A series of new derivatives of the natural β-carboline alkaloid harmine, introducing hydrophobic substituents into positions 7 and 9 were synthetized as potential anticancer agents. Their binding affinities for human serum albumin (HSA) and α 1 -acid-glycoprotein (AAG) were investigated by affinity chromatography combined with fluorescence, circular dichroism (CD) and UV absorption spectroscopy. The weak binding of harmine to both proteins (K a ~ 3 × 10 4 M -1 ) was highly increased by aromatic substitutions (K a ~ 10 5 -10 6 M -1 ).Derivatives having a substituted benzyl group in the N 9 -position of the β-carboline nucleus showed about tenfold and hundred fold affinity enhancement for HSA and AAG, respectively.Such a strong plasma protein interaction would be of pharmacokinetic relevance for these potential drug candidates. Induced CD spectra indicated the variant selective, dimeric binding of the 7-pyridylethoxy derivative to AAG. Absorbance and fluorescence spectra refer to the binding preference of the neutral form of the studied β-carbolines for both proteins.
The stereoselective synthesis of chiral heterocyclic carbene precursors and the structural features of their silver and gold complexes were investigated. The prepared compounds are all based on the imidazolidine scaffold and bear the bulky tert-butyl substituent on the backbone in a stereocontrolled manner. The majority of the synthesized carbene precursors carry an additional element of central chirality in the side chain, and for some of them on formation of their silver or gold complexes a third element of asymmetry, axial chirality through hindered rotation of the aromatic substituent, is also present. The systematic study of the stereoselective formation of the NHC precursors led to scalable routes without the need for chiral chromatography. The NHC precursors were transformed efficiently into their silver and gold complexes, whose structural features were studied in detail both in solution and in the solid phase.
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