MnC(OEt)Ar'(OEt)CMn(CO)2 Cp] (Ar'=Th'=2,5-thienylene (1 b), Ar'=Fu'=2,5-furylene (2 b), Ar'=Fc'=1,1'-ferrocendiyl (3 b)) was synthesized and characterized. Chemical oxidation of [Cp(CO)2 MnC(OEt)Fc] (3 a) and isolation of the oxidised species [3 a][PF6 ] possessing a Mn(II) centre proved possible below -30 °C in dichloromethane solution. The ESR spectrum of the transiently stable radical cation, [3 a][PF6 ], confirmed the presence of a low-spin Mn(II) centre characterized by a rhombic g tensor (gx =1.975, gy =2.007 and gz =2.130) in frozen dichloromethane at 77 K with (55)  Mn hyperfine coupling constants A1 , A2 and A3 of 115, 33 and 43 G, respectively. Electrochemical studies demonstrated the influence of the Ar substituent on the oxidation potential. All complexes showed that the redox potentials of carbene double bond reduction and Mn(I) oxidation were dependent on the type of Ar group, but only 3 b showed resolved oxidations for the two Mn(I) centres. Surprisingly, Mn(I) oxidation occurs at lower potentials than ferrocenyl oxidation. Density functional theory (DFT) calculations were carried out to delineate the nature of the species involved in the oxidation and reduction processes and clearly confirm that oxidation of Mn(I) is favoured over that of ferrocene.

Biodistribution (as determined by the radiolabelled equivalent) of a gold(III) bis(pyrrolide-imine) Schiff base complex: a potential chemotherapeutic.

The biodistribution of an N2 N2 ' tetradentate gold(III) chelate, which is known to be cytotoxic towards a range of human cancer cell lines, was determined by a radiolabelled equivalent of the compound. The (198) Au-labelled gold(III) chelate of a bis(pyrrolide-imine) Schiff base ligand with a three-carbon di(azomethine) linkage was successfully synthesised with a high radiochemical yield of 73% and radiochemical purity of >95%. The high energy γ-ray emitted by the (198) Au nucleus was used to follow the biodistribution of the compound in vivo in six male Sprague Dawley rats on a gamma camera. The log Po/w value of the (nat) Au analogue, -1.92(2), showed that the compound is hydrophilic and therefore likely to largely remain in the blood pool. This was confirmed by the biodistribution study, which showed 21% of the injected dose (ID) remained in the blood pool 4.5 h after injection. This decreased to 10.8% over a 24-h period. The activity measured in the lungs, 1.48%ID/g, remained relatively constant over a 24-h period suggesting that the complex had accumulated in the lungs in the form of particulates, and could not be cleared by the test subjects. The t½ for the heart and lungs was greater than 24 h. Excretion of the test compound is seemingly via the kidneys, but is slow with approximately 30% of the ID excreted within 24 h.

Gold(III) complexes of pyridyl- and isoquinolylamido ligands: structural, spectroscopic, and biological studies of a new class of dual topoisomerase I and II inhibitors.

The structures, spectroscopy, and cytotoxicity of four novel nominally square-planar gold(III) chelates 1-4 with the general formula cis-AuCl2(X), where the ligand X is an anionic bidentate pyridyl- or isoquinolylamido chelating agent, are described. The Au-N(amido), Au-N(pyridyl), and Au-N(isoquinolyl) distances are 2.002(9)-2.016(3), 2.01(1)-2.037(3), and 2.037(3) Å, respectively. Density functional theory simulations afforded accurate gold(III) coordination geometries for 1-4 (bond distances and angles to within 5% of the X-ray values), while accurate transition energies were limited to those calculated in the UV spectral region. The complexes had variable stability in dimethyl sulfoxide: compound 3 (relatively rigid) was indefinitely stable, compounds 1 and 2 (conformationally flexible) slowly demetalated over 30 days, and 4 (extensively aromatic) formed an insoluble precipitate after 10 days (72 h in an aqueous buffer). The isoquinolylamido derivative 4 was sufficiently cytotoxic in the NCI-60 screen to undergo full five-dose testing. Notably low GI50 (1.8, 2.3, and 3.2 µM) and IC50 (4.0, 9.8, and 15 µM) values were recorded for the OVCAR-3, IGROV1, and SW-620 cell lines, respectively. Hierarchical cluster analysis employing the National Cancer Institute (NCI) data for known anticancer drugs and 4 revealed that compound 4 is mechanistically identical with the topoisomerase IIα (Top2) poison zorubicin and statistically similar to the topoisomerase IB (Top1) poisons camptothecin and 9-methoxycamptothecin. The Top2-catalyzed decatenation reaction of kinetoplast DNA was studied as a function of the concentration of 4: the compound acts as an interfacial poison of Top2 at low concentrations (<1 µM) and a catalytic inhibitor of the enzyme above 5 µM. Gel mobility shift assays (plasmid DNA substrate) showed that the catalytic inhibition of Top2 likely correlates with DNA binding by 4 at concentrations >5 µM. Compound 4 is also a catalytic inhibitor of Top1 at higher concentrations, consistent with DNA binding by the complex.

