|Title||Synthesis and serum protein binding of novel ring-substituted harmine derivatives|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Domonkos, C, Zsila, F, Fitos, I, Visy, J, Kassai, R, Balint, B, Kotschy, A|
A series of new derivatives of the natural [small 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 [small 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 (Ka [similar] 3 [times] 104 M-1) was highly increased by aromatic substitutions (Ka [similar] 105-106 M-1). Derivatives having a substituted benzyl group in the N9-position of the [small 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 [small beta]-carbolines for both proteins.