4 research outputs found
Biológiailag aktív béta-karbolin vegyületek humán szérumfehérje kötődésének vizsgálata spektroszkópiai, kromatográfiás és in silico módszerek alkalmazásával
Synthesis and serum protein binding of novel ring-substituted harmine derivatives
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
Fatty Acid Modulated Human Serum Albumin Binding of the β‑Carboline Alkaloids Norharmane and Harmane
Harmane and norharmane are representative
members of the large
group of natural β-carboline alkaloids featured with diverse
pharmacological activities. In blood, these agents are transported
by human serum albumin (HSA) which has a profound impact on the pharmacokinetic
and pharmacodynamic properties of many therapeutic drugs and xenobiotics.
By combination of various spectroscopic methods, the present contribution
is aimed to elucidate how nonesterified fatty acids (FAs), the primary
endogenous ligands of HSA, affect the binding properties of harmane
and norharmane. Analysis of induced circular dichroism (CD) and fluorescence
spectroscopic data indicates the inclusion of the neutral form of
both molecules into the binding pocket of subdomain IIIA, which hosts
two FA binding sites, too. The induced CD and UV absorption spectra
of harmane and norharmane exhibit peculiar changes upon addition of
FAs, suggesting the formation of ternary complexes in which the lipid
ligands significantly alter the binding mode of the alkaloids via
cooperative allosteric mechanism. To our knowledge, it is the first
instance of the demonstration of drug-FA cobinding at site IIIA. In
line with these results, molecular docking calculations showed two
distinct binding positions of norharmane within subdomain IIIA. The
profound increase in the affinity constants of β-carbolines
estimated in the presence of FAs predicts that the unbound, pharmacologically
active serum fraction of these compounds strongly depends on the actual
lipid binding profile of HSA
Fatty acid modulated human serum albumin binding of the β-carboline alkaloids norharmane and harmane
Harmane and norharmane are representative members of the large group of natural β-carboline alkaloids featured with diverse pharmacological activities. In blood, these agents are transported by human serum albumin (HSA) which has a profound impact on the pharmacokinetic and pharmacodynamic properties of many therapeutic drugs and xenobiotics. By combination of various spectroscopic methods, the present contribution is aimed to elucidate how non-esterified fatty acids (FAs), the primary endogenous ligands of HSA, affect the binding properties of harmane and norharmane. Analysis of induced circular dichroism (CD) and fluorescence spectroscopic data indicates the inclusion of the neutral form of both molecules into the binding pocket of subdomain IIIA, which hosts two FA binding sites, too. The induced CD and UV absorption spectra of harmane and norharmane exhibit peculiar changes upon addition of FAs suggesting the formation of ternary complexes in which the lipid ligands significantly alter the binding mode of the alkaloids via cooperative allosteric mechanism. To our knowledge, it is the first instance of the demonstration of drug-FA co-binding at site IIIA. In line with these results, molecular docking calculations showed two distinct binding positions of norharmane within subdomain IIIA. The profound increase in the affinity constants of β-carbolines estimated in the presence of FAs predicts that the unbound, pharmacologically active serum fraction of these compounds strongly depends on the actual lipid binding profile of HSA