Among macrocyclic triand tetraamines tested, a 12-membered triamine, [12]aneN3, is the most appropriate ligand that mimics the ligand field surrounding Zn" in carbonic anhydrases. In its 1:1 ZnnL complex, the H20 bound at the fourth coordination site deprotonates with the pK, value of 7.30 at 25 °C, / = 0.1 (NaC104), almost the same value being reported for the Zn"-enzymes. The resulting hydroxo complex is precipitated as a trimer from pH 8 aqueous solution, which with a formula of [ZnIIL(0H)]3(C104)3'HC104 has been analyzed by X-ray crystal study. The crystals of (11 )3•(004)• 004, C27H67N,019Cl4Zn3, are trigonal, space group R3c with six molecules of 11 in the unit cell of dimensions a = 22.103 (1) A, c = 16.514 (2) A. Anion binding affinity to the Zn"L complex is determined by pH titration to have an order of OH" (log K = 6.4) » CH3COO" (2.6) > SCN" (2.4) > I" (1.6) > Br" (1.5) > F" (0.8), which is almost comparable with the anion inhibition order and magnitude reported for carbonic anhydrase activities. Moreover, like the Znu-enzymes, the [Zn"L(OH)]+ species catalyzes methyl acetate hydrolysis and acetaldehyde hydration, where the Zn^-bound OH" commonly acts as a nucleophile to the carbonyl carbons. The plots of these rate constants vs pH in either case show the kinetic pAa values of ZnnL(OH2) to be nearly the same as the thermodynamically obtained values of 7.3 at 25 °C and 7.9 at 0 °C. Various outstanding properties of Zn11 in enzymes (over other metal ions such as Com), which contribute to its biological significance, have been well demonstrated by the present macrocyclic triamine complex behaviors.

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

A computationally efficacious free-energy functional for studies of inhomogeneous liquid water J. Chem. Phys. 137, 044107 (2012) Fourth virial coefficients of asymmetric nonadditive hard-disk mixtures J. Chem. Phys. 136, 184505 (2012) Equation of state and jamming density for equivalent bi-and polydisperse, smooth, hard sphere systems J. Chem. Phys. 136, 124508 (2012) On the theoretical determination of the Prigogine-Defay ratio in glass transition J. Chem. Phys. 136, 124502 (2012) Communication: Thermodynamics of condensed matter with strong pressure-energy correlations Hugoniot data of diamond was obtained using laser-driven shock waves in the terapascal range of 0.5-2 TPa. Strong shock waves were generated by direct irradiation of a 2.5 ns laser pulse on an Al driver plate. The shock wave velocities in diamond and Al were determined from optical measurements. Particle velocities and pressures were obtained using an impedance matching method and known Al Hugoniot. The obtained Hugoniot data of diamond does not show a marked difference from the extrapolations of the Pavlovskii Hugoniot data in the TPa range within experimental errors.

Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.