Metal-Based Catalytic Drug Development for Next-Generation Cancer Therapy

Considering the high increase in mortality caused by cancer in recent years, cancer drugs with novel mechanisms of anticancer action are urgently needed to overcome the drawbacks of platinum-based chemotherapeutics. Recently, in the area of metal-based cancer drug development research, the concept of catalytic cancer drugs has been introduced with organometallic Ru^II, Os^II, Rh^III and Ir^III complexes. These complexes are reported as catalysts for many important biological transformations in cancer cells such as nicotinamide adenine dinucleotide (NAD(P)H) oxidation to NAD⁺, reduction of NAD⁺ to NADH, and reduction of pyruvate to lactate. These unnatural intracellular transformations with catalytic and nontoxic doses of metal complexes are known to severely perturb several important biochemical pathways and could be the antecedent of next-generation catalytic cancer drug development. In this concept, we delineate the prospects of such recently reported organometallic Ru^II, Os^II, Rh^III and Ir^III complexes as future catalytic cancer drugs. This new approach has the potential to deliver new cancer drug candidates.     

Reductively Induced Catalytic DNA Cleavage of Water Soluble Rh<Superscript>III</Superscript>-Br<Subscript>8</Subscript>TMPyP

Abstract  

The Rh^III(Br₈TMPyP)⁵⁺ showed a catalytic DNA cleavage in the presence of ascorbic acid. The UV–visible, Cyclic Votlammetric (CV) and Electron Spin Resonance (ESR) data confirmed involvement of the reduced form of the Rh^III-Br₈TMPyP, Rh^III(Br₈TMPyP)^4+· radical, in the catalytic cycle. Gel-electrophoresis, results revealed that, Rh^III(Br₈TMPyP)⁵⁺ could cleave DNA at 0.01–0.1 μM levels which is significantly higher than that of other metalloporphyrins.     

N‐Alkylation of Amines with Alcohols Catalyzed by a Water‐Soluble Cp*Iridium Complex: An Efficient Method for the Synthesis of Amines in Aqueous Media

An efficient and environmentally benign catalytic system for the synthesis of various organic amines catalyzed by the water‐soluble and air‐stable (pentamethylcyclopentadienyl)‐iridium‐ammine iod‐ ide complex, [Cp*Ir(NH₃)₃][I]₂ (Cp*=pentamethylcyclopentadienyl), has been developed. A wide variety of secondary and tertiary amines were synthesized by the N‐alkylation reactions of theoretical equivalents of amines with alcohols in water under air without a base. The synthesis of cyclic amines was also achieved by the N‐alkylation of benzylamine with diols. Furthermore, the recycle use of the present water‐soluble Cp*Ir catalyst was accomplished.     

Photooxidation Products of Ethanol During Photoelectrochemical Operation Using a Nanocrystalline Titania Anode and a Two Compartment Chemically Biased Cell

ZnMe^IIIFeO₄ catalysts with different trivalent metal (Me^III = Fe, Al, Cr, Mn, and Co) were prepared by a co-precipitation method, and were applied to the oxidative dehydrogenation of n-butene to 1,3-butadiene. Successful formation of ZnMe^IIIFeO₄ catalysts was confirmed by XRD and ICP-AES analyses. Catalytic performance of ZnMe^IIIFeO₄ catalysts in the oxidative dehydrogenation of n-butene strongly depended on the identity of trivalent metal (Me^III). Acid properties of ZnMe^IIIFeO₄ catalysts were measured by NH₃-TPD experiments, with an aim of correlating the catalytic performance with the surface acid property of the catalysts. It was revealed that yield for 1,3-butadiene increased with increasing surface weak-acid density of ZnMe^IIIFeO₄ catalyst. Among the catalysts tested, ZnFeFeO₄ catalyst with the largest surface weak-acid density showed the best catalytic performance in the oxidative dehydrogenation of n-butene.     