An X-ray crystallographic and density functional theory study of (3Z)-4-(5-ethylsulfonyl-2-hydroxyanilino)pent-3-en-2-one and (3Z)-4-(5-tert-butyl-2-hydroxyanilino)pent-3-en-2-one.

The Schiff base enaminones (3Z)-4-(5-ethylsulfonyl-2-hydroxyanilino)pent-3-en-2-one, C13H17NO4S, (I), and (3Z)-4-(5-tert-butyl-2-hydroxyanilino)pent-3-en-2-one, C15H21NO2, (II), were studied by X-ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C-C=C-N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino-phenol group canted relative to the rest of the molecule; the twist about the N(enamine)-C(aryl) bond leads to dihedral angles of 40.5 (2) and -116.7 (1)° for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N-H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one-dimensional hydrogen-bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H-O hydrogen bond, and consequently also forms a one-dimensional hydrogen-bonded chain. The DFT-calculated structures [in vacuo, B3LYP/6-311G(d,p) level] for the keto tautomers compare favourably with the X-ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol(-1) lower in energy than the enol tautomers for (I) and (II), respectively.

π-π Dimerization of a mono(pyridyl-imine) platinum(II) chelate.

The cation of the title complex salt, chlorido{2,2-dimethyl-N-[(E)-1-(pyridin-2-yl)ethylidene]propane-1,3-diamine}platinum(II) tetrafluoridoborate, [PtCl(C(12)H(19)N(3))]BF(4), exhibits a nominally square-planar Pt(II) ion coordinated to a chloride ion [Pt-Cl = 2.3046 (9) Å] and three unique N-atom types, viz. pyridine, imine and amine, of the tridentate Schiff base ligand formed by the 1:1 condensation of 1-(pyridin-2-yl)ethanone and 2,2-dimethylpropane-1,3-diamine. The cations are π-stacked in inversion-related pairs (dimers), with a mean plane separation of 3.426 Å, an intradimer Pt···Pt separation of 5.0785 (6) Å and a lateral shift of 3.676 Å. The centroid (Cg) of the pyridine ring is positioned approximately over the Pt(II) ion of the neighbouring cation (Pt···Cg = 3.503 Å).

Sorption of small molecule vapours by single crystals of [Pt{4'-(Ph)trpy}(NCS)]SbF6 where trpy = 2,2':6',2''-terpyridine: a porous material with a structure stabilised by extended π-π interactions.

Treatment of [Pt{4'-(Ph)trpy}Cl]SbF(6) with AgSCN in a metathesis reaction in refluxing acetonitrile affords, after work-up, single crystals of [Pt{4'-(Ph)trpy}(NCS)]SbF(6)·CH(3)CN, where trpy is 2,2':6',2''-terpyridine. These crystals lose solvent to give single crystals of [Pt{4'-(Ph)trpy}(NCS)]SbF(6) (1). An X-ray crystal structure determination of 1 shows that the SCN(-) ion is N-bound and that the cation as a whole is approximately planar. Compound 1 is porous with "empty" channels that corkscrew through the crystal: this crystal structure is stabilised by extended π-π interactions between the planar cations. When a single crystal of 1 is exposed to vapours of acetonitrile the vapours are sorbed without loss of single crystallinity, as confirmed by crystal structure determinations of 1 and 1·CH(3)CN using the same single crystal. Similarly, single crystals of 1 sorb vapours of methanol without loss of single crystallinity, as confirmed by a crystal structure determination of 1·CH(3)OH. We also report the crystal structure of 1·(CH(3))(2)CO; however, in this case the single crystal was grown directly from acetone. Compound 1 and its solvates are all yellow. Nevertheless, there are differences between the emission spectra recorded for 1 and its solvates in the solid state. Thus, whereas 1 exhibits very weak multiple emission from (3)MLCT (MLCT = metal-to-ligand charge transfer) and excimeric (3)π-π* excited states, 1·CH(3)CN and 1·(CH(3))(2)CO both exhibit more intense (3)MLCT emission; and the emission by 1·CH(3)OH is complicated by the presence of metallophilic interactions in the crystal. We discuss the role of the solvent in causing these differences.