An alternative to MMP2

The potentials and parameters of MM2 were used in MMP1 for molecular mechanics calculations of conjugated molecules.     

An efficient method for synthesis of succinate-based MMP inhibitors

A differentially protected fumarate undergoes radical addition followed by allylstannane trapping to provide disubstituted succinates in good yields and high anti diastereoselectivity. The conversion of the succinate to a known MMP inhibitor has been accomplished. [reaction: see text]     

A new calculational method adapted to the experimental conditions for determining thorium and uranium contents in geological samples

The thorium to uranium ratio has been determined in different geological samples by using a new theoretical method based on calculating the probability for an emitted -particle to reach and be registered on a solid state nuclear track detector (SSNTD). Thorium as well as uranium contents of the samples studied have been determined by exploiting the track densities, due to the -particles of the thorium and uranium series, registered on the CR-39 and LR-115 SSNTD. Results obtained by this calculational method which does not need any calibration were compared to data obtained by isotope dilution mass spectrometry. The influence of the granulation on the uranium content in sedimentary phosphate samples has also been investigated.     

Expression of MMP2 and MMP9 (Gelatinases A and B) in Human Colon Cancer Cells

Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases, collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs are detected in tumor tissue or serum of patients with advanced cancer, and they are the major prognostic indicators in cancer. Inhibition of MMPs has been explored as a therapeutic goal for almost two decades. Nitric oxide (NO), a free radical plays an important role in signaling pathways in regulation of MMP expression. In the present study, we demonstrated the role of exogenous NO levels in the regulation of MMP2 and MMP9 (gelatinases A and B) in colon cancer cell line WiDr and its inhibition with emodin (a naturally occurring anthraquinone).     

MMP-2和Hydroxamate类抑制剂绝对自由能的计算

采用基于线性响应近似的自由能计算方法计算了一类hydroxamate抑制剂和MMP-2的绝对结合自由能。计算中,催化锌离子和MMP-2以及配体之间采用了非键模型。分子动力学模拟结果显示,采用非键模型时,催化Zn离子采用五配位的形式,但配位键的形式和初始结构比较有很大的差别。通过拟合,分别得到了单参数、双参数以及三参数的自由能预测模型,其中,含有常数校正项的三参数模型具有最佳的预测能力,预测自由能和实际自由能之间平均绝对误差仅为2.38kJ/mol。     

NMR and calculational studies on the regioselective lithiation of 1-methoxynaphthalene

1-Methoxynaphthalene (1) undergoes regioselective lithiation in position 2 (n-BuLi/TMEDA) or in position 8 (t-BuLi), respectively. The detected formation of a n-BuLi/1 complex (1:1 n-BuLi/1 mixture) appears to have only minor influence on the regioselectivity (both products are obtained). The exchange of hydrogen atom H2 by deuterium results in a remarkably reduced reaction rate for the lithiation with n-BuLi in THF-d(8). This isotope effect and the formation of the thermodynamically less favorable 2-lithio compound suggest a kinetically controlled mechanism. The lack of an isotope effect for the reaction of 8-deuterio-1-methoxynaphthalene with t-BuLi and the formation of the thermodynamically preferred 8-lithiated product indicate a thermodynamically controlled mechanism. Slow conversion of the 2- into the 8-lithiated species (at higher temperatures) gives further evidence that n-BuLi and t-BuLi afford the kinetically and thermodynamically preferred products, respectively.     

A simple calculational model for predicting the site for nucleophilic substitution in aromatic perfluorocarbons

We present a simple model for predicting the principal site for nucleophilic substitution in aromatic perfluorocarbons. Our model is based on the relative stabilities of the Meisenheimer complexes as calculated using density functional theory with a modest basis set. (Hartree-Fock theory will do just as well.) Although such calculations were essentially impossible to carry out when early theoretical work on this topic was undertaken in the mid-1960s and early 1970s, they are now routine and full geometry optimization for any of the systems studied in this work can be completed in a matter of minutes with modern quantum chemistry programs and computational hardware. Predictions from our model agree with experimental observations for 16 aromatic perfluorocarbons, and together with additional NMR calculations, lead us to conclude that the earlier prediction that perfluoroanthracene undergoes nucleophilic substitution in the 2-position is incorrect, and is based on a misinterpretation of the experimental ¹⁹F NMR spectrum.     

Study of gamma-photon self-absorption in stainless steel samples by experimental and calculational methods

Gamma-ray self-absorption in stainless steel samples has been studied with an experimental method based on fast neutron activation and a Monte Carlo calculation technique adapted to the experimental conditions. A relation between self-absorption and absorption of -photons inside stainless steel samples was found. The influence of the -ray energy and sample depth have been investigated. Agreement between the two methods has been found.     

