Guilherme A. M. Jardim a, Tiago T. Guimarães b, Maria do Carmo F. R. Pinto c, Bruno C. Cavalcanti d, Kaio M. de Farias d, Claudia Pessoa de, Claudia C. Gatto f, Divya K. Nair g, Irishi N. N. Namboothiri *g and Eufrânio N. da Silva Júnior *a
aInstitute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, CEP 31270-901, Belo Horizonte-MG, Brazil. E-mail: eufranio@ufmg.br; Fax: +55 31 34095700; Tel: +55 31 34095720
bInstituto Nacional de Câncer, Hospital do Câncer – Unidade I – Seção de Medicina Nuclear, 20230-130, Rio de Janeiro, RJ, Brazil
cNúcleo de Pesquisas de Produtos Naturais, UFRJ, 21944-971, Rio de Janeiro, RJ, Brazil
dDepartamento de Fisiologia e Farmacologia, UFC, 60430-270, Fortaleza, CE, Brazil
eFiocruz – Ceará, 60180-900, Fortaleza, CE, Brazil
fInstitute of Chemistry, University of Brasilia, CEP 70904970, Brasilia-DF, Brazil
gDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India. E-mail: irishi@iitb.ac.in; Fax: +91-22-2576-7152; Tel: +91-22-2576-7196
First published on 24th September 2014
Novel COMPOUND LINKS
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Explore further on Open PHACTSnaphthoquinone-based chalcones were prepared from the reaction between 3-bromo-nor-β-lapachone and amino-chalcones. Lapachone derivatives are also described here. All the substances were evaluated against cancer and normal cell lines and several compounds demonstrated potent antitumor activity.
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Explore further on Open PHACTSNaphthoquinone containing natural products belong to an important class of naturally occurring secondary metabolites found in the bignoniaceae family.4 Among these, naphthoquinoidal compounds obtained from natural products, such as COMPOUND LINKS
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Explore further on Open PHACTSlapachol and COMPOUND LINKS
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Explore further on Open PHACTS2-hydroxy-1,4-naphthoquinone), have received considerable attention because of their antitumor potential.5–8 1,4- and 1,2-naphthoquinones, and for instance, dehydro-α-lapachone, an important anti-vascular agent,9 and β-lapachone, a potent antitumoral compound, have also been used as prototypes for the development of new drugs.10 Generally, quinones are able to provoke apoptosis and act as topoisomerase inhibitors via DNA intercalation. Their toxicity can also be explained by inducing oxidative stress through reactive oxygen species (ROS) generation.11 Recently, described by Bolognesi and coworkers, quinones have attracted attention due to their activity being intrinsically related by a multitarget mechanism.12
In recent years, lapachones were employed as key substrates for the synthesis of complex diazaazulenones,13 spirolactones,14 oxazoles15 and other potentially bioactive heterocyclic compounds.15 Our research group has explored the potential of quinones against cancer, mainly, via structural modification of the nor-β-lapachone, particularly, the C-ring and redox centre modification16 since these moieties are deeply related with the generation of ROS (Scheme 1).
Earlier, we reported the synthesis of nor-β-lapachone-based COMPOUND LINKS
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Explore further on Open PHACTS1,2,3-triazole and 3-arylamino derivatives with potent antitumor activity via C-ring modification of nor-β-lapachone and molecular hybridization19 with the junction of 1,2,3-triazole groups (Scheme 1).17,18 Recently, we described a derivative of nor-β-lapachone coupled COMPOUND LINKS
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Explore further on Open PHACTSbenzothiadiazole (Scheme 1) with potent activity against twenty cancer cell lines and low cytotoxicity against three normal cells.20 These results were very promising and the mechanism of action of this substance in tumor cells is being currently investigated in our laboratories and it will be reported in due course.
Using redox centre modification, imidazoles and an oxirane derivative were obtained from nor-β-lapachone and β-lapachone (Scheme 1), with antimycobacterial21 and trypanocidal22 activities, indicating the importance of this approach. The C-ring modification in the α-lapachone was also accomplished and thio-derivatives with antitumor activities and 1,2,3-triazoles with leishmanicidal activity were recently reported.23,24
Finally, following our program to develop new bioactive molecules, particularly, new nor-β-lapachones with activity against cancer cell lines and low cytotoxicity against normal cells, the synthesis of quinone-based chalcones, is described herein for the first time. The strategies of molecular hybridization and C-ring modification were used because of chalcone's known antitumor activity.25 Redox centre modification in lapachones to obtain hydrazone derivatives and C-ring modification in α-lapachone in addition to nor-β-lapachone coupled with para-quinones were also accomplished. All the substances were evaluated against cancer and normal cell lines.
