Chemical reactivity and biological activity of chalcones and other α,ß-unsaturated carbonyl compounds.

Abstract 1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti-inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction. 2. The present study used a model system estimating the reactivity of different synthetic chalcones and other α,ß-unsaturated carbonyl compounds with thiols and compared the chemical reactivity with the biological activity, measured by HO-1 expression in human dermal fibroblasts. 3. Chemical reactivity with the thiol group of N-acetylcysteine was determined with 5,5'-dithiobis-(2-nitrobenzoic acid) and followed chemical principles of structure-reactivity relationship. Most reactive were sulforaphane, dimethylfumarate, chalcone 3 ((2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one) and chalcone 7 (1,3-diphenylprop-2-yn-1-one). This result demonstrates that α,ß-unsaturated carbonyl derivatives react with thiols differently. All compounds were also biologically active; however, expression of HO-1 was not only related to the chemical reactivity but also to the lipophilicity of the molecules which likely affected transmembrane uptake. Most efficient inducers of HO-1 expression were BAP, 4-hydroxynonenal and chalcone 1 (4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile), chalcone 5 ((2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one) and chalcone 7.

Fourier transform infrared spectroscopy of 2'-deoxycytidine aggregates in CDCl3 solutions.

We investigated the self-aggregation of 2'-deoxy-3',5'-bis(tert-butyldimethylsilyl)-cytidine dC(TBDMS)(2) in CDCl(3) solutions by Fourier transform infrared (FT-IR) spectroscopy and report the formation of larger aggregates than dimers in this solvent for the first time. The hydrogen bonding patterns in these complexes, which occur with increasing concentration may serve as a model for DNA super-structures such as triplexes. From the IR spectra, wavelength dependent absolute extinction coefficients of the monomer, dimer as well as a contribution from larger clusters which are supposedly trimers are deduced on the basis of a simple deconvolution method. Our results are supported by RI-B3LYP/TZVP calculations within the conductorlike screening model framework, to account for solvent effects in the ab initio calculations.

The α,5-dicarboxy-2-nitrobenzyl caging group, a tool for biophysical applications with improved hydrophilicity: synthesis, photochemical properties and biological characterization.

Earlier we reported on the synthesis of α,4-dicarboxy-2-nitrobenyzl caged compounds (Schaper, K. et al. [2002] Eur. J. Org. Chem., 1037-1046). These compounds have the advantage of an increased hydrophilicity compared with the well-established α-carboxy-2-nitrobenzyl caged compounds; however, the release of the active compound becomes slower due to the introduction of the additional carboxy group. Based upon theoretical calculations we predicted that the release would become faster when the additional carboxy group is moved to the 5-position. Here we describe the synthesis and the photochemical and biological characterization of an α,5-dicarboxy-2-nitrobenyzl caged compound. The high hydrophilicity of the new caging group is maintained due to the fact that the additional carboxy moiety is preserved, while the release of the active species from the new derivative is even faster than for the reference, an α-CNB caged compound.

Structural assignment of adenine aggregates in CDCl3.

We reinvestigated the self-association of 9-substituted adenine derivatives in CDCl3 solutions and present the infrared spectra of 9-ethyladenine and N-methyl-9-ethyladenine and its aggregates in the spectral regions between 1500 and 1800 cm(-1) and between 2700 and 3600 cm(-1). Wavelength dependent absolute extinction coefficients of the monomer and dimers are presented on the basis of a simple deconvolution method. Comparison of the deconvoluted dimer spectra with quantum chemical calculations allows for a structural assignment of the two dimer structures that coexist in 9-ethyladenine/CDCl3 solutions. In contrast, the dimer spectrum of N-methyl-9-ethyladenine is dominated by a single isomer.