The Potent Inhibitory Effect of a Naproxen‐Appended Cobalt(III)‐Cyclam Complex on Cancer Stem Cells

We report the potency against cancer stem cells (CSCs) of a new cobalt(III)‐cyclam complex ( 1 ) that bears the nonsteroidal anti‐inflammatory drug, naproxen. The complex displays selective potency for breast CSC‐enriched HMLER‐shEcad cells over breast CSC‐depleted HMLER cells. Additionally, it inhibited the formation of three‐dimensional tumour‐like mammospheres, and reduced their viability to a greater extent than clinically used breast cancer drugs (vinorelbine, cisplatin and paclitaxel). The anti‐mammosphere potency of 1 was enhanced under hypoxia‐mimicking conditions. Detailed mechanistic studies revealed that DNA damage and cyclooxygenase‐2 (COX‐2) inhibition contribute to the cytotoxic mechanism of 1 . To the best of our knowledge, 1 is the first cobalt‐containing compound to show selective potency for CSCs over bulk cancer cells.     

Screening the structural and functional properties of bicyclo-DNA: bc(ox)-DNA

The synthesis of two novel pyrimidine bicyclonucleosides (bc(ox)-nucleosides) has been accomplished. These bicyclonucleosides each carry a lipophilic benzyloxime substituent on the carbocyclic ring and show improved conformational similarity to 2'-deoxyribonucleosides as shown by their X-ray structures. The thymine-containing bc(ox)-nucleoside was converted into the corresponding phosphoramidite building block and incorporated into oligodeoxyribonucleotides by standard phosphoramidite chemistry. T(m) data with complementary RNA and DNA were measured and compared to corresponding cases of natural and unfunctionalized bc-DNA. It was found that single incorporations of bc(ox) residues destabilize duplexes by roughly 5 degrees C per modification. The destabilization was found to be due to the oxime substituent and not to the bicyclic scaffold itself. No significant alteration of the base-pairing selectivity as a function of the modification was observed. With RNA (but not with DNA) as a complement the relative thermal destabilization of bc(ox)-oligothymidylates was gradually reduced and converted into a stabilizing interaction with increasing numbers of consecutive modifications. While no cellular uptake of bc(ox)-oligonucleotides into HeLa cells occurred without transfecting agents, a significant increase in the transfection rate relative to unmodified DNA was observed in complexation with lipofectamine.     

RevErbα Preferentially Deforms DNA by Induced Fit

Using free‐energy simulations, we have shown that RevErbα‐induced DNA deformation preferentially occurs by induced fit rather than by conformational selection, even though the DNA is only slightly distorted in the complex. Our study shows that information on the sequence of binding events is needed to establish whether conformational selection or induced fit is operative, and that the presence of multiple apo‐state structures might not be enough to distinguish between these binding models.     

不对称钴配合物的合成及其催化苯乙烯环氧化

将合成的N-取代的吡啶-2-醛亚胺制备成2∶1型不对称吡啶亚胺钴(Ⅱ)配合物(CoL2n,n=1,2…6),并通过红外光谱、元素分析、核磁共振氢谱、热重分析等对相关化合物进行表征。以分子氧为氧源,考察催化剂的种类、溶剂、反应温度、反应时间对苯乙烯环氧化反应性能的影响。研究表明,配合物CoL42是最有效的催化剂;配合物中亚氨氮上取代基的供电子性和空间位阻有利于提高配合物的催化活性;在优化的反应条件下,苯乙烯的转化率达99.9%,环氧苯乙烷的选择性为62.4%。     

Molecular dynamics simulations of Na+/Cl(-)-dependent neurotransmitter transporters in a membrane-aqueous system

We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5-HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X-ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5-HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand-binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT-5HT and hSERT-escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies.     

