Ruthenium half-sandwich complexes as protein kinase inhibitors: an N-succinimidyl ester for rapid derivatizations of the cyclopentadienyl moiety

Cyclopentadienyl half-sandwich ruthenium complexes have been demonstrated to be promising scaffolds as protein kinase inhibitors. In order to rapidly identify derivatives which display modified pharmacological properties, we developed the synthesis of an organoruthenium compound bearing an N-succinimidyl ester at the cyclopentadienyl moiety. The quenching of this activated ester with a library of primary amines, followed by testing of the resulting amide library, led to the identification of organometallic Pim-1 and GSK-3 inhibitors with improved potencies and kinase selectivities. [structure: see text].     

我国生物无机化学的发展

叙述了生物无机在我国的发展。着重从金属离子及其配合物与生物大分子的作用、药物中的金属及抗癌活性配合物的作用机理、稀土元素生物无机化学、金属离子与细胞的作用、金属蛋白与金属酶、生物矿化、环境生物无机化学等七个方面综述了我国已取得的进展和成绩。     

Mono‐ and Dinuclear Phosphorescent Rhenium(I) Complexes: Impact of Subcellular Localization on Anticancer Mechanisms

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes ( Re1 and Re2 ), along with their corresponding dinuclear complexes ( Re3 and Re4 ), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1–Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase‐independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase‐independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes.     

Transition metal complexes of 6‐mercaptopurine: Characterization,Theoretical calculation,DNA‐Binding,molecular docking,and anticancer activity

6‐mercaptopurine (6‐MP) is used for treating various cancers and autoimmune disorders. A few examples of transition metal complexes of 6‐MP have been shown to enhance its anticancer activity, but many remain untested. We isolated five highly stable and colored metal complexes of 6‐MP and confirmed their structures by elemental analysis, spectral, and thermal techniques. Infrared (IR) spectra revealed that 6‐MP is a bidentate ligand that interacts through sulfur and pyrimidine nitrogen in a 1:2 (M:L) molar ratio. The magnetic susceptibility and electron paramagnetic resonance (EPR) spectra for the Cu(II) complex revealed an octahedral arrangement around the metal ion with strong covalent bonding. The fully optimized geometries of the metal structures obtained using density function theory (DFT)/B3LYP calculations were used to verify the structural and biological features. DNA titration revealed that the octahedral Cu(II) complex has a critical binding constant value of K_b = 8 × 105. Docking studies using three different cancer protein receptors were used to predict the biological applications of the synthesized drug‐metal complexes. Finally, cytotoxicity assays against a myeloma cancer cell line (MM) and a colon cancer cell line (Caco‐2) revealed favorable anticancer activity for the copper complex, exceeding that of the gold‐standard chemotherapeutic cisplatin.     

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.     

Complete assignments of NMR data of salens and their cobalt (III) complexes

Salens, derived from 1,2‐ethylenediamine and salicylaldehydes, have been widely used as ligands for metal complexes which have been showing enormous potential in chemical properties of asymmetric catalysts as well as biological properties such as anticancer agents. Almost all of the salen–metal complexes with their corresponding metal (II)‐complexes show the evidences of chelation of two oxygens in salens. However, several metal (II) complexes, especially cobalt (II) complexes, could not show NMR spectra due to their paramagnetism. Recently, it has been reported that one of the cobalt (III) complexes was used for NMR spectroscopy to evaluate its stereoselectivity as a catalyst. Even though many salen ligands are known, their NMR data are not assigned completely. It was possible that modification in northern part of salen with 2‐hydroxyphenyl group afforded another oxygen chelation site in salen ligand. Here we report that synthesis and full NMR assignment of new salen ligands, which form meso 1,2‐bis(2‐hydroxyphenyl)ethylenediamine) and their cobalt (III) complexes. The assignments of ¹H and ¹³C NMR data obtained in this experiment can help us to predict the NMR data of other salen ligands. Copyright © 2008 John Wiley & Sons, Ltd.     

Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60

Identification of the molecular target(s) of anticancer metal complexes is a formidable challenge since most of them are unstable toward ligand exchange reaction(s) or biological reduction under physiological conditions. Gold(III) meso‐tetraphenylporphyrin ( gold‐1 a ) is notable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities. Herein, extensive chemical biology approaches employing photo‐affinity labeling, click chemistry, chemical proteomics, cellular thermal shift, saturation‐transfer difference NMR, protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat‐shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of gold‐1 a in vitro and in cells. Structure–activity studies with a panel of non‐porphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand.     

6-氮杂吲唑类Pim-1激酶抑制剂的3D-QSAR、药效团模型研究和分子设计

Pim-1 激酶通过作用于多种信号通路或靶点影响肿瘤的发生发展,近年来被认为是肿瘤治疗的良好靶标。本文采用SYBYL-X2. 1. 1软件中的TopomerCoMFA、GALAHAD模块建立计算机模型,研究39个基于6-氮杂吲唑环的Pim-1激酶抑制剂的三维定量构效关系及药效团特征元素。结果显示,TopomerCoMFA建模所得交叉验证系数（q2）和相关系数（r2）分别为0. 756和0. 951,结合外部验证表明此3D-QSAR模型具有较高预测能力及较好的统计学稳定性,同时,用等势图描述了R1、R2基团处立体场、静电场对活性的具体影响。药效团研究结果表明,含氢键受体的芳香杂环母核结构,以及侧链取代基中含有芳香杂环结构对化合物的活性贡献较大。最后根据上述模型信息新设计了15个Pim-1激酶抑制剂分子并完成活性预测及分子对接模式研究,其中4个分子的预测pIC50高于建模分子中活性最好的化合物17,Surflex-Dock分析显示新设计分子均与Pim-1激酶形成较强氢键相互作用。基于6-氮杂吲唑环的Pim-1激酶抑制剂的3D-QSAR模型以及药效团模型可用于指导新型抑制剂的结构优化,为设计和开发具有较高活性的新型Pim-1激酶抑制剂提供有效帮助。     

An Organoruthenium Anticancer Agent Shows Unexpected Target Selectivity For Plectin

Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, using an integrated proteomics-based target-response profiling approach as a potent hypothesis-generating procedure, we found an unexpected target selectivity of a ruthenium(arene) pyridinecarbothioamide (plecstatin) for plectin, a scaffold protein and cytolinker, which was validated in a plectin knock-out model in vitro. Plectin targeting shows potential as a strategy to inhibit tumor invasiveness as shown in cultured tumor spheroids while oral administration of plecstatin-1 to mice reduces tumor growth more efficiently in the invasive B16 melanoma than in the CT26 colon tumor model.     

芳基钌抗癌化合物的研究进展

无机药物化学领域正在快速发展,尤其是有机金属配合物作为癌症的治疗和诊断试剂有很大的潜力.芳基钌配合物中芳基对抗癌活性有重要影响,并能调控配合物金属中心的热力学和动力学性能.配合物的构效关系研究,对进一步合理设计/合成具有潜在药用价值的有机金属配合物至关重要.本文选取钌芳基配合物作为抗癌药物的具体实例进行讨论,重点介绍了多种芳基钌配合物的构效关系及抗癌机理.     

Expanding the utility of proteins as platforms for coordination chemistry

Whether for constructing advanced materials and complex biological devices or for building sophisticated coordination complexes with diverse metal-based functions, proteins are nature's favorite building blocks. Yet, our ability to control the assembly of proteins or to use them as ligand platforms for inorganic chemistry has been somewhat limited. In this review, we highlight our work from the past four years, which has aimed to exploit the utility of a protein scaffold in both regards. First, by considering proteins as “simple” ligand platforms and controlling the metal coordination chemistry on their surfaces, we show how their self-assembly can be readily dictated by metal binding. Second, we show how metal-mediated protein self-assembly leads to novel metal centers buried within protein interfaces. While on one hand our studies have pointed out the challenges of using proteins as ligands, they have also revealed how the extensive, chemically-rich protein surfaces can be exploited to form a network of covalent and non-covalent interactions around interfacial metal centers, providing a powerful handle to control their coordination chemistry.     