A kinetic study of novel bimetallic titanocene catalyst for syndiospecific styrene polymerization

A kinetic study of a syndiospecific polymerization was performed with two kinds of catalysts: Cp*Ti(O(C₆H₄)CMe₂(C₆H₄)O)TiCp* [bimetallic system] and Cp*Ti(OMe)₃ [monometallic system]. The purpose of this study was to determine the reasons behind the high activity of a bimetallic catalyst system. The active site structures of the two kinds of catalysts appears to be similar to the cationic Ti [III] species having η⁵‐pentamethylcyclopentadienyl ligand, while the rate of the activation process of the bimetallic catalyst was found to be higher than that of the monometallic catalyst. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Synthesis and Structure of New Dimeric Cyclopentadienyl Titanium Fluorine–Oxygen Systems: [Cp*TiF(μ-F)(μ-OPOPh2)]2, [Cp*TiF(μ-F)(μ-OSO2-p-C6H4Me)]2 and [Cp*TiF2(μ-OMe)]2

The reactions of Cp*TiF₃ with Me₃SiOPOPh₂, Me₃SiOSO₂-p-C₆H₄Me, and Al(OMe)₃ resulted in the formation of the dimers [Cp*TiF(μ-F)(μ-OPOPh₂)]₂ 1 , [Cp*TiF(μ-F)(μ-OSO₂-p-C₆H₄Me)]₂ 2 , and [Cp*TiF₂(μ-OMe)]₂ 3 , respectively, in good yields. In contrast to the formation of 3 , Cp*TiF₃ reacts with Al(OH)₃ to afford the known tetramer [Cp*TiF(μ-O)]₄ 4 . The structures of 1–3 have been determined by X-ray crystallography; compounds 1 and 3 crystallize in the monoclinic space group P2₁/c and compound 2 in the monoclinic space group P2/n. Compound 1 is the first example of a dimeric Cp*-titanium phosphinate containing a fluorine ligand. The core of the dimeric structure of both 1 and 2 consists of two Ti atoms bridged by two fluorine atoms and two bidentate groups. In contrast, the dimeric structure of 3 consists of two Ti atoms bridged only by two methoxy groups. An equilibrium of isomers of 1 and 2 has been observed in solution by ¹H and ¹⁹F NMR. The ¹⁹F NMR spectra of 1–3 are discussed in detail.     

Polymerization of vinyl chloride with butyllithiums and metallocene catalysts

Polymerizations of vinyl chloride (VC) with butyllithium (BuLi) and metallocene catalysts were investigated. In the polymerization of VC with BuLi, the activity for polymerization decreased in the following order; t‐BuLi > n‐BuLi > s‐BuLi. A polymer controlled structurally in the main chain was found to be synthesized from the polymerization of VC with BuLi. The molecular weights of polymers obtained in bulk polymerization were higher than those of polymers obtained in solution. A linear relationship of the M_n of the polymer and the polymer yields was observed. The M_w/M_n of the polymer did not change significantly during polymerization, although the M_w/M_n was around 2. Thermal stability of the polymer obtained with BuLi was higher than that of polymer obtained with radical initiators, as determined by TGA measurements. In the polymerization of VC with Cp*TiX₃/MAO (X: Cl and OCH₃) catalysts, polymers were obtained with both catalysts, although the rate of polymerization was slow. The Cp*Ti(OCH₃)₃//MAO catalyst in CH₂Cl₂ gave higher‐molecular‐weight polymers in a better yield than in toluene. From elemental analysis and the NMR spectra of the polymers, the Cp*Ti(OCH₃)₃/MAO catalyst gave polymers consisting of repeating regular head‐to‐tail units, in contrast to the Cp*TiCl₃/MAO catalyst, which gave polymers having anomalous units.     

