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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Available from: Mercedes Campillo, Oct 07, 2015
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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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    ABSTRACT: A series of 2-substituted amino-3-chloro-1,4-naphthoquinone derivatives (3-12) were synthesized as anticancer agents and tested against four cancer cell lines including HepG2, HuCCA-1, A549 and MOLT-3. The most potent cytotoxic activity against the HepG2, HuCCA-1 and A549 cell lines was found to be m-acetylphenylamino-1,4-naphthoquinone (8) affording IC50 values of 4.758, 2.364 and 12.279 μM, respectively. On the other hand, p-acetylphenylamino-1,4-naphthoquinone (9) exhibited the most potent cytotoxic activity against the MOLT-3 cell line with an IC50 of 2.118 μM. Quantitative structure-activity relationship (QSAR) investigations provided good predictive performance as observed from cross-validated R of 0.9177-0.9753 and RMSE of 0.0614-0.1881. The effects of substituents at the 2-amino position on the naphthoquinone core structure and its corresponding influence on the cytotoxic activity were investigated by virtually constructing additional 1,4-naphthoquinone compounds (13-36) for which cytotoxic activities were predicted using equations obtained from the previously constructed QSAR models. Interpretation of informative descriptors from QSAR models revealed pertinent knowledge on physicochemical properties governing the cytotoxic activities of tested cancer cell lines. It is anticipated that the QSAR models developed herein could provide guidelines for further development of novel and potent anticancer agents.
    European Journal of Medicinal Chemistry 09/2014; 84:247–263. DOI:10.1016/j.ejmech.2014.07.024 · 3.45 Impact Factor
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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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    ABSTRACT: This work deals with the synthesis and evaluation of new compounds designed by combination of 1,4-naphthoquinone and ferrocene fragments in a 3-ferrocenylmethyl-2-hydroxy-1,4-naphthoquinone arrangement. A practical coupling reaction between 2-hydroxy-1,4-naphthoquinone and ferrocenemethanol derivatives has been developed. This procedure can be carried out "on-water", at moderate temperatures and without auxiliaries or catalysts, with moderate to high yields. The synthesized derivatives have shown significant in vitro antiplasmodial activity against chloroquine-sensitive and resistant Plasmodium falciparum strains and it has been shown that this activity is not related to the inhibition of biomineralization of ferriprotoporphyrin IX. Binding energy calculations and docking of these compounds to cytochrome b in comparison with atovaquone have been performed.
    European Journal of Medicinal Chemistry 10/2013; 70C:548-557. DOI:10.1016/j.ejmech.2013.10.011 · 3.45 Impact Factor
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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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    ABSTRACT: Apatone™, a combination of menadione (2-methyl-1,4-naphthoquinone, VK3) and ascorbic acid (vitamin C, VC) is a new strategy for cancer treatment. Part of its effect on tumor cells is related to the cellular pro-oxidative imbalance provoked by the generation of hydrogen peroxide (H2O2) through naphthoquinone redox cycling. In this study, we attempted to find new naphthoquinone derivatives that would increase the efficiency of H2O2 production, thereby potentially increasing its efficacy for cancer treatment. The presence of an electron-withdrawing group in the naphthoquinone moiety had a direct effect on the efficiency of H2O2 production. The compound 2-bromo-1,4-naphthoquinone (BrQ), in which the bromine atom substituted the methyl group in VK3, was approximately 10- and 19-fold more efficient than VK3 in terms of oxygen consumption and H2O2 production, respectively. The ratio [H2O2]produced / [naphthoquinone]consumed was 68 ± 11 and 5.8 ± 0.2 (µM/µM) for BrQ and VK3, respectively, indicating a higher efficacy of BrQ as a catalyst for the autoxidation of ascorbic acid. Both VK3 and BrQ reacted with glutathione (GSH), but BrQ was the more effective substrate. Part of GSH was incorporated into the naphthoquinone, producing a nucleophilic substitution product (Q-SG). The depletion of BrQ by GSH did not prevent its redox capacity since Q-SG was also able to catalyze the production of reactive oxygen species. VK3/VC has already been submitted to clinical trials for the treatment of prostate cancer and has demonstrated promising results. However, replacement of VK3 with BrQ will open new lines of investigation regarding this approach to cancer treatment.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 05/2012; 45(8):701-10. DOI:10.1590/S0100-879X2012007500078 · 1.01 Impact Factor
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