A Multitargeted Approach: Organorhodium Anticancer Agent Based on Vorinostat as a Potent Histone Deacetylase Inhibitor

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2‐pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.     

Organometallic ruthenium and iridium phosphorus complexes: Synthesis,cellular imaging,organelle targeting and anticancer applications

The use of metal complexes containing phosphorus ligands as anticancer agents has not been well studied. In this work, eight novel half‐sandwich Ir^III and Ru^II compounds with P^P‐chelating ligands have been synthesized and fully characterized, and alongside two crystal structures were reported. All eight complexes displayed highly potent antiproliferative activity, up to nine times more potent than the clinical anticancer drug cisplatin towards A549 lung cancer cells. Complex Ir1 , which has a simpler structure and highly potent antiproliferative activity, was selected to investigate in further mechanistic studies. No hydrolysis and nucleobase binding occurred for complex Ir1 . In order to elucidate subcellular localization, the self‐luminescence of the complex Ir1 was utilized. Ir1 can specifically target lysosomes and facilitate excessive production of reactive oxygen species, resulting in lysosomal membrane permeabilization in A549 cells. Release of cathepsin B and changes in the mitochondria membrane potential also contributed to the observed cytotoxicity of Ir1 , which demonstrated an anticancer action mechanism that was different from that of cisplatin. The favorable results from biological and chemical research demonstrated that these types of complexes hold significant theranostic potential.     

Harnessing chemoselective imine ligation for tethering bioactive molecules to platinum(IV) prodrugs

Platinum(II) anticancer drugs are among the most effective and often used chemotherapeutic drugs. In recent years, there has been increasing interest in exploiting inert platinum(IV) scaffolds as a prodrug strategy to mitigate the limitations of platinum(II) anticancer complexes. In this prodrug strategy, the axial ligands are released concomitantly upon intracellular reduction to the active platinum(II) congener, offering the possibility of conjugating bioactive co-drugs which may synergistically enhance cytotoxicity on cancer cells. Existing techniques of tethering bioactive molecules to the axial positions of platinum(IV) prodrugs suffer from limited scope, poor yields and low reliability. This report explores the applications of current chemoselective ligation chemistries to platinum(IV) anticancer complexes with the aim of addressing the aforementioned limitations. Here, we describe the synthesis of a platinum(IV) complex bearing an aromatic aldehyde functionality and explored the scope of imine ligation with various hydrazide and aminooxy functionalized substrates. As a proof of concept, we tethered a six sequence long peptide mimetic (AMVSEF) of the anti-inflammatory protein, ANXA1.     

New nanobidentate Schiff base ligand of 2-aminophenol with 2-acetyl ferrocene with some lanthanide metal ions: synthesis,characterization and Hepatitis A,B, C and breast cancer docking studies

Three lanthanide complexes (La(III), Er(III), and Yb(III)) derived from ferrocene-based Schiff base ligand (HL) were synthesized from condensation of 2-aminophenol with 2-acetylferrocene. The ligand and metal complexes were characterized based on elemental analyses, IR, ¹H NMR, molar conductance, SEM and thermal analyses (TG, DTG). The molar conductance revealed that all the metal chelates were electrolytes having the general composition [M(L)(Cl)(H₂O)₃]Cl·4H₂O. HL and its complexes were screened for their antibacterial and antifungal activity by agar diffusion method. The results of these studies showed that the metal complexes are more effective antibacterial and antifungal agents as compared with the free ligand. The anticancer activity was screened against human breast cancer cell line (MCF-7). Results indicated that metal complexes showed an increased cytotoxicity in proliferation to cell lines as compared to free ligand. Molecular docking studies were performed to identify the binding orientation or conformation of a complex in the active site of the protein. HL and its complexes were docked with crystal structure of DDB1 of breast cancer, crystal structure of HCV, RNA-dependent RNA polymerase, receptors of HBV core protein, crystal structure of the Fab fragment of anti-HAV.     

