On the Stereochemistry of Natural Irones,Dihydroirones, and their Precursors

Natural irones from the essential oil of Iris rhizomes develop by oxidative degradation of C₃₁-triterpenoids produced by the plant. Two enantiomeric forms of irones are found in Iris, oils of different origin. The optical properties and CD spectra of irones, dihydroirones and their C₃₁-precursors are reported and their absolute stereochemistry is determined.     

Synthesis of Cannabinoid Model Compounds. Part 3. (6aR, 10aR)-N-ethyl-Δ8-tetrahydrocannabinol-18-amide, (6aR, 10aR, 17 RS)-N-ethyl-17-methyl-Δ8- tetrahydrocannabinol-18-amide and (6aR, 10aR)-17,18-didehydro-Δ8-tetrahydrocannabinol

The novel cannabinoids (6aR, 10aR)-N-ethyl-Δ⁸-tetrahydrocannabinol-18-amide (15) and (6aR, 10aR, 17 RS)-N-ethyl-17-methyl-Δ⁸- tetrahydrocannabinol-18-amide (16) , designed as cannabinoid affinity ligands, were synthesized from the corresponding acids 11 and 12 via the N-hydroxysuccinimide esters. Amide 16 was tested in the rat and was generalized to Δ⁹-tetrahydrocannabinol, being 5 times less potent than the training drug. An improved synthesis of (6aR, 10aR)-17,18-didehydro-Δ⁸-tetrahydrocannabinol (23) is reported. As model reaction for the preparation of a tritiated Δ⁸-tetrahydrocannabinol, compound 23 was selectively deuterated at C(17) and C(18) in benzene/Et₃N using [(C₆H₅)₃P]₃RuCl₂ as catalyst.     

Structure Determination of a New Spirobicyclic Triterpenoid from Iris foetidissima

The novel iridal 10 has been isolated from rhizome extracts of Iris foetidissima. Its structure was established by spectroscopic methods and oxidative degradation. Final proof of the spirobicyclic nature of the compound – a new feature in the triterpenoid field – was afforded by the correlations observed in the 2D-HMBC- (¹H-detected multiple-bond heteronuclear multiple-quantum coherence) spectrum. The possible biogenesis of this unusual compound is discussed.     

Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC₅₀) of 2.7 × 10⁻⁴ and 1.9 ×  10⁻⁴ M, respectively, were observed.     

Molecular dynamics of a liquid-crystalline polymer with laterally fixed mesogenic side groups

Abstract

The long range molecular dynamical behaviour of liquid-crystalline side chain polymers with the mesogenic groups linked laterally to the backbone have been studied by using dielectric relaxation spectroscopy over a broad temperature and frequency range. The samples were oriented homeotropically and homogenously by electric and magnetic fields and the relaxations were recorded during alignment and with the fully aligned samples. By fitting the data to theoretical relaxation curves, accurate relaxation parameters could be determined, allowing us to perform a comparison with end-fixed liquid-crystalline side chain polymers on the one hand and with low molecular weight liquid crystals on the other. The relaxation in homeotropic alignment for the laterally fixed compound has more analogies in some aspects, for example, the relaxation time distribution, with low molecular weight liquid crystals than with the corresponding end-fixed compounds, though the activation energy is very large (241 kJ/mol). We relate this to the length of the rigid mesogenic unit and the resulting stronger repulsion by the neighbouring side chains during reorientation. In homogeneous alignment the relaxation is very broad and also has a large activation energy. Different molecular processes are related to this relaxation regime. The relationship between the different relaxation processes and the molecular structure is discussed.     

Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

Human histone deacetylase 8 is a well-recognized target for T-cell lymphoma and particularly childhood neuroblastoma. PD-404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys₁₀₂ and Cys₁₅₃. This study on the distinct effects of PD-404,182 on HDAC8 reveals that this compound induces the dose-dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD-404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges.     

Comparison of two force fields in MD-simulations of α-helical structures in keratins

Molecular dynamic (MD) simulations based on two different force fields, CVFF and CFF91, were carried out in order to check their feasibility for the structural investigation of the wool intermediate filament (IF) monomeric unit. Selecting an ideal α-helix as start conformation, all MD-simulations with CVFF in vaccum show the α-helix to be unstable. Independently of the amino acid sequence of the α-helix, a new helical structure with a larger diameter arises during the MD-simulation, due to a shift of the intrahelical hydrogen bonds. However in simulations with surrounding water the α-helix remains stable throughout the simulations with the CVFF force field. In contrast to this, MD-simulations in vaccume based on the CFF91 force field are able to determine different stabilities for the α-helical start conformation of various IF-segments, that agree well with secondary structure predictions. The simulation results obtained with CFF91 in vacuum can like wise be verified using an explicit water environment. We found that higher partial charges attributed to the atoms of the amide groups that form the intrahelical hydrogen bonds are the reason for the superiority of the CFF91 force field.