Cobalt(III) EDTA complex removal from aqueous alkaline borate solutions by nanofiltration

At the PWR Paks diluted low-level radioactive waste water (LLW) contains the long-lived ⁶⁰Co isotope in EDTA complex form, which has no simple separation procedure. In this research nanofiltration(NF) was studied for selective removal of the cobalt(III) EDTA complex from a drain waste water model solution, which contains mainly sodium borate at an alkaline pH. A suitable NF membrane was chosen to separate the cobalt complex from the borate solution. The NF experiments were performed at constant temperature (25°C) and pressure range 1-10 bar. The cobalt complex and the borate ion rejection (R) as well as the permeate flux of the membrane was investigated as a function of pH. The rejection of the cobalt(III) EDTA complex ion and especially the borate were strongly pH dependent. The rejection of the complex ion and the borate was increased at alkaline pH (at pH 8, R = 73%; at pH 11.5, R = 96% for the cobalt complex; at pH 8, R = 7%; at pH 11.5, R = 59% for borate). NF seems to be a suitable separation method for the removal of the Co(III) EDTA complex from nuclear power plant waste streams. The removal of the cobalt complex ion from an alkaline borate solution by NF is possible in two ways: at slightly alkaline pH by a two-step separation, or at a more alkaline pH (pH > 9.5) by a one-step separation.     

Cobalt(III) Acetylacetonate Chemisorbed on Aluminum-Nitride-Modified Silica: Characteristics and Hydroformylation Activity

Co/AlN/SiO₂ catalysts were prepared by the saturative chemisorption of cobalt(III) acetylacetonate (Co(acac)₃). The support was bare silica or silica that had been modified with aluminum nitride (AlN) by repeated separate, saturated chemisorptions of trimethylaluminum and ammonia two or six times. Chemisorption of Co(acac)₃ occurred on all the supports up to a saturation ligand density of 2.7 acac nm^-2; the amount of bonded cobalt decreased from 2.1 to 1.5 at_Co nm^-2 with increasing extent of AlN modification of the support. Ligand exchange reaction, releasing Hacac, occurred less on AlN-modified silica than on bare silica. This induced difference in the reduction behavior of the catalysts, and catalytic activity in gas-phase hydroformylation of ethene, was lower with Co/AlN/SiO₂ than with Co/SiO₂ catalyst.     

Pervaporation Separation of Water/Ethanol Mixtures through Polycarbonate/Cobalt(III) Acetylacetonate Membranes

ABSTRACT

In the present work, cobalt(III) acetylacetonate [Co(acac)₃] was added to polycarbonate (PC) to improve its performance on pervaporation separation of water/ethanol mixtures. By adding 3 wt% of Co(acac)₃ the resulting PC/Co(acac)₃ complex membrane possessed a permeation rate similar to a pure polycarbonate membrane, but the separation factor (water/ethanol) was about three times higher. The stability of the complex membrane was tested, and it was found that, after being immersed in an aqueous ethanol solution for 72 hours, the complex membrane was still stable. In addition, the effects of the added amount of Co(acac)₃ and the feed composition on pervaporation performance are presented in this work, and the mechanism of the improvement in pervaporation performance is briefly discussed.     

Selective Disruption of Survivin's Protein-Protein Interactions: A Supramolecular Approach Based on Guanidiniocarbonylpyrrole

Targeting specific protein binding sites to interfere with protein-protein interactions (PPIs) is crucial for the rational modulation of biologically relevant processes. Survivin, which is highly overexpressed in most cancer cells and considered to be a key player of carcinogenesis, features two functionally relevant binding sites. Here, we demonstrate selective disruption of the Survivin/Histone H3 or the Survivin/Crm1 interaction using a supramolecular approach. By rational design we identified two structurally related ligands ( L_NES and L_HIS ), capable of selectively inhibiting these PPIs, leading to a reduction in cancer cell proliferation.     

Base Flip in DNA Studied by Molecular Dynamics Simulations of Differently-Oxidized Forms of Methyl-Cytosine

Distortions in the DNA sequence, such as damage or mispairs, are specifically recognized and processed by DNA repair enzymes. Many repair proteins and, in particular, glycosylases flip the target base out of the DNA helix into the enzyme’s active site. Our molecular dynamics simulations of DNA with intact and damaged (oxidized) methyl-cytosine show that the probability of being flipped is similar for damaged and intact methyl-cytosine. However, the accessibility of the different 5-methyl groups allows direct discrimination of the oxidized forms. Hydrogen-bonded patterns that vary between methyl-cytosine forms carrying a carbonyl oxygen atom are likely to be detected by the repair enzymes and may thus help target site recognition.     