FTIR study of the rearrangement of adsorbed CO species on Al2O3-supported rhodium catalysts

The adsorption of CO at low temperatures (130–293 K) has been investigated on Rh/Al₂O₃ catalysts of low (0.001–1 wt%) Rh loadings by means of Fourier transform infrared spectroscopy. The surface structure of Rh produced at different reduction temperatures (573 and 1173 K) was shock-cooled to 130 K, where the addition of CO caused the appearance of the band due to bridge-bonded CO ((Rh⁰)₂–CO) on all samples. The appearance of the bands due to gem-dicarbonyl (Rh⁺(CO)₂) and linearly bonded CO (Rh_x–CO) depended on the Rh content and the reduction temperature of the catalysts. The positions and the integrated absorbances of the symmetric and asymmetric stretchings of the Rh⁺(CO)₂ changed with temperature. On the basis of the above findings the rearrangement of the adsorbed CO species (indirectly that of surface Rh) is discussed. This revised version was published online in July 2006 with corrections to the Cover Date.     

First-Generation Bispidine Chelators for 213BiIII Radiopharmaceutical Applications

Hepta- and octadentate bispidines (3,7-diazabicyclo[3.3.1]nonane, diaza-adamantane) with acetate, methyl-pyridine, and methyl-picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate Bi^III coordination chemistry. Crystal structure and solution spectroscopic data (NMR spectroscopy and mass spectrometry) confirm that the rigid and relatively large bispidine cavity with an axially distorted geometry is well suited for Bi^III and in all cases forms nine-coordinate complexes; this is supported by an established hole size and shape analysis. It follows that nonadentate bispidines probably will be more suited as bifunctional chelators for ²¹³Bi^III-based radiopharmaceuticals. However, two isomeric picolinate-/acetate-based heptadentate ligands already show very efficient complexation kinetics with ²¹³Bi^III at ambient temperature and kinetic stability that is comparable with the standard ligands used in this field. The experimentally determined hydrophilicities (log D_7.4 values) show that the Bi^III complexes reported are relatively hydrophilic and well suited for medicinal applications. We also present a very efficient and relatively accurate method to compute charge distributions and hydrophilicities, and this will help to further optimize the systems reported here.     

Recyclable plant tannin‐chelated Rh(III) complex catalysts for aqueous–organic biphasic hydrogenation of quinoline

BACKGROUND: Synthetic ligands have conventionally been used for the preparation of homogenous Rh complex catalyst but biomass has rarely been utilized for this purpose. In the present investigation, plant tannins (natural polyphenols) were used as water‐soluble ligands for the preparation of homogenous Rh³⁺ complex catalysts. RESULTS: Based on X‐ray photoelectron spectroscopy (XPS) and proton nuclear magnetic resonance (HNMR) analyses, the preparation mechanism of these complex catalysts was proven to involve chelating interactions between Rh³⁺ and the adjacent phenolic hydroxyls of plant tannins. As a result, the use of plant tannin promoted aqueous‐organic biphasic interactions and the plant tannin‐chelated Rh³⁺ complex catalysts exhibited much higher catalytic activity than commercial Rh complex catalysts in the biphasic hydrogenation of quinoline. Furthermore, the plant tannin‐chelated Rh³⁺ complex can be reused three times without significant loss of catalytic activity CONCLUSION: Our experimental results suggested that black wattle tannin (BWT) can be used as water‐soluble ligands for the preparation of highly active and recyclable Rh³⁺ complex catalysts. Copyright © 2012 Society of Chemical Industry     

Ruthenium(II)‐Catalyzed Regioselective Synthesis of Allyl Ketones from Alkynes and their Silver(I)‐Catalyzed Hydroarylation into γ‐Functionalized Ketones

The regioselective synthesis of β,γ‐unsaturated ketones from terminal alkynes is achieved by cooperative action of tris(acetonitrile)pentamethylcyclopentadieneruthenium hexafluorophosphate [Cp*Ru(NCMe)₃⁺ PF₆⁻] and para‐toluenesulfonic acid catalysts. These allyl ketones undergo direct regioselective hydroarylation/Friedel–Crafts reaction to introduce an electron‐rich aryl group at the γ‐position in the presence of ligand‐free silver triflate (AgOTf) catalyst. Both catalytic reactions take place with atom economy and provide an alternative to the synthesis of a variety of allyl ketones and γ‐arylated ketones.     

