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.

The development of cost-effective and easily accessible bifunctional materials, which can be effectively used for energy storage and energy generation, is highly desirable. Herein, a new molecular precursor [tris(morpholinodithiocarbamato)Co (III)] has been synthesized and the X-ray crystal structure of the complex determined. The precursor was used to prepare oleylamine (OLA)-capped cobalt sulfide nanoplatelets, using a facile hot injection method at two different temperatures (200°C and 260°C). The characterization of the samples shows that CoS synthesized at 200°C is slightly sulfur rich, whereas CoS synthesized at 260°C is slightly cobalt rich. The effect of off-stoichiometry of CoS nanoplatelets on the energy gener-ation and storage applications was studied. The oxygen evolution reaction catalytic performance of both samples indicate overpotentials of 307 and 276 mV as well as Tafel slopes of 96 and 82 mV/dec, respectively. Similarly, overpotentials of 132 and 153 mV were observed for the hydrogen evolution reaction, with Tafel slopes of 159 and 154 mV/dec, respectively. The capacitive behavior of the samples was also examined, and specific capacitance values of 298 and 440 F/g were obtained with cycling stabilities of 73 and 97 %, after 5000 cycles, respectively. The results indicate that sulfur-deficient CoS can show superior performance for efficient energy generation and storage devices.[a] C.

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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 synthesis and structural characterization of ruthenium complexes supported by 2-(2-pyridyl)benzoazole ligands and their evaluation as catalysts in the transfer hydrogenation of ketones are reported. Reactions of 2-(2-pyridyl)benzoimidazole (L1), 2-(2-pyridyl)benzothiazole (L2) and 2-(2-pyridyl)benzoxazole (L3) with RuCl3·3H2O produced the corresponding complexes [RuCl3(L1)] (1), [RuCl3(L2)] (2) and [RuCl3(L3)] (3), respectively. Similarly, treatment of L1-L3 with RuCl2(PPh3)2 afforded the corresponding Ru(II) complexes [RuCl2(PPh3)2(L1)] (4), [RuCl2(PPh3)2(L2)] (5) and [RuCl2(PPh3)2(L3)] (6), respectively. Solid state structures of 1 and 2 confirmed the bidentate coordination mode of L1 and L2 to ruthenium. (31)P{(1)H} NMR spectroscopy revealed coordination of two PPh3 ligands trans to each other in an octahedral environment in 4-6 as confirmed by the solid state structure of 6. Complexes 1-6 produced active catalysts in the transfer hydrogenation of ketones in 2-propanol at 82 °C. Ruthenium(II) complexes 4-6, containing the PPh3 ligand, exhibited higher catalytic activities than the corresponding ruthenium(III) compounds 1-3. Complexes 1 and 4 of L1 were more active than the corresponding complexes of L2 and L3. Density functional theoretical calculations showed that dipole moments of 1-6 control their catalytic activities.

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Reductions of imine compounds 2-methoxy-N-(1-(pyridin-2-yl)ethylidene)ethanamine (L1), 2-methoxy-N-((pyridin-2-yl)methylene)ethanamine (L2), N,N-diethyl-N-((pyridin-2-yl)methylene)ethane-1,2-diamine (L3) and 2-((pyridin-2-yl)methyleneamino)ethanol (L4) using NABH4 produced their corresponding amine analogues N-(2-methoxyethyl)-1-(pyridin-2-yl)ethanamine (L1a), 2-methoxy-N-((pyridin-2-yl)methyl)-ethanamine (L2a), N,N-diethyl-N-((pyridin-2-yl)methyl)ethane-1,2-diamine (L3a) and 2-((pyridin-2-yl)methylamino)ethanol (L4a) in good yields. Reactions of the (amino)pyridine ligands L1a–L4a with [NiBr2(DME)] afforded nickel(II) complexes, [NiBr2(L1a)2] (1), [NiBr2(L2a)2] (2), [NiBr2(L3a)2] (3) and [NiBr2(L4a)2] (4), respectively in quantitative yields. Molecular structures of complexes 2 and 4 confirmed the formation of the bis(chelated)nickel(II) complexes. Activation of complexes 1–4 with either EtAlCl2 or methylaluminoxane (MAO), produced active ethylene oligomerization catalysts to afford mostly ethylene dimers (C4), in addition to trimmers (C6) and tetramers (C8). Density functional theory studies provided valuable insight into the reactivity trends and influence of complex structure on the ethylene oligomerization reactions.

A series of single-chained N-acyl tyrosine surfactants with varying chain lengths (C 10 -C 18 ) and degree of unsaturation, as well as an N-acyl Gemini tyrosine surfactant with chain length C 12 , were synthesized, and the structures were confirmed using spectral analysis. The effect of chain length and level of unsaturation on the physicochemical and antibacterial properties of the N-acyl tyrosine surfactants was evaluated. The C 12 derivative displayed the optimum antibacterial activity among the single chain surfactants, and the presence of double bond in the oleoyl derivative enhanced the antibacterial activity over its saturated analogue. The N-acyl Gemini surfactant displayed the highest antibacterial activity among the series and also showed greater micelle forming ability than its single chain analogue. Mixed micellar behavior of the N-acyl Gemini surfactant with conventional cationic (CTAB) and anionic (SDS) surfactants in aqueous solution was studied. The negative value of the interaction parameter β 12 observed for the N-acyl Gemini in binary mixture with CTAB surfactant indicated a synergistic interaction within the mixed micellar system. However, the binary mixture with SDS displayed antagonistic behavior. The binary mixture of N-acyl Gemini surfactant with CTAB displayed better antibacterial activity and foaming properties than with SDS mixtures. Optimum antibacterial activity was observed for N-acyl Gemini surfactant with mole ratio 0.4 to 0.6 in the CTAB binary mixture, at which the lowest ocular irritation index was observed. Overall, the study showed that the Gemini surfactant in combination with the conventional surfactant CTAB can be used as potential ingredients in detergent and pharmaceutical formulations. FIGURE 7 Variation of CMC with mole fraction of surfactant 8 in (A) SDS and (B) CTAB mixed systems. CMC indicates critical micelle concentration; CTAB, cetyl trimethyl ammonium bromide; SDS, sodium dodecyl sulfate JOONDAN ET AL.