Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality

Diketopiperazines (DKPs) are a common motif in various biologically active natural products, and hence they may be useful scaffolds for the rational design of receptor probes and therapeutic agents. We constructed a new bicyclic scaffold that combines a DKP bridged with a 10-membered ring. In this way we obtained a three-dimensional molecular skeleton, with several amendable sites that provide a starting point to design a new combinatorial library having diverse substituent groups. Structural variation is based upon the flexibility of alkylation of the nitrogen atoms of the DKP and on the side-chain olefin. We obtained a 10-membered secondary ring through a ring-closure metathesis reaction using the second generation Grubbs catalyst. Rings containing both O-ethers and S-ethers were compared. N-Alkyl or arylalkyl groups were introduced optionally at the two Nalpha-atoms. This is a general scheme that will allow us to test rings of varying sizes, linkages, and stereochemical parameters. The DKP derivatives were tested for activity in astrocytoma cells expressing receptors coupled to phospholipase C. Inhibitory effects were observed for signaling elicited by activation of human nucleotide P2Y receptors but not m3 muscarinic receptors. Compound 20 selectively inhibited calcium mobilization (IC50 value of 486 +/- 16 nM) and phosphoinositide turnover elicited by a selective P2Y1 receptor agonist, but this compound did not compete for binding of a radiolabeled nucleotide-competitive receptor antagonist. Therefore, the new class of DKP derivatives shows utility as pharmacological tools for P2Y receptors.     

Probes for narcotic receptor-mediated phenomena. 33. Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine. synthesis of the penultimate oxide-bridged phenylmorphans

The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9beta-ol ((+/-)-10), an intermediate containing an aromatic nitro-activated fluorine atom. The fluorine atom was used as the leaving group for the formation of the strained tetracyclic trans-fused 5,6-ring system in rac-(1alpha,4aalpha,9aalpha)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-2H-1,4a-propanobenzofuro[2,3-c]pyridine ((+/-)-11), although preference for cis ring fusion during the formation of tricyclic tetra- and hexahydrodibenzofurans has been well-documented. Single-crystal X-ray crystallographic study of the desired para-e isomer ((+/-)-2), as well as of two intermediates in its synthesis, provided assurance of the correct structures. The e-isomers are among the last of the 12 oxide-bridged 5-phenylmorphans to be synthesized. We envisioned the syntheses of these rigid, tetracyclic compounds in order to determine the three-dimensional pattern of a ligand that would enable interaction with opioid receptors as agonists or antagonists.     

Van der Waals density functional for layered structures

To understand sparse systems, we must account for both strong local atom bonds and weak nonlocal van der Waals forces between atoms separated by empty space. A fully nonlocal functional form [Phys. Rev. B 62, 6997 (2000)]] of density-functional theory (DFT) is applied here to the layered systems graphite, boron nitride, and molybdenum sulfide to compute bond lengths, binding energies, and compressibilities. These key examples show that the DFT with the generalized-gradient approximation does not apply for calculating properties of sparse matter, while use of the fully nonlocal version appears to be one way to proceed.     

Horizon Entropy

Although the laws of thermodynamics are well established for black hole horizons, much less has been said in the literature to support the extension of these laws to more general settings such as an asymptotic de Sitter horizon or a Rindler horizon (the event horizon of an asymptotic uniformly accelerated observer). In the present paper we review the results that have been previously established and argue that the laws of black hole thermodynamics, as well as their underlying statistical mechanical content, extend quite generally to what we call here causal horizons. The root of this generalization is the local notion of horizon entropy density.     

Studying the Complexity of Global Verification for NP-Hard Discrete Optimization Problems

This paper examines the complexity of global verification for MAX-SAT, MAX-k-SAT (for k3), Vertex Cover, and Traveling Salesman Problem. These results are obtained by adaptations of the transformations that prove such problems to be NP-complete. The class of problems PGS is defined to be those discrete optimization problems for which there exists a polynomial time algorithm such that given any solution , either a solution can be found with a better objective function value or it can be concluded that no such solution exists and is a global optimum. This paper demonstrates that if any one of MAX-SAT, MAX-k-SAT (for k3), Vertex Cover, or Traveling Salesman Problem are in PGS, then P=NP.     

Analysis of the Xedni Calculus Attack

The xedni calculus attack on the elliptic curve discrete logarithm problem (ECDLP) involves lifting points from the finite field to the rational numbers and then constructing an elliptic curve over that passes through them. If the lifted points are linearly dependent, then the ECDLP is solved. Our purpose is to analyze the practicality of this algorithm. We find that asymptotically the algorithm is virtually certain to fail, because of an absolute bound on the size of the coefficients of a relation satisfied by the lifted points. Moreover, even for smaller values of p experiments show that the odds against finding a suitable lifting are prohibitively high.     

Determination of Albuterol Enantiomers in Animal Tissue Matrices by LC–MS/MS: Application in Therapeutic Myoanabolic Studies

Albuterol (salbutamol) is a widely used medication in respiratory disease including asthma and chronic obstructive airways disease; however, like other beta2-agonists, it also exerts some extrapulmonary effects on muscle and fat. Surprisingly, there have been relatively few reports of albuterol tissue distribution, and the distribution of individual albuterol enantiomers into tissue has not been reported. The method presented here explores the use of an HPLC tandem mass spectrometry (LC–MS/MS) system (LTQ Orbitrap hybrid mass spectrometer) with deuterated standard and solid-phase extraction to determine low levels of albuterol enantiomers in tissue. The lower limit of quantification (LLOQ) was 0.156 ng g⁻¹, with a precision RSD <15% for both enantiomers. The assay was linear over the calibration range of LLOQ-10.0 ng g⁻¹ in muscle tissue (r ² > 0.98). The assay was successfully applied to pharmacokinetic studies in rats and mice. By utilizing a deuterated internal standard and LC–MS/MS detection, this assay can be used to measure albuterol enantiomers in muscle tissue. This assay has also identified that albuterol uptake appears to be stereoselective, and enantioselective assays are clearly warranted for myoanabolic studies involving administration of racemic-albuterol.

     

Mixing Closures for Conservation Laws in Stratified Flows

A closure for shocks involving the mixing of the fluids in two-layer stratified flows is proposed. The closure maximizes the rate of mixing, treating the dynamical hydraulic equations and entropy conditions as constraints. This closure may also be viewed as yielding an upper bound on the mixing rate by internal shocks. It is shown that the maximal mixing rate is accomplished by a shock moving at the fastest allowable speed against the upstream flow. Depending on whether the active constraint limiting this speed is the Lax entropy condition or the positive dissipation of energy, we distinguish precisely between internal hydraulic jumps and bores. Maximizing entrainment is shown to be equivalent to maximizing a suitable entropy associated to mixing. By using the latter, one can describe the flow globally by an optimization procedure, without treating the shocks separately. A general mathematical framework is formulated that can be applied whenever an insufficient number of conservation laws is supplemented by a maximization principle.