Multicomponent Assembly of the Kinesin Spindle Protein Inhibitor CPUYJ039 and Analogues as Antimitotic Agents.

The potent kinesin spindle protein inhibitor CPUYJ039 and a set of analogues were prepared by a target-oriented approach based on a Ugi reaction that uses 2-nitrophenyl isocyanides as key building blocks. The herein documented strategy provides straightforward and atom economical access to potent benzimidazole-based antimitotic agents by exploring the versatility and exploratory power of the Ugi reaction. The results of docking studies and biological activity evaluations of the benzimidazole compounds are also reported.

Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.

Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.

Gas phase elimination kinetics of methyl mandelate: experimental and DFT studies.

The gas phase elimination kinetics of racemic methyl mandelate was determined in a static system, and yielded on decomposition benzaldehyde, methanol, and carbon monoxide. The reaction was homogeneous, unimolecular, and follows a first-order law in the temperature range 379.5-440 degrees C and pressure range of 21.5-71.1 Torr. The variation of the rate coefficient with temperature is expressed by the following Arrhenius equation: log k1 = (12.70 +/- 0.14)-(206.5 +/- 1.9) kJ/mol (2.303RT)(-1). The theoretical estimations of the kinetics and thermodynamics parameters were carried out using DFT methods B3LYP, B3PW91, MPW1PW91, and PBEPBE. Calculation results are in reasonably good agreement with the experimental energy and enthalpy values when using the PBEPBE DFT functional. However, regarding the entropy of activation, the MPW1PW91 functional is more adequate to describe the reaction. These calculations imply a molecular concerted nonsynchronous mechanism involving a two-step process, where the formation of the unstable alpha-lactone intermediate is the rate-determining factor. The lactone intermediate rapidly decarbonylates to produce benzaldehyde and carbon monoxide. The transition state is late in the reaction coordinate, resembling the lactone configuration.

Joint experimental and theoretical studies of the mechanism for the gas phase elimination kinetics of methyl 2,2-dimethyl-3-hydroxypropionate.

Methyl 2,2-dimethyl-3-hydroxypropionate was found to decompose, in a static system, mainly to methyl isobutyrate and formaldehyde. The reaction rates were affected in packed and unpacked clean Pyrex vessels, demonstrating little but significant surface effect. However, in vessels seasoned with allyl bromide this reaction was homogeneous and unimolecular and followed a first-order law. The working temperature range was 349-410 degrees C and the pressure range was 64-162 Torr. The variation of the rate coefficient with temperature is expressed by the following Arrhenius expression: log k(1) (s(-1)) = [(11.43 +/- 0.57) - (180.4 +/- 7.2) kJ mol(-1)] x (2.303RT)(-1). Methyl 2,2-dimethyl-3-hydroxypropionate was found to be 1.4 times greater in the rate of elimination than methyl 3-hydroxypropionate. Apparently, steric acceleration may be considered responsible in the process of decomposition. The theoretical calculation of the kinetics and thermodynamics parameters, at the B3LYP/6-211G** level of theory, are in reasonably good agreement with the experimental values obtained. These calculations imply a molecular mechanism involving a concerted nonsynchronous transition state where abstraction of the hydroxyl hydrogen by the oxygen of the carbonyl ester is a determining factor and the transition state is late in the reaction coordinate.

Brønsted Acid-promoted intramolecular carbocyclization of alkynals leading to cyclic enones.

TFA-promoted exo carbocyclizations of nonterminal 7-alkynals gave good to excellent yields of seven-membered cycloalkenones, a medium-sized functionalized ring present in natural products with relevant pharmacological properties. Nonterminal 5- and 6-alkynals also gave very good yields of the corresponding exo cyclopentenones and cyclohexenones. On the other hand, terminal 5-alkynals gave endo carbocyclizations to cyclohexenones. These carbocyclizations can be considered as tandem alkyne hydration/aldol condensation processes.