Potent "clicked" MMP2 inhibitors: synthesis, molecular modeling and biological exploration

A new series of MMP2 inhibitors is described, following a fragment-based drug design approach. One fragment containing an azide group and a well known hydroxamate Zinc Binding Group in a α-sulfone, α-tetrahydropyrane scaffold, has been synthesized. Water-LOGSY, STD and competition-STD experiments indicate that this fragment binds to the active site of the enzyme. A click chemistry reaction was used to connect the azide to lipophilic alkynes selected to interact selectively with the S1' subunit of MMP2, as shown by docking and molecular dynamic experiments of the designed compounds. The most potent compounds 18 and 19 displayed an IC(50) of 1.4 and 0.3 nM against MMP2 respectively, and showed negligible activity towards MMP1 and MMP7, two metalloproteinases which have a shallow S1' subsite. Compound 18 also showed a promising selectivity profile against some antitarget metalloproteinases, such as MMP8, and considerably less activity against MMP14 (IC(50) = 65 nM), and MMP9 (IC(50) = 98 nM), other MMPs characterized by having a deep S1' pocket and, therefore, more similar to MMP2.     

Theoretical calculational investigation on the regioselectivity of the ring opening of thiiranes with ammonia and amines

The course, especially the regioselectivity, of the nucleophilic ring opening of thiiranes with ammonia and amines was investigated with the density functional theory (DFT) calculation. In the ring-opening reaction, thiiranes could be attacked on either their less or more substituted carbon atoms. The analyses of the potential energy surfaces, the bond lengths, and charges of key species in both pathways indicate that alkyl-substituted thiiranes are attacked dominantly on their less substituted ring carbon atom, whereas arylthiiranes are on their more substituted one due to the existence of the p-π conjugative effect, which stabilizes the transition states generated in the reaction. Furthermore, the Lewis acid can modulate the regioselectivity. However, the steric hindrance of nucleophiles and solvents affect the regioselectivity slightly as they show similar influence on both pathways, despite the fact that they can put an impact on the energy. NBO and MO analyses also support the substituent-depended regioselectivity. This is the first DFT calculational investigation on the regioselective ring opening of thiiranes and provides a rational explanation for the experimental results. The theoretical investigation gives a general understanding and a rule for the rationale and prediction of the regioselectivity in the nucleophilic ring opening of thiiranes, even other three-membered heterocycles.     

The externally contracted CI method applied to N2

An approximate multireference CI method is presented. By grouping together configurations with the same internal parts and freezing their relative weights by the use of perturbation theory, the number of variational parameters is drastically reduced. The loss of correlation energy is shown to be usually less than 2%, and the timing is less than one ordinary CI iteration. Examples from calculations on some states of the nitrogen atom and nitrogen molecule are given. The basis set convergence for the lowest excitation energy in the atom is very slow. Less than 50% of the correlation effect is obtained at the s, p, d limit. After the inclusion of ? functions this value is improved to 83%. The dissociation energies of the molecule also show slow basis set convergence with errors of 0.5 eV even after addition of ? functions. The bond distances are, howeever, accurately reproduced with errors of less than 0.005 Å for all the states. A qualitative discussion of predissociation in the a ¹Π_g and B ³Π_gstates caused by spin–orbit interaction with the ⁵Σ_g⁺ state, is finally presented. Rapidly oscillating lifetimes between the different vibrational states are predicted.     

Experimental and ab initio calculational studies on nitrato[2,4-dichloro-6-((pyridin-2-ylmethylimino)methyl)phenolato]copper(II)

The mononuclear Schiff-base copper(II) compound, [Cu(C₁₃H₉C_l2N₂O)(NO₃)], has been synthesized and characterized by elemental analysis and X-ray single crystal determination. The compound crystallizes in the orthorhombic, space group Cmc2₁ with unit cell dimensions a?=?6.713(1), b?=?22.147(3), c?=?9.976(1)?Å?, M _r?=?405.67, V?=?1483.2(3)?ų, Z?=?4, R ₁?=?0.0568 and wR ₂?=?0.1331. X-ray structure determination revealed that the compound possesses crystallographic mirror symmetry. The Cu^II ion in the compound is five-coordinate in a distorted trigonal bipyramid with one O and two N atoms of the Schiff-base and by two O atoms of the nitrate anion. In the crystal structure, the molecules are linked via intermoleclular C?H?···?O non-classical hydrogen bonds, forming a two-dimensional network. Density functional theory (DFT) and Hartree-Fock (HF) calculations of the structure, atomic charge distribution and natural bond orbital analyses have been performed. The calculated results show that the Cu^II ion mainly adopts spd² hybridization and forms five bonds with the NNO donor set of the Schiff-base ligand and with two O atoms of nitrate from four orientations. The coordinate stabilization energies show that the Schiff-base copper(II) compound is very stable.     