Controlling the Heterodimerisation of the Phytosulfokine Receptor 1 (PSKR1) via Island Loop Modulation

Phytosulfokine (PSK) is a phytohormone responsible for cell-to-cell communication in plants, playing a pivotal role in plant development and growth. The binding of PSK to its cognate receptor, PSKR1, is modulated by the formation of a binding site located between a leucine-rich repeat (LRR) domain of PSKR1 and the loop located in the receptor’s island domain (ID). The atomic resolution structure of the extracellular PSKR1 bound to PSK has been reported, however, the intrinsic dynamics of PSK binding and the architecture of the PSKR1 binding site remain to be understood. In this work, we used atomistic molecular dynamics (MD) simulations and free energy calculations to elucidate how the PSKR1 island domain (ID) loop forms and binds PSK. Moreover, we report a novel “druggable” binding site which could be exploited for the targeted modulation of the PSKR1-PSK binding by small molecules. We expect that our results will open new ways to modulate the PSK signalling cascade via small molecules, which can result in new crop control and agricultural applications.     

一种不对称希夫碱配合物的合成及其对氯仿分子的选择性识别

利用邻苯二胺的分步缩合反应得到不对称希夫碱（HL）并合成了相应的金属配合物.采用自制空气舱进行氯仿清除率测量,配体HL和配合物MgL、CaL、TiL、Cr （Ⅲ）L、Co（Ⅱ）L、NiL、CuL、ZnL等对氯仿清除率的测量结果对比表明,铜配合物CuL对氯仿具有显著的清除效果.对铜配合物CuL和氯仿形成的单晶进行了晶体结构分析,发现氯仿分子已稳定地包合于配合物晶体骨絮中,并且氯仿分子上的氢和配体上的2个氧原子形成了氢键,其距离分别为2.176和2.637 A,这是由于氯仿分子中氢原子具有一定的酸性以及Cu（Ⅱ）的外围3d9电子构型中的单电子对该氢键的形成也起到一定的促进作用.     

Characterization of Cobalt(II) Phthalocyanine Catalyst Incorporated into Poly(aminosiloxane) Matrices

Cobalt phthalocyanine (CoPc) has been incorporated into various polysiloxane matrices by adding CoPc to appropriate mixtures of tri- and tetra-alkoxysilanes during hydrolytic condensation. The matrices contained Si(CH₂)₃NH₂ groups with alkyl or phenyl spacer groups between them. The cobalt content, the surface area and the pore volume all decrease as the spacer groups become larger. EPR and UV-visible spectroscopic data show that the CoPc is bound to the amine groups and that some are in the oxygenated form, (–NH₂)CoPc–O₂.     

Receptor‐Based Virtual Screening and Biological Characterization of Human Apurinic/Apyrimidinic Endonuclease (Ape1) Inhibitors

The endonucleolytic activity of human apurinic/apyrimidinic endonuclease (AP endo, Ape1) is a major factor in maintaining the integrity of the genome. Conversely, as an undesired effect, Ape1 overexpression has been linked to resistance to radio‐ and chemotherapeutic treatments in several human tumors. Inhibition of Ape1 using siRNA or the expression of a dominant negative form of the protein has been shown to sensitize cells to DNA‐damaging agents, including various chemotherapeutic agents. Therefore, inhibition of the enzymatic activity of Ape1 might result in a potent antitumor therapy. A number of small molecules have been described as Ape1 inhibitors; however, those compounds are in the early stages of development. Herein we report the identification of new compounds as potential Ape1 inhibitors through a docking‐based virtual screening technique. Some of the compounds identified have in vitro activities in the low‐to‐medium micromolar range. Interaction of these compounds with the Ape1 protein was observed by mass spectrometry. These molecules also potentiate the cytotoxicity of the chemotherapeutic agent methyl methanesulfonate in fibrosarcoma cells. This study demonstrates the power of docking and virtual screening techniques as initial steps in the design of new drugs, and opens the door to the development of a new generation of Ape1 inhibitors.