Directed Divergent Evolution of a Thermostable D‐Tagatose Epimerase towards Improved Activity for Two Hexose Substrates

Functional promiscuity of enzymes can often be harnessed as the starting point for the directed evolution of novel biocatalysts. Here we describe the divergent morphing of an engineered thermostable variant (Var8) of a promiscuous D ‐tagatose epimerase (DTE) into two efficient catalysts for the C3 epimerization of D ‐fructose to D ‐psicose and of L ‐sorbose to L ‐tagatose. Iterative single‐site randomization and screening of 48 residues in the first and second shells around the substrate‐binding site of Var8 yielded the eight‐site mutant IDF8 (ninefold improved k_cat for the epimerization of D ‐fructose) and the six‐site mutant ILS6 (14‐fold improved epimerization of L ‐sorbose), compared to Var8. Structure analysis of IDF8 revealed a charged patch at the entrance of its active site; this presumably facilitates entry of the polar substrate. The improvement in catalytic activity of variant ILS6 is thought to relate to subtle changes in the hydration of the bound substrate. The structures can now be used to select additional sites for further directed evolution of the ketohexose epimerase.     

Synthesis and characterization of polybutadiene with monotitanocene/methylaluminoxane catalyst

Butadiene was polymerized using a monotitanocene complex of η⁵‐pentamethylcyclopentadienyltribenzyloxy titanium [Cp*Ti(OBz)₃] in the presence of four types of modified methylaluminoxanes (mMAO), which contained different amounts of residual trimethylaluminum (TMA). The titanium oxidation states in Cp*Ti(OBz)₃/mMAO and Cp*Ti(OBz)₃/mMAO/triisobutylaluminum (TIBA) catalytic systems were determined by redox titration method. The effects of various oxidation states of titanium active species on butadiene polymerization were investigated. It was found that Ti(III) active species is more effective for preparing polybutadiene with high molecular weight. The addition of TIBA to the Cp*Ti(OBz)₃/mMAO system could reduce a greater number of Ti(IV) complexes to Ti(III) species and lead to significant increases of polymerization activity and molecular weight of polymer, whereas the polybutadiene microstructure was only slightly changed. On the basis of microstructure and property characterization by FTIR, ¹³C‐NMR, DSC, and WAXD, all resultant polymers were proved to be amorphous polybutadiene with mixed 1,2; cis‐1,4; and trans‐1,4 structures. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 2494–2500, 2004     

Directed Evolution of an Enantioselective Enoate‐Reductase: Testing the Utility of Iterative Saturation Mutagenesis

Directed evolution utilizing iterative saturation mutagenesis (ISM) has been applied to the old yellow enzyme homologue YqjM in the quest to broaden its substrate scope, while controlling the enantioselectivity in the bioreduction of a set of substituted cyclopentenone and cyclohexenone derivatives. Guided by the known crystal structure of YqjM, 20 residues were selected as sites for saturation mutagenesis, a pooling strategy based on the method of Phizicky [M. R. Martzen, S. M. McCraith, S. L. Spinelli, F. M. Torres, S. Fields, E. J. Grayhack, E. M. Phizicky, Science 1999 , 286, 1153–1155] being used in the GC screening process. The genes of some of the hits were subsequently employed as templates for randomization experiments at the other putative hot spots. Both (R)‐ and (S)‐selective variants were evolved using 3‐methylcyclohexenone as the model substrate in the asymmetric bioreduction of the olefinic functionality, only small mutant libraries and thus minimal screening effort being necessary. Some of the best mutants also proved to be excellent catalysts when testing other prochiral substrates without resorting to additional mutagenesis/screening experiments. Thus, the results constitute an important step forward in generalizing the utility of ISM as an efficient method in laboratory evolution of enzymes as catalysts in organic chemistry.     

