Synthesis and serum protein binding of novel ring-substituted harmine derivatives

A series of new derivatives of the natural beta-carboline alkaloid harmine, introducing hydrophobic substituents into positions 7 and 9 were synthesized as potential anticancer agents. Their binding affinities for human serum albumin (HSA) and alpha(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 similar to 3 x 10(4) M-1) was highly increased by aromatic substitutions (K-a similar to 10(5)-10(6) M-1). Derivatives having a substituted benzyl group in the N-9-position of the beta-carboline nucleus showed about tenfold and hundredfold 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 beta-carbolines for both proteins.