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

Domonkos, Celesztina Diána and Zsila, Ferenc and Fitos, Ilona and Benéné Visy, Júlia and Kassai, Rudolf and Kotschy, András (2015) Synthesis and serum protein binding of novel ring-substituted harmine derivatives. RSC ADVANCES, 5. pp. 53809-53818. ISSN 2046-2069

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Abstract

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 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.

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