Synthesis of a diverse library of mechanism-based cysteine protease inhibitors

We report improvements of our method for the solid-phase synthesis of mechanism-based mercaptomethyl ketone inhibitors of cysteine proteases (Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907-9914). Specifically, Fmoc-protected chloromethyl ketones were used, rather than the Alloc-protected counterparts. In addition, we further demonstrated that diverse polar functionality can be incorporated at the R1', R1, and R2 sites, in contrast to our previous efforts, where primarily hydrophobic groups were incorporated at these positions. On the basis of these results, a 2016-membered library of potential mercaptomethyl ketone inhibitors was prepared that incorporated diverse functionality. The library was screened against cathepsin B, which is implicated in cancer, resulting in the identification of single-digit nanomolar inhibitors. Because of the diverse functionality incorporated in this library, it should be a rich source of potent inhibitors against many other cysteine proteases.     

Synthesis and structural investigation of N,N',N' '-trialkylguanidinato-supported zirconium(IV) complexes

The addition of 2 equiv of N,N',N' '-triisopropylguanidine (guanH(2)) to Zr(CH(2)Ph)(4) produced the bis(guanidinato)bis(benzyl)zirconium complex [((i)PrNH)C(N(i)Pr)(2)](2)Zr(CH(2)Ph)(2) (1). The mono(guanidinato) complex [((i)PrN)(2)C(NH(i)Pr)]ZrCl(3) (2) was accessible by the reaction of 2 equiv of guanH(2) with ZrCl(4). Guanidinium hydrochloride, [C(NH(i)Pr)(3)]Cl, is a byproduct of this reaction. When crystallized from THF, complex 2 was isolated as the THF adduct [((i)PrNH)C(N(i)Pr)(2)]ZrCl(3)(THF) (2-THF). The mixed cyclopentadienyl guanidinato complex [eta(5)-1,3-(Me(3)Si)(2)C(5)H(3)][((i)PrNH)C(N(i)Pr)(2)]ZrCl(2) (3) was prepared by treatment of [1,3-(Me(3)Si)(2)C(5)H(3)]ZrCl(3) with the in situ generated lithium triisopropylguanidinate salt. The reaction of guanH(2) with [1,3-(Me(3)Si)(2)C(5)H(3)]ZrMe(3) affords the dimethyl derivative [eta(5)-1,3-(Me(3)Si)(2)C(5)H(3)][((i)PrNH)C(N(i)Pr)(2)]ZrMe(2) (4). Definitive evidence for the molecular structures of these products is provided through single-crystal X-ray characterization of 1, 2-THF, and 3, which are presented. The extent of pi delocalization within the guanidinato ligand is discussed in the context of the metrical parameters obtained from these structural studies.     

Routes of nitrogen formation in reduction of nitrogen oxide by carbon monoxide and hydrogen over nickel chromite catalyst

The route of NO reduction to N₂ over nickel chromite catalyst is dependent on the nature of the reducing agent. NO reduction by dihydrogen proceeds mainly through the step of N₂O formation, whereas NO reduction to N₂ by carbon monoxide is mainly direct without a step of N₂O formation.

---

NO N₂ NO , , N₂O, NO , , NO N₂, . . N₂O.

     

Influence of size,ellipticity and charge separation on the free energy of some aqueous bolaform electrolyte models

The free energy of some models of aqueous bolaform electrolytes have been calculated at the Debye-Hückel limiting law plus B ₂ level of approximation. The repulsive forces are modeled by hard spheres or hard ellipsoids. The charges are placed either at the center of the sphere or at the foci of the ellipsoid. Parameters were chosen to approximate the size and shape of sodium and calcium p-benzenedisufonate and sodium 4,4-biphenyldisulfonate. The results show that contrary to the standard explanations for the unusual properties of bolaform electrolytes, separating the charges has little effect on the excess free energy. It is also shown that changing from a sphere to an ellipse has little effect on the excess free energy. The most important determinates of the properties of these salts are the sizes of the ions. Agreement of the model calculations with experimental results is reasonable considering the simplicity of the models.     

