Issue 66, 2015

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

Abstract

A series of new derivatives of the natural β-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 α1-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 ∼ 3 × 104 M−1) was highly increased by aromatic substitutions (Ka ∼ 105–106 M−1). Derivatives having a substituted benzyl group in the N9-position of the β-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 β-carbolines for both proteins.

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

Supplementary files

Article information

Article type
Paper
Submitted
10 apr 2015
Accepted
09 jun 2015
First published
10 jun 2015

RSC Adv., 2015,5, 53809-53818

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

C. Domonkos, F. Zsila, I. Fitos, J. Visy, R. Kassai, B. Bálint and A. Kotschy, RSC Adv., 2015, 5, 53809 DOI: 10.1039/C5RA06426K

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