Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

Abstract

Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC 50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin ( 11), potently inhibited the proliferation of various cancer cell lines with IC 50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 μM, respectively. Treatment of cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified quinones as Aurora kinase inhibitors that can serve as a lead for future drug discovery endeavors.

Biological Activity of Naphthoquinones Derivatives in the Search of Anticancer Lead Compounds

“…Ten naphthoquinones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) selected from the wheat coleoptile bioassay (Figure 2) were evaluated in a first screening of cytotoxicity on HeLa cells at 100 µM for 24 h using the Trypan blue dye exclusion method. An untreated control (cells treated with 0.1% DMSO) and a positive control (cells treated with etoposide at 100 µM) were also included and evaluated for 24 h. This is a simple, rapid, economic, and widely used method to assess cell viability after treatment with desired compounds [19].…”

“…(1 and 2), products (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) classified by skeleton using different colors, and positive control (etoposide) were evaluated at 100 μM for 24 h. Experiments were performed in triplicate, and data are expressed as mean ± SD, n = 3, * p < 0.05 vs. untreated cells (DMSO 0.1%).…”

“…This cytotoxicity has been mainly ascribed to the ability of naphthoquinones to generate reactive oxygen species (ROS) as well as the electrophilicity of the quinone moiety to react with different biological targets through 1,4-Michael addition by the nucleophilic thiol species, proteins, DNA and RNA [ 8 , 9 , 10 ]. Other mechanisms of action have also been described, including the regulation of the tumor suppressor factor p53, inhibition of topoisomerase II, induction of apoptosis via ERS (endoplasmic reticulum stress) or Aurora-kinase inhibitors [ 11 , 12 , 13 ].…”

Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance

“…With interest in developing new anticancer agents, ,− this study aimed to prepare a concise library of podophyllotoxin derivatives and investigate its antiproliferative potential. SSE1806 was identified as the most potent derivative and was characterized as a microtubule polymerization inhibitor that could overcome multidrug resistance.…”

Halogen Regulation in Vinylene-Linked Covalent Organic Frameworks for Efficient Photocatalytic C–H Thiolation of Quinone Derivatives

“…Quinones are important chemicals in nature and are widely used in various therapeutic drugs, such as anticancer, antibacterial, antifungal, antiviral, and antimalarial, because of their various biological and pharmacological activities. − Naphthoquinone is a significant branch of quinones and is known for its various biological and pharmacological activities, which have been widely reported and studied. − In particular, the quinonyl aryl thioether is a kind of molecule with proven biological activity and has wonderful applications in the synthesis and design of valuable medicine. Currently, although various transition-metals-based catalysts were explored to mediate the thiolation of naphthoquinones, − some drawbacks, including high cost, high toxicity, and environmental pollution, have further restricted their development.…”