Late-Stage Diversification of Tryptophan-Derived Biomolecules

Pd-mediated reactions have emerged as a powerful tool for the site-selective and bioorthogonal late-stage diversification of amino acids, peptides and related compounds. Indole moieties of tryptophan derivatives are susceptible to C²H-activation, whereas halogenated aromatic amino acids such as halophenylalanines or halotryptophans provide a broad spectrum of different functionalisations. The compatibility of transition-metal-catalysed cross-couplings with functional groups in peptides, other biologically active compounds and even proteins has been demonstrated. This Review primarily compiles the application of different cross-coupling reactions to modify halotryptophans, halotryptophan containing peptides or halogenated, biologically active compounds derived from tryptophan. Modern approaches use regio- and stereoselective biocatalytic strategies to generate halotryptophans and derivatives on a preparative scale. The combination of bio- and chemocatalysis in cascade reactions is given by the biocompatibility and bioorthogonality of Pd-mediated reactions.     

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles,Arenes, Olefins,and Alkanes using TMPZnCl⋅LiCl

The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl?LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pK_a values of functionalized N‐, S‐, and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.     

C−N,C−S and S−S Bond Cleavage by Rhodium PCcarbeneP Pincer Complexes

Rhodium PC_carbeneP complexes 1‐L {L=PPh₃, PPh₂(C₆F₅)} react with isothiocyanate, carbodiimide and disulphide to enable C?S, C?N and S?S bond cleavage. The cleaved molecules are sequestered by the metal center and the pincer alkylidene linkage, forming η²‐coordinated sulfide or imide centered pincer complexes. When a C?S or S?S bond is cleaved, the resulting complexes can bridge two rhodium centers through sulphur forming dimeric complexes and eliminating a monodentate phosphine ligand.     

Anti-Inflammatory Dysidazirine Carboxylic Acid from the Marine Cyanobacterium Caldora sp. Collected from the Reefs of Fort Lauderdale,Florida

Dysidazirine carboxylic acid (1) was isolated from the lipophilic extract of a collection of the benthic marine cyanobacterium Caldora sp. from reefs near Fort Lauderdale, Florida. The planar structure of this new compound was determined by spectroscopic methods and comparisons between HRMS and NMR data with its reported methyl ester. The absolute configuration of the single chiral center was determined by the conversion of 1 to the methyl ester and the comparison of its specific rotation data with the two known methyl ester isomers, 2 and 3. Molecular sequencing with 16S rDNA indicated that this cyanobacterium differs from Caldora penicillata (Oscillatoriales) and represents a previously undocumented and novel Caldora species. Dysidazirine (2) showed weak cytotoxicity against HCT116 colorectal cancer cells (IC₅₀ 9.1 µM), while dysidazirine carboxylic acid (1) was non-cytotoxic. Similar cell viability patterns were observed in RAW264.7 cells with dysidazirine only (2), displaying cytotoxicity at the highest concentration tested (50 µM). The non-cytotoxic dysidazirine carboxylic acid (1) demonstrated anti-inflammatory activity in RAW264.7 cells stimulated with LPS. After 24 h, 1 inhibited the production of NO by almost 50% at 50 µM, without inducing cytotoxicity. Compound 1 rapidly decreased gene expression of the pro-inflammatory gene iNOS after 3 h post-LPS treatment and in a dose-dependent manner (IC₅₀ ~1 µM); the downregulation of iNOS persisted at least until 12 h.     

Ambident electrophilicity of O,O-diethyl-S-phenyl phosphorothiolate

Reaction between O,O-diethyl-S-phenyl phosphorothiolate and lithium dialkylamides results in the displacement of the PhS substituent by the R₂N group. With Grignard reagents, the same substrate gives products of the nucleophilic substitution at both the phosphorus and the sulfur atom.     

C=X π-Systeme

Im Rahmen des Graduiertenkollegs “Hochreaktive Mehrfachbindungssysteme” hatten G. Erker und J. Grobe vom 16. bis 18. November 1994 schon zum zweiten Mal nach Münster eingeladen. “Organic and Inorganic Chemistry of Reactive C=X π-Systems” waren diesmal das Thema.     

THEORETICAL PREDICTIONS OF STRUCTURES AND VIBRATIONAL INFRARED FREQUENCIES. I. MERCAPTANS AND SULFIDES

Abstract

We report the computed equilibrium geometries and vibrational infrared frequencies of a group of thirteen mercaptans and sulfides. The computations were based on the Gaussian 86 Program Package utilizing 3-21G basis sets. The theoretical bond distances and bond angles are in agreement with the available experimental data. The agreement between computed frequencies and available experimental values seems reasonable. We also used the computations as guidelines for the assignment of available experimental infrared frequencies. We believe that it is possible to make reliable frequency predictions by combining computations with available experimental data for groups of similar molecules. However, it is necessary to introduce different correction factors for different types of vibrational modes if we use 3-21G basis sets.     

Recognition hysteresis of the acetylcholine receptor of torpedo Californica

The nicotinic acetylcholine receptor (nAcChR) of the electric organ of Torpedo californica fish exhibits a pronounced hysteresis loop in the high affinity binding of the neurotransmitter acetylcholine (AcCh). When increasing amounts of AcCh are added (pulse mode) an extremely long-lived, metastable conformer distribution is obtained (lower hysteresis branch) between low affinity AcCh binding states (R_l) and high (R_h) and very high (R_vh) affinity states. Dialysis conditions always lead to the equilibrium binding curve (upper hysteresis branch; K̄_A = 5 × 10⁻⁹M, 4°C; one A bound to the R-monomer of M_r ≈ 290 000). Cyclic, pulse mode addition and dilution of AcCh results in scanning loops within the main hysteresis. The kinetic analysis of the changes in free and bound AcCh during the open-system conditions of dialysis, that releases the metastability, shows that the AcCh (A) binding proceeds along an induced-fit pathway according to A+R_h ⇋ AR_n ⇋ AR_vh. The rate constant of the step AR_h → AR_vh is k₂ = 6 × 10⁻³s⁻¹ and that of the reverse step is k₋₂ = 3 × 10⁻⁴s⁻¹. Direct binding of A to free R_vh can be excluded. Therefore, the state R_vh does not preexist, it is induced and only stable, as AR_vh, by bound AcCh. The metastability can be described in terms of long-lived AR_vh ·R₁ hybrid dimers. Physiologically, the metastable hybrid may be viewed as a saving device: the functionally important, channel-active R₁ conformer is, at low AcCh-concentrations [A] < 1μM, prevented to convert to the desensitized states R_h and AR_vh. Furtheron, AcCh enhances the phosphorylation of phosphatidyl inositol and the auto-phosphorylation of the receptor. If the AcCh binding hysteresis causes a phosphorylation hysteresis the desensitized nAcChR may serve as a memory molecule of the transsynaptic information signalling of the neurotransmission.     

Systematic event generator tuning for the LHC

In this article we describe Professor, a new program for tuning model parameters of Monte Carlo event generators to experimental data by parameterising the per-bin generator response to parameter variations and numerically optimising the parameterised behaviour. Simulated experimental analysis data is obtained using the Rivet analysis toolkit. This paper presents the Professor procedure and implementation, illustrated with the application of the method to tunes of the Pythia 6 event generator to data from the LEP/SLD and Tevatron experiments. These tunes are substantial improvements on existing standard choices, and are recommended as base tunes for LHC experiments, to be themselves systematically improved upon when early LHC data is available.