Synthesis,anticancer screening,and in silico ADME prediction of novel 2-pyridones as Pim inhibitors

A novel series of 26 substituted N-(2-ethylphenyl)-2-oxo-pyridine-3-carbonitriles have been designed and synthesized via one-pot synthesis of various aromatic aldehydes, different aromatic acetophenones, and 2-cyano-N-(2-ethylphenyl)acetamide 1 . Moreover, cytotoxicity of the target compounds was evaluated by NCI, which selected 14 compounds for one-dose screening. Among them, compound 21 was selected for five-dose screening, which confirmed its potency against most of cancer cell lines. This compound elicited selectivity profile against human cell line WI-38. Cell cycle analysis was carried out, revealed that compound 21 is an apoptosis inducer causing cell cycle arrest at G2/M. Further exploration on the mode of action by evaluating its effect against Pim-1, Pim-2, and Pim-3 demonstrated its inhibitory effect on Pim-1 and Pim-3 rather than Pim-2. Molecular docking showed that compound 21 binds with high affinity to the active site of Pim-1 enzyme through three hydrogen bonds and two arene-H bonds.     

Potent Anticancer Activity and Possible Low Toxicity of Platinum(II) Complexes with Functionalized 1,1‐Cyclobutanedicarboxylate as a Leaving Ligand

Two platinum(II) complexes, DN603 and DN604, were designed and prepared by using 3‐oxocyclobutane‐1,1‐dicarboxylate as a ligand. The compounds were prepared according to the concept that incorporation of a functionalized moiety in the leaving ligand that did not affect its coordination bonding to the metal atom would play a key role in the anticancer activity of the resulting platinum complex. The newly prepared compounds were found to show potent in vitro anticancer activity comparable to cisplatin and oxaliplatin; especially DN604, which exhibited low acute toxicity similar to carboplatin, and presented acceptable solubility and stability in water. Chemical and biological results indicated that the functionalized moiety, uncoordinated, led to potent anticancer activity and low apparent toxicity of the platinum complexes by affecting the kinetic properties of the compounds.     

Multitargeted Platinum(IV) Anticancer Complexes Bearing Pyridinyl Ligands as Axial Leaving Groups

Although multitargeted Pt^IV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O-donors. Herein, we report the synthesis of Pt^IV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted Pt^IV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt-resistant tumor in vivo. This research adds to the array of synthetic methods for accessing Pt^IV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a Pt^IV center.     

Elaborated spectral,modeling, QSAR,docking, thermal,antimicrobial and anticancer activity studies for new nanosized metal ion complexes derived from sulfamerazine azodye

New azodye ligand (H₂L) and its relative Cr(III)-, Mn(II)-, Fe(III)-, Co(II)-, Ni(II)-, Cu(II)-, Zn(II)- and Cd(II)-nanosized complexes were prepared. A new synthesized compounds were characterized using spectral (mass, IR, UV–Vis, XRD, and ESR) and analytical (elemental, molar conductance, thermal and magnetic moment measurements) tools. Infrared spectra showed that the ligand behaves as a monobasic bidentate, coordinating with central atoms through carbonyl oxygen and α-hydroxyl group. The geometrical structures of Cr(III) and Fe(III) complexes were found to be in octahedral configuration, whereas Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes have tetrahedral forms. XRD patterns reflect an amorphous appearance of all investigated complexes. TEM images showed nanosized particles and identical distribution over the complex surface. Molecular modeling for the drug ligand and its metal ion complexes were performed using Gaussian09 program to assert on their structural formulae. Some essential parameters were extracted using HOMO and LUMO energies. AutoDock tools 4.2 was used to simulate the interaction process with infected cell proteins to expect the experimental pathway. The inhibition activity of drug ligand and its metal ion complexes was evaluated towards different types of bacteria and fungi through in vitro antimicrobial activities. The antitumor activities of all compounds are straightened towards human liver carcinoma (HEPG2) cell lines. Fe(III) and Co(II) complexes exhibited IC₅₀ of 2.90 and 4.23 µg mL^?1, respectively, which means they are more potent anticancer drug than the standard (doxorubicin, IC₅₀ = 4.73 µg mL^?1). Therefore, the two complexes may consider promising anticancer drugs.