A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies

Summary Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 Å) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation.Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.     

(Benzo[4, 5]cyclohepta[l, 2-b]thiophen-4-ylidene)acetic Acids: Novel Non-ulcerogenic Antiinflammatory Agents

Compound (Z)- 8a has been found to display interesting antiinflammatory activity. In order to prepare derivatives with a wide variety of substituents in the aromatic part of the molecule, a new synthesis of the key intermediates 9a-g was developed starting from thiophene-3-carboxylic acid ( 11 ) and substituted benzyl bromides. The conversion of 9a-g to 10a-g follows a known procedure. Ketones 10a-g , on reaction with alkyl (dialkoxy-phosphoryl)acetate, followed by isomer separation and alkaline ester hydrolysis, yielded the desired derivatives (Z)- 8a-g and (E)- 8a-g . The biologically most interesting compound (Z)- 8a is currently undergoing clinical trials.     

High-temperature collisional energy transfer in highly vibrationally excited molecules II: Isotope effects in isopropyl bromide systems

Values for 〈ΔE_down〉, the average downward energy transferred from the reactant to the bath gas upon collision, have been obtained for highly vibrationally excited undeuterated and per-deuterated isopropyl bromide with the bath gases Ne, Xe, C₂H₄, and C₂D₄, at ca. 870 K. The technique of pressure-dependent very low-pressure pyrolysis (VLPP) was used to obtain the data. For C₃H₇Br, the 〈ΔE_down〉 values (cm^?1) are 490 (Ne), 540 (Xe), 820 (C₂H₄), and 740 (C₂D₄), and for C₃D₇Br, 440 (Ne), 570 (Xe), 730 (C₂H₄), and 810 (C₂D₄). The uncertainties in these values are ca. ±10%. The 〈ΔE_down〉 values for the inert bath gases Ne and Xe show excellent agreement with the theoretical predictions of the semi-empirical biased random walk model for monatomic/substrate collisional energy exchange [J. Chem. Phys., 80 , 5501 (1984)]. The relative effects of deuteration of the reactant molecule on 〈ΔE_down〉 also compare favorably with the predictions of this theoretical model. Extrapolated high-pressure rate coefficients (s^?1) for the thermal decomposition of reactant are 10^13.6±0.3 exp(?200 ± 8 kJ mol^?1/RT) for C₃H₇Br and 10^13.9±0.3 exp(?207 ± 8 kJ mol^±1/RT) for C₃D₇Br, which are consistent with previous studies and the expected isotope effect.     

Experimental and kinetic modeling study of oxidation of acetonitrile

Oxidation of acetonitrile has been studied in a flow reactor in the absence and presence of nitric oxide. The experiments were conducted at atmospheric pressure in the temperature range 1150–1450 K, varying the excess air ratio from slightly fuel-lean to very lean. Oxidation of CH₃CN was slow below 1300 K. Nitric oxide, hydrogen cyanide and nitrous oxide were detected as important products. A detailed chemical kinetic model for oxidation of acetonitrile was developed, based on a critical evaluation of data from literature. The rate coefficients for the reactions of CH₃CN and CH₂CN with O₂ were calculated from ab initio theory. Modeling predictions were in satisfactory agreement with experiments. Calculations were sensitive to thermal dissociation of CH₃CN and to the branching fraction for CH₃CN + OH to CH₂CN + H₂O and HOCN + CH₃, respectively. More work is desirable for these steps, as well as for reactions of CH₂CN and HCCN.     

Evaluation of Vanadium(IV) as a Non-radioactive Surrogate for Technetium(IV) by Comparison of Stability Constants for Polyamino Polycarboxylate Ligand Complexation

The stability constants for the Tc(IV) and V(IV) complexation with the polyamino polycarboxylate ligands IDA, NTA, HEDTA and DTPA were determined using liquid–liquid extraction techniques. These stability constants were then used to evaluate the validity of using V(IV) as a chemical analogue for Tc(IV). Results suggest that Tc(IV), as TcOOH⁺, will form β _1?11 complexes with the selected ligands, while V(IV), as VO²⁺, will form β ₁₀₁ complexes. The values for these determined stability constants are (in log₁₀ unit) 10.9 ± 0.1, 11.4 ± 0.1, 14.9 ± 0.1, and 20.1 ± 0.1 for Tc(IV) in 0.5 mol·L^?1 NaCl at 25 °C, for IDA, NTA, HEDTA and DTPA, respectively, they are 9.3 ± 0.1, 11.6 ± 0.2, 15.8 ± 0.1, and 20.8 ± 0.1 for V(IV) in 0.5 mol·L^?1 NaCl at 25 °C, for the same suite of ligands. The incorporation of a hydroxide into the metal ligand complexes formed by Tc(IV) is proposed as the largest factor differentiating the apparent stability constants of Tc(IV) and V(IV). This work shows that V(IV) is a poor analog for Tc(IV); however, despite the differences in complexation mechanism between V(IV) and Tc(IV), V(IV) still appears to have some use for predicting Tc(IV) complexation behavior.     

Self-similar fluid-dynamic limits for the Broadwell system

This report discusses a new approach for the resolution of the fluid-dynamic limit for the Broadwell system of the kinetic theory of gases, appropriate in the case of Riemann, Maxwellian data. Since the formal limiting system is expected to have self-similar solutions, we are motivated to replace the Knudsen number in the Broadwell model so that the resulting model admits self-similar solutions =x/t and then let go to zero. The limiting procedure is justified and the resulting limit is a solution of the Riemann problem for the fluid-dynamic limit equations. A class of Riemann data for which this program can be carried out is exhibited. Furthermore, it is shown that for the Carleman model the complete program can be done successfully for arbitrary Riemann data.