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 Au3+ 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, Au3+ 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.

and the fast-growing species are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant strains and the high level of intrinsic resistance of 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 and We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating 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 and 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 gyrase. 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 and 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.

The substitution kinetics of the complexes [Pt(terpy)Cl]ClÁ2H 2 O (PtL1), [Pt( t Bu 3 terpy)Cl]ClO 4 (PtL2), [Pt{4 0 -(2 000 -CH 3 -Ph)terpy}Cl]BF 4 (PtL3), [Pt{4 0 -(2 000 -CF 3 -Ph)terpy}Cl]CF 3 SO 3 (PtL4), [Pt{4 0 -(2 000 -CF 3 -Ph)-6-Phbipy}Cl] (PtL5) and [Pt{4 0 -(2 000 -CH 3 -Ph)-6-2 00 -pyrazinyl-2,2 0 -bipy}Cl]CF 3 SO 3 (PtL6) with the nucleophiles imidazole (Im), 1-methylimidazole (MIm), 1,2-dimethylimidazole (DIm), pyrazole (Pyz) and 1,2,4-triazole (Trz) were investigated in a methanolic solution of constant ionic strength. Substitution of the chloride ligand from the metal complexes by the nucleophiles was investigated as a function of nucleophile concentration and temperature under pseudo firstorder conditions using UV/Visible and stopped-flow spectrophotometric techniques. The reactions follow the rate lawThe results indicate that changing the nature or distance of influence of the substituents on the terpy moiety affects the p-back-donation ability of the chelate. This in turn controls the electrophilicity of the metal centre and hence its reactivity. Electron-donating groups decrease the reactivity of the metal centre, while electron-withdrawing groups increase the reactivity. Placing a strong r-donor cis to the leaving group greatly decreases the reactivity of the complex, while the addition of a good p-acceptor group significantly enhances the reactivity. The results indicate that the metal is activated differently by changing the surrounding atoms even though they are part of a conjugated system. It is also evident that substituents in the cis position activate the metal centre differently to those in the trans position. The kinetic results are supported by DFT calculations, which show that the metal centre is less electrophilic when a strong r-donor is cis to the leaving group and more electrophilic when a good p-acceptor group is part of the ring moiety. The temperature dependence studies support an associative mode of activation. An X-ray crystal structure of Pyz bound to PtL3 was obtained and confirmed the results of the DFT calculations as to the preferred N-atom as a binding site.

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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.

The reaction between [Pt(terpy)Cl]·2H2O (terpy = 2′,2′′:6′,2′′-terpyridine) and 1-methyl­imidazole (MIm) in the presence of two equivalents of AgClO4 in nitro­methane yields the title compound, [Pt(C15H11N3)(C4H6N2)](ClO4)2·CH3NO2. The dicationic complexes are arranged in a staggered configuration. The torsion angle subtended by the 1-methyl­imidazole ring relative to the terpyridine ring is 114.9 (5)°. Inter­molecular C—H⋯O inter­actions between the perchlorate anions and the H atoms of the terpy ligand are observed. Consideration of related phenyl­bipyridyl complexes of platinum(II), which are monocationic, leads to the conclusion that the electrostatic repulsion between the dicationic chelates prevents the formation of Pt⋯Pt inter­actions. These inter­actions are a common feature associated with the monocationic species.

The reaction between [PtCl(terpy)]·2H(2)O (terpy is 2,2':6',2''-terpyridine) and pyrazole in the presence of two equivalents of AgClO(4) in nitromethane yields the title compound, [Pt(C(3)H(4)N(2))(C(15)H(11)N(3))](ClO(4))(2)·CH(3)NO(2), as a yellow crystalline solid. Single-crystal X-ray diffraction shows that the dicationic platinum(II) chelate is square planar with the terpyridine ligand occupying three sites and the pyrazole ligand occupying the fourth. The torsion angle subtended by the pyrazole ring relative to the terpyridine chelate is 62.4 (6)°. Density functional theory calculations at the LANL2DZ/PBE1PBE level of theory show that in vacuo the lowest-energy conformation has the pyrazole ligand in an orientation perpendicular to the terpyridine ligand (i.e. 90°). Seemingly, the stability gained by the formation of hydrogen bonds between the pyrazole NH group and the perchlorate anion in the solid-state structure is sufficient for the chelate to adopt a higher-energy conformation.

Key indicators: single-crystal X-ray study; T = 296 K; mean (C-C) = 0.003 Å; R factor = 0.050; wR factor = 0.131; data-to-parameter ratio = 15.5.The title compound, C 16 H 20 N 4 ÁH 2 O, was synthesized from cis-1,2-diaminocyclohexane (a racemic mixture of the (1R,2S) and (1S,2R) enantiomers). The compound crystallized with two molecules (A and B) in the asymmetric unit with a single water solvent molecule per Schiff base molecule. Molecules A and B have similar conformations as illustrated by the least-squaresfit with an r.m.s. deviation of 0.242 Å . The molecules within the asymmetric unit are bridged by hydrogen bonds to the two water molecules, resulting in a heterotetramer. The water molecule acts as both a hydrogen-bond donor and acceptor. The pyrrole-imine units are not co-planar, making an angle of 73.9 (3) and 76.9 (3) in molecules A and B, respectively. Related literatureFor a study of the helical structures formed by both the S,S and R,R bis(pyrrolide-imine) ligands as well as the Zn Table 1 Hydrogen-bond geometry (Å , ).0.86 ( respectively. The mean imine C=N bond lengths are 1.270 (4) and 1.269 (3) Å for molecules A and B, respectively. These bond lengths highlight the double bond character of the imine bond. The pyrrole-imine moieties of both molecules A and B in the asymmetric unit are not co-planar. The angle subtended by the two seven atom mean planes comprising the pyrrole ring and imine carbon and nitrogen atoms is 73.9 (3)° and 76.9 (3)° for molecules A and B, respectively. This angle allows for hydrogen bonding to two water molecules. Both the imine nitrogen atoms and the pyrrole NH groups are involved in the hydrogen bonding, giving a total of eight hydrogen bonds. The hydrogen bonds result in a water-bridged dimer structure (Figure 3). The hydrogen bonds are considerably shorter than the sum of the van der Waals radii and the bond angles are approaching ideality, suggesting that they are likely to be relatively strong interactions. The hydrogen bond lengths and bond angles are summarized in Table 1. S2. ExperimentalThe enatiomerically pure diamine, (1R,2S)-diaminocyclohexane, (0.303 g, 2.65 mmol) was ground in an agate pestle and mortar with pyrrole-2-carboxaldehyde (0.500 g, 5.30 mmol) for 10 minutes. The resulting brown oil was dissolved in dichloromethane and dried over magnesium sulfate to remove the water, a by-product from the condensation reaction. The dichloromethane solution was then concentrated and layered with hexane to re-crystallize the ligand by liquid-liquid difussion (0.512 g, 72% yield). Crystals suitable for single-crystal X-ray crystallography, were obtained from the crystallization process. supporting information sup-2Acta Cryst. (2012). E68, o3354-o3355 S3. RefinementThe positions of all C-bonded hydrogen atoms were calculated using the standard riding model of SHELXL97 (Sheldrick, 2008) with C-H(aromatic) distances of 0.95 Å and U iso = 1.2 U eq , C-H(methylene) distances of 0.99 Å and U iso = 1.2 U eq and a C-H(methine) distance of 1.00 Å and U iso = 1.2 U eq ....