Oil-CO2 MMP Determination in Competition of Neural Network,Support Vector Regression,and Committee Machine

Oil-CO₂ minimum miscible pressure (MMP) has significance in selecting appropriate reservoir for miscible gas injection and greatly governs performance of local displacement. Accurate determination of MMP is very expensive, time-consuming, and labor intensive. Therefore, the quest for a method to determine MMP accurately and save time and money is necessary. This study held a competition between neural network and support vector regression models and assessed their performance in prediction of MMP for both pure and impure miscible CO₂ injection. Subsequently, a committee machine was constructed based on divide and conquer principle to reap benefits of both model and increases the precision of final prediction. Results indicated committee machine performed more satisfyingly compared with individual intelligent models performing alone.      

Identification of Broad-Spectrum MMP Inhibitors by Virtual Screening

Matrix metalloproteinases (MMPs) are the family of proteases that are mainly responsible for degrading extracellular matrix (ECM) components. In the skin, the overexpression of MMPs as a result of ultraviolet radiation triggers an imbalance in the ECM turnover in a process called photoaging, which ultimately results in skin wrinkling and premature skin ageing. Therefore, the inhibition of different enzymes of the MMP family at a topical level could have positive implications for photoaging. Considering that the MMP catalytic region is mostly conserved across different enzymes of the MMP family, in this study we aimed to design a virtual screening (VS) workflow to identify broad-spectrum MMP inhibitors that can be used to delay the development of photoaging. Our in silico approach was validated in vitro with 20 VS hits from the Specs library that were not only structurally different from one another but also from known MMP inhibitors. In this bioactivity assay, 18 of the 20 compounds inhibit at least one of the assayed MMPs at 100 μM (with 5 of them showing around 50% inhibition in all the tested MMPs at this concentration). Finally, this VS was used to identify natural products that have the potential to act as broad-spectrum MMP inhibitors and be used as a treatment for photoaging.     

Monte Carlo simulation of RRKM unimolecular decomposition in molecular beam experiments. I. Basic considerations and calculational procedure

A simulation method is described for the comparison of a molecular decomposition theory, based on the fundamental RRKM theory, with crossed molecular beam experiments. In the present formulation, the method is applied to the case with long-lived collision complexes surrounded by a centrifugal barrier. The procedure uses Monte Carlo techniques to simulate the formation and decomposition of the complexes, thus effectively solving the high-dimensional integrals resulting but seldom solved in the analytical treatments. Several computational problems, like singularities in the c.m. angular distributions, have been circumvented in this procedure. Angular momentum conservation, the simultaneous interaction of several decomposition channels and strict flux conservation are included in the procedure. Dynamical features can be introduced, as will be shown in forthcoming papers.     

Cubane, cuneane, and their carboxylates: a calorimetric, crystallographic, calculational, and conceptual coinvestigation

[reaction: see text] This study is a multinational, multidisciplinary contribution to the thermochemistry of dimethyl1,4-cubanedicarboxylate and the corresponding isomeric, cuneane derivative and provides both structural and thermochemical information regarding the rearrangement of dimethyl 1,4-cubanedicarboxylate to dimethyl 2,6-cuneanedicarboxylate. The enthalpies of formation in the condensed phase at T = 298.15 K of dimethyl 1,4-cubanedicarboxylate (dimethyl pentacyclo[4.2.0.0.(2,5)0.(3,8)0(4,7)]octane-1,4-dicarboxylate) and dimethyl 2,6-cuneanedicarboxylate (dimethyl pentacyclo[3.3.0.0.(2,4)0.(3,7)0(6,8)]octane-2,6-dicarboxylate) have been determined by combustion calorimetry, delta(f) H(o)m (cr)/kJ x mol(-1) = -232.62 +/- 5.84 and -413.02 +/- 5.16, respectively. The enthalpies of sublimation have been evaluated by combining vaporization enthalpies evaluated by correlation-gas chromatography and fusion enthalpies measured by differential scanning calorimetry and adjusted to T = 298.15 K, delta(cr) (g)Hm (298.15 K)/kJ x mol(-1) = 117.2 +/- 3.9 and 106.8 +/- 3.0, respectively. Combination of these two enthalpies resulted in delta(f) H(o)m (g., 298.15 K)/kJ x mol(-1) of -115.4 +/- 7.0 for dimethyl 1,4-cubanedicarboxylate and -306.2 +/- 6.0 for dimethyl 2,6-cuneanedicarboxylate. These measurements, accompanied by quantum chemical calculations, resulted in values of delta(f) Hm (g, 298.15 K) = 613.0 +/- 9.5 kJ x mol(-1) for cubane and 436.4 +/- 8.8 kJ x mol(-1) for cuneane. From these enthalpies of formation, strain enthalpies of 681.0 +/- 9.8 and 504.4 +/- 9.1 kJ x mol(-1) were calculated for cubane and cuneane by means of isodesmic reactions, respectively. Crystals of dimethyl 2,6-cuneanedicarboxylate are disordered; the substitution pattern and structure have been confirmed by determination of the X-ray crystal structure of the corresponding diacid.