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A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

We construct an effective Hamiltonian via Monte Carlo from a given action. This Hamiltonian describes physics in the low energy regime. We test it by computing spectrum, wave functions and thermodynamical observables (average energy and specific heat) for the free system and the harmonic oscillator. The method is shown to work also for other local potentials.Comment: LaTeX file (text) + 9 PS files (figures + tables

We suggest a closed form expression for the path integral of quantum transition amplitudes. We introduce a quantum action with renormalized parameters. We present numerical results for the V ∼ x 4 potential. The renormalized action is relevant for quantum chaos and quantum instantons.

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A synthesis of the complete carbon skeleton of the nargenicins, represented by tricyclic lactone 45, is described. The key step of the synthesis of 45 is the Yamaguchi macrolactonization of hydroxy acid 44 which is followed by the facile transannular Diels−Alder reaction of the 18-membered macrolide 22. This sequence provides tricycle 45 in 66% yield, along with a 14% yield of tricycle 46 which is epimeric at C(10). Macrolide 22 was obtained in 38% yield when the macrolactonization was performed at 80 °C. The transannular Diels−Alder reaction of 22 at 80 °C provided tricycle 45 as the exclusive product (85% yield). In contrast, the intramolecular Diels−Alder reaction of seco ester 43 provided a mixture of trans-fused 47 in 56% yield and the desired cis-fused cycloadduct 48 in only 27% yield. Two independent stereochemical control features determine the success of the transannular Diels−Alder reaction of 22:  the C(6)−Br steric directing group that dictates that only one of the two faces of the diene is accessible to the dienophile in transition state 14 and allylic strain considerations involving the C(16)−Me substituent which enable only one face of the dienophile to be accessible to the diene in transition state 14. The latter effect is operational only in the transannular cycloaddition mode as indicated by the results with 43. An added benefit of this strategy is that the 10-membered lactone is established by a formal ring contraction of the more easily synthesized 18-membered lactone. Attempts to extend this strategy to the transannular Diels−Alder reaction of the C(13)-hydroxyl substituted macrolide 13 have not been successful.

An exhaustive compilation of biologically active libraries covering the years 1992-1997 was presented in a previous review [1a]. In that review, libraries were divided among 4 major categories, including those active against proteases, non-proteolytic enzymes, Gprotein coupled receptors, and non-G-protein coupled receptors. A generic structure for each library was provided as well as the structure of the most active member. The number of biologically active libraries reported in the literature during this time period (86 total) represents <25% of the total number of published library constructs. Disclosure of library synthesis without accompanying screening data is a more common occurrence. Because these types of libraries are equally important to the practicing combinatorial chemist, it was thought that a comprehensive listing of such libraries spanning the years 1992-1997 would be a useful supplement to the previous review [1a,b].Library constructs [2-248] listed herein are relegated to one of five tables. Table 1 is entitled 'Scaffold derivatization' and includes all constructs in which a multi-functional scaffold is modified in some fashion to create a library. An example of a construct found in Table 1 would be the sequential addition of three nucleophiles to trichloropyrimidine. Table 2, entitled 'Acyclic synthesis', lists all linear constructs such as those derived from multi-component Ugi condensations.

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