Synthesis and Pharmacophore Modeling of Naphthoquinone Derivatives with Cytotoxic Activity in Human Promyelocytic Leukemia HL-60 Cell Line

Universidad de La Laguna, San Cristóbal de La Laguna, Canary Islands, Spain
Journal of Medicinal Chemistry (Impact Factor: 5.45). 02/2007; 50(4):696-706. DOI: 10.1021/jm060849b
Source: PubMed


Catalyst/HypoGen pharmacophore modeling approach and three-dimensional quantitative structure-activity relationship (3D-QSAR)/comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to explain the cytotoxic activity of a set of 51 natural and synthesized naphthoquinone derivatives tested in human promyelocytic leukemia HL-60 cell line. The computational models have facilitated the identification of structural elements of the ligands that are key for antitumoral properties. The four most salient features of the highly active beta-cycled-pyran-1,2-naphthoquinones [0.1 microM < IC50 < 0.6 microM] are the hydrogen-bond interactions of the carbonyl groups at C-1 (HBA1) and C-2 (HBA2), the hydrogen-bond interaction of the oxygen atom of the pyran ring (HBA3), and the interaction of methyl groups (HYD) at the pyran ring with a hydrophobic area at the receptor. The moderately active 1,4-naphthoquinone derivatives accurately fulfill only three of these features. The results of our study provide a valuable tool in designing new and more potent cytotoxic analogues.

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    • "Compounds at 50 mg/mL exhibiting less than 50% inhibition were considered to be inactive whereas ones exhibiting greater than 50% inhibition were considered to be active and their IC 50 values were calculated. Compounds 1 and 3e12 were categorized by their cytotoxic activities as highly active (IC 50 < 1 mM), moderately active (1 mM < IC 50 < 10 mM), weakly active (IC 50 > 10 mM) [37] and inactive (IC 50 > 50 mg/mL) as shown in Table 1. "
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    • "Also, exogenous synthetic quinones (or quinones isolated from natural sources) have been shown to inhibit different physio-pharmacological targets, to cause oxidative stress and cell death of microbes [7]. Furthermore, different naphthoquinones have been reported and clinically used as anticancer, antifungal, antiprotozoal, and antibacterial therapeutic agents, as well as platelet antiaggregants and to prevent the myotoxicity of snake venom [8] [9] [10] [11] [12] [13] [14]. Their biological activity has been ascribed to their electronic properties and, in some cases, to specific interactions with defined targets such as DNA and dihydroorotate dehydrogenase [15]. "
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    • "We studied the capacity of naphthoquinone derivatives in terms of their efficacy as generators of H2O2 when combined with ascorbic acid. The naphthoquinone moiety is an important pharmacophoric element for cytotoxic activity (23) and the reduction potential of the aromatic compounds is sensitive to the presence of substituent groups in the ring (24). Thus, we compared the redox properties of menadione with BrQ and MQ (Figure 1). "
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