Scheme 2 Synthesis of the chalcone intermediates 1–6. |
Using the Hooker oxidation methodology29 nor-lapachol COMPOUND LINKS
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Download mol file of compound8 was prepared from lapachol COMPOUND LINKS
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Download mol file of compound7 and used to obtain the classic intermediate 3-bromo-nor-β-lapachone COMPOUND LINKS
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Download mol file of compound9 in quantitative yield. Compound COMPOUND LINKS
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Download mol file of compound9 was reacted with the previously prepared amine-chalcones 1–6 to provide nor-β-lapachone-based chalcones 10–15 (Scheme 3).
Scheme 3 Nor-β-lapachone-based chalcones obtained from lapachol COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound7. |
New compounds 10–15 were well characterized by 1H and 13C NMR and high resolution mass spectrometry and all the data are in accordance with the proposed structures. It was observed in the 1H NMR spectrum of chalcone derivatives that the respective doublet signals with coupling constant, J = 15.6 Hz indicated the presence of the trans-olefin of the quinone coupled COMPOUND LINKS
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Explore further on Open PHACTSchalcone. Another important observation is a singlet at around δ 4.90–5.00 corresponding to the hydrogen attached to the C-3 in the chalcone derivatives. It is more shielded, compared to its counterpart in the bromo derivative COMPOUND LINKS
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Download mol file of compound9, which is observed at δ 5.40. In addition, the 13C NMR spectra showed all the expected signals. The structure of quinone-based chalcone COMPOUND LINKS
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Download mol file of compound14 was reconfirmed by X-ray crystallography (Fig. 1).
Fig. 1 An ORTEP-3 representation (50% probability displacement ellipsoids) of the asymmetric unit of compound COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound14. |
Recently, the second class of substances was reported by us (Scheme 4).30 COMPOUND LINKS
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Explore further on Open PHACTSLawsone was reacted with Morita–Baylis–Hillman acetates of nitroalkenes in the presence of a quinine–squaramide organocatalyst to provide enantioenriched disubstituted α-lapachones. This methodology allowed us to access asymmetric lapachones that are C-ring modified in a single step. In general, the products were obtained in high yields with excellent diastereo- and enantioselectivities.30 The catalyst shown in Scheme 4 was the most effective.
The compounds 16–25 assayed against cancer cell lines here were previously described.30
In view of the ease of access to lapachone derivatives by selective chemical transformation of lapachol COMPOUND LINKS
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Download mol file of compound7, we invested to study the corresponding hydrazone derivatives. In addition, the hydrazones of the β-lapachone COMPOUND LINKS
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Download mol file of compound26, 3-iodo-β-lapachone COMPOUND LINKS
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Download mol file of compound27, 3-bromo-β-lapachone COMPOUND LINKS
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Download mol file of compound32, nor-β-lapachone COMPOUND LINKS
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Download mol file of compound34, nor-α-lapachone COMPOUND LINKS
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Download mol file of compound36 and 3-hydroxy-nor-β-lapachone COMPOUND LINKS
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Download mol file of compound38, were obtained in high yields. In fact, the hydrazones of naturally occurring quinones have been considered for a long time as simple derivatives to confirm the identity of quinones. To the best of our knowledge, the use of hydrazones from quinones of the lapachol's group was not considered for major antitumor studies until now.
Initially, β-lapachone COMPOUND LINKS
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Download mol file of compound26, its derivatives COMPOUND LINKS
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Download mol file of compound32, were prepared from lapachol COMPOUND LINKS
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Download mol file of compound7, by reaction with COMPOUND LINKS
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Explore further on Open PHACTSsulfuric acid, iodine, bromine and COMPOUND LINKS
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Explore further on Open PHACTSHCl, respectively, as previously reported.31,32 Nor-lapachol COMPOUND LINKS
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Download mol file of compound8 was used to obtain 3-hydroxy-nor-β-lapachone COMPOUND LINKS
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Download mol file of compound38, nor-β-lapachone COMPOUND LINKS
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Download mol file of compound34 and nor-α-lapachone COMPOUND LINKS
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Download mol file of compound36.33 The hydrazone derivatives were prepared according to the methodology previously published with minor modifications.34 The reaction of the appropriate quinones with COMPOUND LINKS
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Explore further on Open PHACTSacetic acid yielded the respective derivatives 29–31, COMPOUND LINKS
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Download mol file of compound39 in excellent yields (Scheme 5).