Freezing temperatures of aqueous solutions of methyl formate and ethyl acetate with a variety of nonelectrolytes. Gibbs energy of interaction of the ester group with other functional groups

Freezing temperatures of dilute aqueous solutions of ethyl acetate and mixtures with myo-inositol, D-mannitol, formamide, 1,3,5-trioxane, 1,4-dioxane, acetamide, hexamethylenetetramine, and methyl formate have been measured. In addition, freezing temperatures of dilute aqueous solutions of methyl formate and mixtures with the above solutes have been measured. From these data, the pairwise molecular Gibbs energies of interaction between the molecules were calculated. Using the additivity principle, the pairwise functional group Gibbs energies of interaction were calculated for ester group interactions with a variety of other functional groups.     

Apparent molar heat capacities of aqueous solutions of acetic,propanoic and succinic acids,sodium acetate and sodium propanoate from 300 to 525 K and a pressure of 28 MPa

The apparent molar heat capacities of dilute aqueous solutions of acetic, propanoic and succinic acid and sodium salts of the two monofunctional acids were measured at 300 Kp,2 ^o . After subtracting the heat capacity of a point mass, the remaining heat capacity was successfully decomposed into functional group contributions at all temperatures. Together with the results of our previous paper on alcohols and diols the heat capacity contributions of the CH₂, CH₃, OH, COOH, (COOH)₂, and COONa groups are now available and these allow reasonably accurate predictions of the heat capacities of all compounds composed of these groups in this temperature range.     

The Mechanism of Photochemical Release of Nitric Oxide from S-Nitrosoglutathione

Abstract— Laser flash photolysis of S-nitroso complexes of glutathione (GSNO) and bovine serum albumin (BSANO) via excitation at 355 nm has been used to investigate the photogeneration of nitric oxide (NO) and subsequent radical reactions. In the case of GSNO, liberation of NO was confirmed by its oxidation of oxyhemoglobin to met hemoglobin. Initial NO release is via homolytic cleavage of the S-N bond to produce the glutathione thiyl radical, GS, which can subsequently react with (a) ground-state GSNO (k= 1.7 × 10⁹M^?1/i> s^?1) to yield additional NO and oxidized glutathione, GSSG; and (b) oxygen (k= 3.0 × 10⁹M^?1 s^?1) to give the glutathione peroxy radical, GSOO, which subsequently reacts with ground-state GSNO (k= 3.8 × 10⁸M^?1 s^?1), also producing additional NO and GSSG. The relative concentrations of oxygen and GSNO in the system determine the major pathway for removal of G'. These secondary reactions occur at such high rates that they preclude radical recombination under low-intensity irradiation conditions. The quantum yield of overall loss of GSNO thus varies with both GSNO and oxygen concentrations; a value of 0.66 was determined for an aerated solution of GSNO (0.86 mM). In the case of GSNO, therefore, generation of NO is not due solely to homolysis of the S-N bond; secondary reactions of the radicals formed lead to further NO liberation. In rationalizing the known phototoxicity of GSNO, possible contributions from thiyl and thiyl-derived radicals should be considered. In contrast to GSNO, direct excitation of BSANO (containing one bound NO group per molecule) led to photodecomposition with a quantum yield of 0.09 but no evidence was obtained for liberation of NO into the bulk medium.     

Rhodium carbenoid-initiated Claisen rearrangement: scope and mechanistic observations

[formula: see text] It has been shown that alpha-diazoketones react with allylic alcohols in the presence of Rh(II) catalysts to furnish intermediate enols which subsequently undergo Claisen rearrangement to alpha-hydroxyketones. Herein we report (1) studies into the mechanism of this transformation which establish that Claisen rearrangement is neither rhodium- nor acid-catalyzed but a reaction intrinsic to the intermediate enols that proceeds at a rate governed by enol substituents (R3, R4, R5) and (2) the reaction of alpha-diazoketones with propargylic alcohols and preliminary investigations into its scope and mechanism.