A convenient synthesis of a selective gelatinase inhibitor as an antimetastatic agent

Compound 1, 2-(4-phenoxyphenylsulfonylmethyl)thiirane, is a potent and selective inhibitor for human gelatinases (J. Am. Chem. Soc. 2000, 122, 6799-6800), enzymes implicated in a number of diseases, including cancer. This compound is showing excellent promise in animal trials in a number of disease models. Large quantities of this compound were necessary for these studies. A convenient four-step synthetic route for compound 1 is described herein. The synthesis is amenable to scale-up to tens of grams and gives an overall yield of 57% for this important compound.     

Ab initio calculations on H transfer in the HF trimer

Systematic ab initio LCAO MO calculations with basis sets of increasing size have been performed to analyze the changes in relative stabilization energies of the two cyclic (D_3h and C_3h symmetry) and the noncyclic HF trimers. The results form the basis for a discussion of cyclic H-transfer reactions.     

Quantenchemische untersuchungen zum mechanismus der elektrophilen substitution. I. Zur potentialhyperfläche des systems benzol/h+

Results of semiempirical calculations (CNDO/2-FK and MINDO/2 methods) for the σ-π complex problem on protonated benzene are given and compared with previous ones. The semiempirical methods were chosen according to the agreement of their results with new theoretical energy data (E_HF + E_korrel) concerning the classical–nonclassical problem of protonated ethylene. By these methods the corresponding part of the energy surface of the benzene/H⁺ system is simulated. The stationary points of this surface are found by a gradient method with complete optimization of the geometry. On the basis of this method we determined the energy profile of a reaction coordinate between the classical (σ-complex) and nonclassical (π-complex) cation. The so called strong π-complex is a saddle point between two σ-complex minima and can be interpreted as transition state of 1,2-proton shifts. Hypotheses for possible minimum energy paths of electrophilic attacks in the given region of the surface are discussed.     

Design, synthesis, and evaluation of a mechanism-based inhibitor for gelatinase A

[structure: see text] Matrix metalloproteinases (MMPs), of which 26 are known, have been implicated in a number of pathological conditions, including tumor metastasis. We have previously described the first mechanism-based inhibitor for MMPs (J. Am. Chem. Soc. 2000, 122, 6799-6800), which in chemistry mediated by the active site zinc ion selectively and covalently inhibits MMP-2, -3, and -9. Computational analyses indicated that this selectivity in inhibition of MMPs could be improved by design of new variants of the inhibitor class. We report herein the syntheses of methyl 2-(4-{4-[(2-thiiranylpropyl)sulfonyl]phenoxy}phenyl)acetate (3) and 2-(4-{4-[(2-thiiranylpropyl)sulfonyl]phenoxy}phenyl)acetic acid (4), and show that compound 3 serves as a mechanism-based inhibitor exclusively for MMP-2. This molecule should prove useful in delineating the functions of MMP-2 in biological systems.     

Structural Basis for Carbapenemase Activity of the OXA-23 β-Lactamase from Acinetobacter baumannii

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Optimization of isothermal batchwise bulk free radical polymerization with and without chain transfer agent for minimum reaction time

In this work the minimum reaction time was studied for a specific final monomer conversion and number-average chain length by adjusting the amount of initial initiator concentration in the presence of a fixed amount of chain transfer agent at the best isothermal temperature. A new method for the determination of the best initial initiator concentration ([I]₀) and isothermal temperature (T) in the presence of chain transfer agent was developed by the application of a simple optimization algorithm, based on the Lagrangian multiplier, to the basic free radical kinetics. Numerical examples for the polymerization of styrene are presented. It is shown that in the presence of a fixed amount of chain transfer agent the best isothermal policy for minimum time would deviate from dead-end polymerization. As the concentration of chain transfer agent increases, a stronger deviation from dead-end polymerization is observed. It was found that for a given pair of desired conversion and number-average chain length the usage of a chain transfer agent would result in a longer reaction time. The results give insights into operation of batchwise bulk free radical polymerization for minimum reaction time under isothermal conditions.     

Synthesis, Characterization, Spectroscopy and Study of Antimicrobial Properties of Two New Substituted Trichloroaluminate（Ⅲ） Complexes [AlCl3X]- （X = SCN-, CN-）

The synthesis and characterization of two new aluminate(Ⅲ) complexes with general formula K[AlCl3X] are reported. These compounds derived from aluminate trichloride and related salts. Potassium trichlorothiocyanoaluminate, PCTA, and potassium trichlorocyanatoalu-minate, PCCA, are two new ionic aluminate complexes. They can be easily synthesized in a nearly quantitative yield by using the direct reaction of AlCl3 and KX. The complexes were characterized by physico-chemical and spectroscopic methods. Theoretical calculations have been used for the extraction of structural and spectroscopic data of these new synthesized complexes. The antibacterial activities of such compounds were studied against the Staphylococcus aureus, Escherichia coli, Staphylococcus Epidermidis, Estreptococo B and Shigella.     

Convergence of zeta functions of graphs

The -zeta function of an infinite graph (defined previously in a ball around zero) has an analytic extension. For a tower of finite graphs covered by , the normalized zeta functions of the finite graphs converge to the -zeta function of .