Incorporation of Core‐Twisted Perylene Bisimide Ligands into a Discrete Cp*Rh‐Based Molecular‐Rectangle via Coordination‐Driven Self‐Assembly

A tetranuclear metallarectangle ( 2 ) derived from dinuclear rhodium(III) building block [Cp*₂Rh₂(μ‐η²‐η²‐C₂O₄)]Cl₂ and imidazole‐based perylene bisimide ditopic ligand ( 1 ) ( 1= 2,9‐bis(4‐(1H‐imidazol‐1‐yl)phenyl)‐5,6,12,13‐tetrachloroanthra‐[2,1,9‐def:6,5,10‐d′e′f′]diisoquinoline‐1,3,8,10(2H,9H)‐tetraone) in presence of silver triflate is reported. The self‐assembled metallarectangle 2 is fully characterized by NMR, ESI‐MS, UV‐vis absorption, fluorescence emission spectroscopy and cyclic voltammetry. The X‐ray diffraction analysis reveals a twisted conformational geometry of metallarectangle 2 caused by essential steric demands of the two side‐by‐side chlorine atoms. In addition, the analyzed structure also elaborates the intermolecular electrostatic interactions between the electron‐deficient diimide moiety of 2 and the electron‐rich planar phenanthrene molecule.     

A potential antitumor drug (arginine deiminase) reengineered for efficient operation under physiological conditions

Arginine deiminase (ADI, EC 3.5.3.6) is a potential antitumor drug for the treatment of arginine‐auxotrophic tumors such as hepatocellular carcinomas (HCCs) and melanomas, and studies on human lymphatic leukemia cell lines have confirmed that ADI has antiangiogenic activity. Recent studies showed that a combination of taxane and ADI‐PEG20, which induces caspase‐independent apoptosis, is more effective than taxane monotherapy for prostate cancer. The main limitation of ADI from Pseudomonas plecoglossicida (PpADI) and of many other ADI enzymes lies in their pH‐dependent activity profile. PpADI has a pH optimum at 6.5 and a pH shift from 6.5 to 7.5 results in an ～80 % activity drop (the pH of human plasma is 7.35 to 7.45). In 2010, we reported a proof of concept for ADI engineering by directed evolution that resulted in variant M2 (K5T/D44E/H404R). M2 has a pH optimum of pH 7.0, a fourfold higher k_cat value than the wild‐type PpADI (pH 7.4, 0.5 M phosphate buffer), and an increased K_m value for substrate arginine. In our latest work, variants M5 (K5T/D38H/D44E/A128T/H404R) and M6 (K5T/D38H/D44E/A128T/E296K/H404R) were generated by directed evolution by employing PBS buffer (pH 7.4), which mimics physiological conditions. The S_0.5 value of parent M3 (K5T/D44E/A128T/H404R) decreased from 2.01 to 1.48 mM (M5) and 0.81 mM (M6). The S_0.5 value of M6 (0.81 mM ) is lower than that of wild‐type PpADI (1.30 mM ); the k_cat values improved from 0.18 s^?1 (wild‐type PpADI) to 17.56 s^?1 (M5, 97.6‐fold) and 11.64 s^?1 (M6, 64.7‐fold).     

Biomimetic Synthesis of a Water‐Soluble Conducting Polymer of 3,4‐Ethylene‐dioxythiophene

A novel biomimetic route for the synthesis of a water‐soluble poly(3,4‐ethylenedioxithiophene) (PEDT) in the presence of poly(styrene sulfonate) (PSS) and using iron(III)‐tetra(p‐sulfonatophenyl)porphyrin (Fe^IIITSPP), cobalt(III)‐tetra(p‐sulfonatophenyl)porphyrin (Co^IIITSPP), manganese(III)‐tetra(p‐sulfonatophenyl)porphyrin (Mn^IIITSPP), and copper(II)‐tetra(p‐sulfonatophenyl)porphyrin (Cu^IITSPP) as effective catalysts is presented. The reactions were performed with different monomer, catalyst, template, and initiator concentrations. The absorbance of the polaron bands at various pH values indicated pH 2 as the best condition for polymerization. Precipitation or salting out was highly dependent on the mentioned factors. The formation of PEDT was confirmed by UV‐Vis and FT‐IR spectroscopy. Cyclic voltammetry proved the convenient electroactivity of the synthesized polymer. The presence of PSS that serves as a charge‐compensating dopant provides processability and water solubility and, in addition, a distinct advantage over similar reactions employing native enzymes due to higher stability and lower cost of the catalysts.     

