Probing The Binding Of Flavonoids And Anthracycline Drugs To Plasma Proteins And Synthesis Of Resveratrol-phenolic Acids Hybrids

In the circulatory system, plasma proteins are the main components of plasma and have many physiological functions, such as maintaining the osmotic pressure and pH of blood and transporting various small molecule drugs. Therefore, studies on the drug-plasma protein binding may play an important role for a deeper understanding of pharmacodynamics and pharmacokinetics in vivo. Flavonoids are a group of naturally occurring polyphenolic compounds, which have diverse physiological and pharmacological activities including antioxidant activity, prooxidant activitiy. anti-inflammatory activity, anti-tumor activity and so on. The anthracycline drugs such as doxorubicin and epirubicin are among the most widely used anticancer chemotherapeutic agents. In this paper, the interactions between the above compounds and plasma albumins were carefully investigated in order to provide valuable information for elucidating the mechanism of drug-protein interaction.In Chapter 2, the interactions of human serum albumin (HSA) with flavonoids. including taxifolin. dihydromyricetin, epicatechin. epigallocatechin, myricetin and myricitrin, have been investigated by NMR methods in combination with surface plasmon resonance (SPR) and molecular modeling. The SPR results showed that the binding capacity between flavonoids and HSA followed the order:myricetin> myricitrin> dihydromyricetin> epicatechin epigallocatechin> taxifolin, which was consistent with the results from NMR relaxation experiments. Competitive STD-NMR experiments using warfarin sodium and L-tryptopan as site-selective probes indicated that flavonoids bind to site I in the subdomain 11A of HSA. In addition, from the analysis of the STD NMR-derived binding epitopes and molecular docking models, we deduced that taxifolin, dihydromyricetin and myricetin have a similar binding mode, in which B ring embeds in the pocket of site I. However, the binding mode of the remaining compounds is slightly different, which A ring is highly buried within hydrophobic cavity.In Chapter 3, we investigated the binding interaction between doxorubicin/epirubicin and HSA. doxorubicin/epirubicin and α1-acid glycoprotein (AGP) respectively by NMR method along with molecular modeling. Our experimental results showed that the epimers stereoselectively bind to HSA and AGP. The two compounds bind HSA to a non-classical drug binding site (subdomain IB), wherease the binding site in AGP is lobe Ⅰ and lobe Ⅱ.In Chapter 4, we synthesized five resveratrol-phenolic acids hybrids, considering the construction of a hybrid, which contains two or more pharmacophore, is a promising approach for drug discovery.