The spectroscopic data of hydrazone derivatives are in accordance with the proposed structures. The formation of these compounds followed the regioselective pattern previously observed and it is possible to conclude that the benzylic carbonyl group formed the hydrazone in all the cases.34 This is evident from 1H NMR data that the peri-hydrogen of the naphthalene ring appeared at δ 7.55 to 7.14 ppm, due to the anisotropic hydrazo group at carbon C-6. In addition, the 13C NMR spectra of COMPOUND LINKS
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Download mol file of compound39, for instance, showed similar chemical shifts for the carbonyls, at δ 179.1, 178.2 and 177.0 ppm, respectively, which is consistent with carbonyl at carbon C-6 (for COMPOUND LINKS
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Download mol file of compound39). A common feature observed for compounds COMPOUND LINKS
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Explore further on Open PHACTSCDCl3 as solvent is the presence of sharp singlet signals in the downfield region (δ 15.5–16.5 ppm) attributed to one N–H, which could form an internal hydrogen bond with the carbonyl of the ortho-hydrazone moiety, a strong H-bond acceptor.
α-Lapachone COMPOUND LINKS
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Download mol file of compound32 gave the regioselective para-hydrazone COMPOUND LINKS
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Download mol file of compound33, which is confirmed by the presence in its 1H NMR spectrum of an isolated downfield doublet in the aromatic region, attributed to one COMPOUND LINKS
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Explore further on Open PHACTSnaphthalene peri-hydrogen. Thus, as in the case of the above ortho-hydrazones, the anisotropic effect of the hydrazine moiety on the peri-hydrogen of COMPOUND LINKS
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Explore further on Open PHACTSnaphthalene is also observed in the case of para-hydrazones. On the other hand, in comparison to the original methylene hydrogens of the pyran ring in COMPOUND LINKS
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Download mol file of compound32, the 1H NMR of the corresponding ones of COMPOUND LINKS
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Download mol file of compound33, shows only negligible effects, indicating that the hydrazo group has little influence over the pyran ring.
Recently, the trypanocidal activity of nor-β-lapachone-derived 1,2,3-triazole-conjugated aminoquinones was described.35 These compounds present ortho- and para-carbonyl moieties that are able to generate ROS and these can be considered as important structures for evaluation against cancer cell lines because the activity of quinoidal molecules is deeply related with ROS generation as previously discussed.11,12 Bearing in mind the importance of these substances, we considered the compounds 41–43, obtained from lapachol COMPOUND LINKS
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Download mol file of compound7 (Scheme 6) for antitumor studies. Nor-lapachol COMPOUND LINKS
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Download mol file of compound8 was cyclized to 3-bromo-nor-β-lapachone that was used to prepare compound COMPOUND LINKS
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Download mol file of compound40. The azido derivative COMPOUND LINKS
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Download mol file of compound40 was used to synthesize 41–43 and all spectroscopy data were in accordance with the literature.35
Scheme 6 Lapachones 41–43 obtained from lapachol (COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound7). |
Compounds | HL-60 | HCT-116 | OVCAR-8 | SF295 | PBMC |
---|---|---|---|---|---|
a Results obtained by nonlinear regression for all assayed cell lines from three independent experiments (deviations in parenthesis). | |||||
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound1 | 6.40 (5.24–7.84) | 14.1 (12.86–15.59) | >22.4 | >22.4 | 20.2 (19.54–22.00) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound2 | 1.75 (0.89–3.46) | 10.96 (9.99–12.01) | >18.65 | >18.65 | 13.83 (13.54–14.54) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound3 | 0.46 (0.08–1.94) | 15.35 (12.73–18.47) | >21.08 | >21.08 | >21.08 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound4 | >16.71 | >16.71 | >16.71 | >16.71 | >16.71 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound5 | 10.50 (8.53–12.99) | >19.75 | >19.75 | >19.75 | >19.75 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound6 | 10.0 (12.52–17.53) | >18.85 | >18.85 | >18.85 | >18.85 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound10 | 0.04 (0.02–0.04) | 0.71 (0.62–0.82) | 1.53 (1.33–1.75) | 0.37 (0.26–0.53) | 2.20 (1.82–2.64) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound11 | 0.20 (0.16–0.26) | 2.22 (1.94–2.57) | 4.35 (3.78–4.81) | 2.89 (2.50–3.39) | 6.51 (5.80–6.88) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound12 | 0.10 (0.04–0.21) | 1.94 (1.77–2.15) | 2.13 (1.81–2.52) | 4.57 (4.14–5.05) | 7.90 (7.66–8.26) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound13 | 2.20 (1.84–2.60) | >9.5 | >9.5 | >9.5 | >9.5 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound14 | 0.10 (0.08–0.12) | 1.54 (0.91–1.89) | 0.64 (0.33–1.08) | 