Understanding cancer and the anticancer activities of naphthoquinones – a review (original) (raw)
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RSC Advances
The non-communicable disease, cancer, is one of the major causes of death across the world and is forecast to increase by 75% to reach close to 25 million cases over the next two decades. Radiotherapy and surgical approaches have been unsuccessful in controlling the incidence of most cancers. The development of chemotherapeutic strategies involving novel small molecule antitumour agents has therefore been the focus area of cancer chemotherapy for several decades as another strategy to combat and control the incidence of cancer. Many natural products as well as several synthetic drugs have a naphthoquinone chromophore. The anticancer activities of naphthoquinones have been the focus of much research to discover novel anticancer agents. The naturally occurring 1,2-naphthoquinone-based compound, ß-Lapachone (ARQ 761), is currently being assessed for its anti-tumour activity against advanced solid tumours. This review describes the most recent applications of naphthoquinones and their d...
The diverse mechanisms and anticancer potential of naphthoquinones
Cancer Cell International, 2019
Cancer is one of the leading causes of death around the world and although the different clinical approaches have helped to increase survival rates, incidence is still high and so its mortality. Chemotherapy is the only approach which is systemic, reaching cancer cells in all body tissues and the search for new potent and selective drugs is still an attractive field within cancer research. Naphthoquinones, natural and synthetic, have garnered much attention in the scientific community due to their pharmacological properties, among them anticancer action, and potential therapeutic significance. Many mechanisms of action have been reported which also depend on structural differences among them. Here, we describe some of the most relevant mechanisms of action reported so far for naphthoquinones and highlight novel targets which are being described in the literature. Furthermore, we gather some of the most impressive efforts done by researchers to harness the anticancer properties of these compounds through specifically designed structural modifications.
Synthesis and Cytotoxic Evaluation of a Series of 2-Amino-Naphthoquinones against Human Cancer Cells
Molecules, 2014
The cytotoxicity of a series of aminonaphthoquinones resulting from the reaction of suitable aminoacids with 1,4-naphthoquinone was assayed against SF-295 (glioblastoma), MDAMB-435 (breast), HCT-8 (colon), HCT-116 (colon), HL-60 (leukemia), OVCAR-8 (ovarian), NCI-H358M (bronchoalveolar lung carcinoma) and PC3-M (prostate) cancer cells and also against PBMC (peripheral blood mononuclear cells). The results demonstrated that all the synthetic aminonaphthoquinones had relevant cytotoxic activity against all human cancer lines used in this experiment. Five of the compounds showed high cytotoxicity and selectivity against all cancer cell lines tested (IC 50 = 0.49 to 3.89 µg•mL −1). The title compounds were less toxic to PBMC, since IC 50 was 1.5 to
Synthetic Communications, 2019
1,4-Naphthoquinones (1,4-NQ) have been reported to possess a variety of pharmacological properties including antibacterial, antifungal, antiviral, anti-inflammatory, anti-artherosclerotic, and anticancer effects. In this study, new Nand S,S-substituted-1,4-NQ derivatives were synthesized in excellent yields and were completely characterized by spectroscopic analysis IR, NMR (1 H and 13 C), MS and microanalysis. The cytotoxic activities of 1,4-NQ derivatives were examined against to A-549, DU145, HCT-116 and MDA-MB-231 cancer cells. Among these compounds, 2-[4-(2-furoyl)piperazine-1-yl]-3-chloro-1,4-NQ 5 and 2,3-bis(cyclobuthylsulfanyl)-1,4-NQ 17 were identified as the most potent anticancer agents with cytotoxic activity against three cell lines (breast (MDA-MB-231), prostate (DU145), colorectal (HCT-116).
2017
Two novel 1,4-naphthoquinone derivatives containing salicylic acid and procaine moieties were synthesized and evaluated for their anticancer activity in vitro. The antiproliferative effect was assayed against MDA-MB-231 cells, a human breast adenocarcinoma cell line, using CellTiter-Glo® Luminescent Cell Viability Assay. Both compounds tested proved a growth inhibition effect on this cell line in a dose-dependent manner. Our results showed that the compound with procaine effectively reduces breast cancer MDA-MB-231 cells viability and proliferation at higher concentration while that with salicylic acid had an inhibitory effect at lower concentrations and might be tested as an anticancer agent.
A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors like half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 display the highest antiproliferative activity against the three cancer cells, therefore, they were subject to further studies. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Furthermore, the expression of some key genes was studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among thes...
Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives
European Journal of Medicinal Chemistry, 2014
A series of 2-substituted amino-3-chloro-1,4-naphthoquinone derivatives (3e12) 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 macetylphenylamino-1,4-naphthoquinone (8) affording IC 50 values of 4.758, 2.364 and 12.279 mM, 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 IC 50 of 2.118 mM. Quantitative structureeactivity relationship (QSAR) investigations provided good predictive performance as observed from crossvalidated R of 0.9177e0.9753 and RMSE of 0.0614e0.1881. 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 (13e36) 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.
British Journal of Haematology, 2009
New therapeutic strategies aimed at eliminating leukaemic cells often involve the activation of apoptosis. Actively proliferating human myeloid leukaemic cells are, however, variably resistant to the apoptosis induced by ionising radiation or chemotherapeutic drugs (Hannun, 1997; Dash & Gilliland, 2001). As such, the search for candidate compounds that may interact with molecular targets specific for leukaemic cells remains ongoing. Certain natural and synthetic quinoid compounds bearing one [benzoquinones (BQs)], two [naphthoquinones (NQs)] or three benzoic rings (anthraquinones), and their derivatives, display bioreductive and alkylating activity and thus serve as anti-tumour agents (Lin et al, 1973, 1975; Thomson, 1987). Indeed, quinones are the most clinically-used anti-cancer drugs in the United States. The cytotoxicity of quinones may be due to two competing mechanisms, namely, soft electrophilic arylation and redox cycling oxidation (Monks et al, 1992). Most quinone anti-tumour drugs present complex chemical structures, containing different active functional groups. Thus, cytotoxic effects may be mediated by a variety of mechanisms, with the exact contribution of the quinone group to antitumour activity remaining uncertain. (Powis, 1989; Myers et al, 1990; Qiu et al, 1998). Among the various quinone drugs, the anthacyclines, doxorubicin, daunorubicin, mitomycin C, as well as BQ derivatives, play a prominent role in cancer chemotherapy (Schultz et al, 1997). The naphthoquinones,
Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells
Pharmaceuticals, 2021
Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, 30 and 32, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib a...
Apoptotic effect of Naphthoquinone derivatives on HCT116 colon cancer cells
Genes & Genomics, 2010
Naphthoquinone is found in the core structure of many natural compounds, most notably the K vitamins. Numerous molecules with the 1,4-naphthoquinone moiety are known to display distinct biological activities including anti-cancer, anti-inflammatory and anti-bacterial activities. Vitamin K2 and doxorubicin, which are used to treat bleeding and lymphoma respectively, belong to this class of chemicals. Although the exact mechanism of action of these molecules is still under investigation, it may include interactions with DNA, inhibition of topoisomerase II, and production of ROS, all of which contribute individually or in combination to DNA damage and cell death. Based on our previous study, 3 novel naphthoquinone derivatives were synthesized and their anti-proliferative activity against HCT116 colon cancer cells was assessed using FACS and Caspase assays. Using this analysis, we found that the production of ROS by naphthoquinones played a critical role in the induction of apoptosis, since pre-treatment of the cells with antioxidant NAC decreased the cytotoxicity level of these compounds.