Synthesis of ethylene and norbornene copolymer with metallocene catalysts and characteristic analysis

To synthesis ethylene (E) and norbornene (NB) copolymer with high glass transition temperature and transparency, three metallocene catalysts with different symmetric structure were evaluated, respectively. The catalyst activity, NB fraction in copolymer and the transparency of copolymers produced under various conditions were investigated. It has been found that C₂ symmetric catalyst such as rac‐[En(Ind)₂]ZrCl₂ was the best choice to produce copolymer with high NB fraction while keeping high catalyst activity. Furthermore, the effects of reaction conditions on activity of rac‐[En(Ind)₂]ZrCl₂ and the resultant copolymer structure have also been thoroughly studied. The results indicate that increasing the NB/E ratio is the effective way to increase NB content of copolymer when NB/E ratio is less than 20. However, when NB/E ratio is over 20, further increase in NB/E ratio will lead to significant lower catalyst activity and very limited increase in NB content of copolymer. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Syndiospecific polymerization of styrene catalyzed by half-titanocene catalysts

Those effective catalyst precursors for syndiotactic styrene polymerization, Cp*Ti(OCH₂-CHCH₂)₃ (I), Cp*Ti(OCH₂-CHCHC₆H₄)₃ (II), Cp*Ti(OCH₂C₆H₅)₃ (III), Cp*Ti(OCH₂C₆H₄OCH₃)₃ (IV) were synthesized, and the influence of catalyst ligands on the catalytic activity and properties of polymer were investigated. The polymer thus obtained coupled with higher molecular weight and higher syndiotacticity determined by GPC and ¹³C NMR as well as solvent extraction manners, respectively. Those catalysts promoted by methyaluminoxane (MAO) as cocatalyst exhibited higher catalytic activity. Of all catalysts mentioned foregoing, Cp*Ti(OCH₂-CHCHC₆H₄)₃ (II), Cp*Ti(OCH₂C₆H₅)₃/MAO (III) and Cp*Ti(OCH₂C₆H₄OCH₃)₃ (IV) catalysts showed higher activity and stability even at fairly low Al/Ti ratio of 600, and possessed excellent control of the stereoregular insertion of monomer, exhibited a significant increase of the ratio of the propagation rates to chain transfer termination. The kinetic and titration results also indicated that those metallocene catalysts (II), (III), and (IV) showed higher catalytic activity and produced polymer with higher molecular weight, because of a great number of active species, and lower ratio of Kβtr/Kp, higher ratio of Kβtr/Ktrs which indicate that β-H elimination was predominant.     

Binuclear rhodium(III) and iridium(III) monoselenocarboxylates: Synthesis,spectroscopy and structure of an ortho-metallated iridium complex featuring an IrCCC(μ-Se) chelate ring

Monoselenocarboxylate–bridged binuclear complexes of Rh^III and Ir^III, [(Cp1MCl)₂(μ-SeCOAr)₂] (1) (M = Rh or Ir; Cp1 = pentamethylcyclopentadienyl; Ar = Ph, C₆H₄Me–4), have been isolated either by the reaction between [Cp1₂M₂(μ-Cl)₂Cl₂] with KSeCOAr in acetonitrile or by treatment of [Cp1MCl(solvent)₂][PF₆] with KSeCOAr in acetone. The novel binuclear complexes, [Cp1IrCl(μ-SeCOAr)(κ²-SeCOC₆H₃R–)IrCp1] (2) (R = H or Me-4) with ortho-metallation at one of the iridium centres have been isolated following the use of excess AgPF₆. The single crystal structure of [Cp1IrCl(μ-SeCOC₆H₅)(κ²-SeCOC₆H₄–)IrCp1] (2a) exhibits two phenylcarboselenolate moieties situated in syn fashion with respect to the “Ir₂Se₂” plane, one of which leans towards the metal centre in order to undergo ortho-metallation after iridium–chlorine bond dissociation.