Abstract
5-Amino-8-hydroxyquinoline (5A8HQ), an amino derivative of 8-hydroxyquinoline, has become a potential anticancer candidate because of its promising proteasome inhibitory activity to overcome and yet synergize bortezomib for fighting cancers. Therefore, in this study, its physicochemical properties and interaction activities with serum protein have extensively been elucidated by both in vitro and in silico approaches to fulfill the pharmacokinetic and pharmacodynamic gaps. 5A8HQ exhibited the drug-likeness properties, where oral administration seems to be a route of choice owing to its high-water solubility and intestinal absorptivity. Multi-spectroscopic investigations suggested that 5A8HQ tended to associate with bovine serum albumin (BSA), a representative of serum protein, via the ground-state complexation. It apparently bound in a protein cleft between subdomains IIA and IIIA of BSA as suggested by the molecular docking and molecular dynamics simulations. The binding was mainly driven by hydrogen bonding and electrostatic interactions with a moderate binding constant at 104 M−1, conforming with the predicted free fraction in serum at 0.484. Therefore, 5A8HQ seems to display a good bioavailability in plasma to reach target sites and exerts its potent pharmacological activity. Likewise, serum albumin is a good candidate to be reservoir and transporter of 5A8HQ in the circulatory system.
Highlights
5-Amino-8-hydroxyquinoline (5A8HQ), an amino derivative of 8-hydroxyquinoline, has become a potential anticancer candidate because of its promising proteasome inhibitory activity to overcome and yet synergize bortezomib for fighting cancers
Albumin is the most abundant protein in serum of mammals, which can be found at a concentration range of 35–50 mg/mL in healthy person to serve as vital physiological functions, such as maintaining homeostasis and oncotic pressure, transporting numerous intrinsic and extrinsic molecules, providing antioxidative and anticoagulant effects, modulating neutrophil adhesion in the inflammatory process, as well as controlling pharmacokinetics and pharmacodynamics of drugs[20,21]
Fluorescence quenching studies indicated that 5A8HQ was associated with bovine serum albumin (BSA) through the ground-state complex formation with a moderate binding constant at 1 04 M−1, which was comparable to other 8HQ derivatives, such as 2‐amino‐8‐hydroxyquinoline[62] and 5-chloro-8-hydroxyquinoline[50], but not clioquinol (5-chloro-7-iodo-8-hydroxyquinoline; KA = 108 M−1)[58]
Summary
5-Amino-8-hydroxyquinoline (5A8HQ), an amino derivative of 8-hydroxyquinoline, has become a potential anticancer candidate because of its promising proteasome inhibitory activity to overcome and yet synergize bortezomib for fighting cancers. In this study, its physicochemical properties and interaction activities with serum protein have extensively been elucidated by both in vitro and in silico approaches to fulfill the pharmacokinetic and pharmacodynamic gaps. Multi-spectroscopic investigations suggested that 5A8HQ tended to associate with bovine serum albumin (BSA), a representative of serum protein, via the ground-state complexation. Multi-spectroscopic methods (e.g., absorption, circular dichroism, and fluorescence spectrometry) together with various biophysical models (e.g., Stern–Volmer’s, Hill’s, and thermodynamic models) have been employed to determine interaction mechanism and conformational alteration of BSA and 5A8HQ. Their binding pocket and structural stability have been explored by molecular docking and coarse-grained protein modeling tools. Physicochemical parameters Molecular weight (g/mol) WLogP MLogP Number of rotatable bonds Number of H-bond acceptors Number of H-bond donors Topological polar surface area (Å2) Molar refractivity
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