1.08 (0.56–1.46) | 1.33 (0.85–1.73) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound15 | 0.14 (0.10–0.18) | 1.56 (1.18–2.23) | 2.54 (1.99–2.91) | 1.62 (1.30–2.13) | 2.28 (1.77–2.64) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound16 | >14.92 | >14.92 | >14.92 | >14.92 | >14.92 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound17 | >12.98 | >12.98 | >12.98 | >12.98 | >12.98 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound18 | >12.65 | >12.65 | >12.65 | >12.65 | >12.65 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound19 | >13.54 | >13.54 | >13.54 | >13.54 | >13.54 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound20 | >14.32 | >14.32 | >14.32 | >14.32 | >14.32 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound21 | >12.10 | >12.10 | >12.10 | >12.10 | >12.10 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound22 | >13.54 | >13.54 | >13.54 | >13.54 | >13.54 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound23 | >13.15 | >13.15 | >13.15 | >13.15 | >13.15 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound24 | >14.66 | >14.66 | >14.66 | >14.66 | >14.66 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound25 | >15.38 | >15.38 | >15.38 | >15.38 | >15.38 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound29 | >15.05 | >15.05 | >15.05 | >15.05 | >15.05 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound30 | >10.91 | >10.91 | >10.91 | >10.91 | >10.91 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound31 | >12.19 | >12.19 | >12.19 | >12.19 | >12.19 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound33 | >15.05 | >15.05 | >15.05 | >15.05 | >15.05 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound35 | >15.71 | >15.71 | >15.71 | >15.71 | >15.71 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound37 | >15.71 | >15.71 | >15.71 | >15.71 | >15.71 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound39 | >14.96 | >14.96 | >14.96 | >14.96 | >14.96 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound41 | 0.45 (0.39–0.54) | 0.58 (0.52–0.66) | 1.33 (1.12–1.58) | 1.29 (1.14–1.43) | 0.27 (0.14–0.37) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound42 | 1.76 (1.43–2.17) | 1.90 (1.65–2.21) | 3.32 (2.82–4.06) | 1.80 (1.55–2.10) | 1.10 (0.83–1.18) |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound43 | 1.75 (1.37–2.25) | 2.32 (2.25–2.72) | 4.36 (3.83–4.78) | 2.21 (1.52–2.79) | 1.00 (0.87–1.07) |
Nor-β-lapachone | 1.75, 1.59–1.83 | 1.41, 1.28–1.54 | 1.25, 1.07–1.43 | 1.58, 1.31–1.88 | >21.90 |
β-Lapachone | 1.65, 1.49–1.78 | 0.97, 0.81–1.04 | 1.16, 0.97–1.25 | 0.91, 0.74–1.11 | >20.60 |
α-Lapachone | 8.18, 7.55–8.92 | 19.11, 18.75–19.88 | 14.79, 14.42–18.15 | 18.77, 18.15–19.03 | >20.66 |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound Explore further on Open PHACTSDoxorubicin | 0.03, 0.01–0.05 | 0.02, 0.01–0.03 | 0.09, 0.04–0.12 | 0.48, 0.37–0.52 | 0.37, 0.30–0.43 |
Our strategy was based on the modification of the prototypes β-lapachone COMPOUND LINKS
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Download mol file of compound26, α-lapachone COMPOUND LINKS
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Download mol file of compound32, nor-β-lapachone COMPOUND LINKS
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Explore further on Open PHACTS1,2,3-triazole-, arylamino- and thio-substituted α-lapachones were synthesized and evaluated against eleven cancer cell lines.24,35,36 Most of them were considered moderately active and several compounds were considered highly active (IC50 < 2 μM). Following this previous work, herein, the antitumor activities of asymmetric α-lapachone C-ring modified 16–25 were evaluated.
The selected compounds have different patterns of substitution with an aryl ring substituted by electron withdrawing (Cl and NO2) and donating (OMe and CH3) groups in different positions, in addition to COMPOUND LINKS
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Explore further on Open PHACTSfuran and thiophene rings. Unfortunately, in this study our strategy has failed and none of the compounds presented antitumor activity with IC50 values > 12.1 μM (Table 1). At present, several modifications of the asymmetric lapachones, for instance the insertion of 1,2,3-triazoles, are being currently investigated and will be reported in due course.
Recently, redox centre modification in quinones was successfully employed to obtain antitumor compounds.16 Imine derivatives obtained from β-lapachone COMPOUND LINKS
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Download mol file of compound26 presented potent antitumor activity.37 In this context, we conducted the synthesis of hydrazone derivatives from β-lapachone COMPOUND LINKS
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Download mol file of compound26, their iodine and bromine derivatives COMPOUND LINKS
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Download mol file of compound28, α-lapachone COMPOUND LINKS
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Download mol file of compound38, all the substances from the lapachol group. The derivatives 29–31, COMPOUND LINKS
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Download mol file of compound39 were evaluated against four cancer cell lines. In the same manner as the asymmetric quinones, the hydrazones were not active against all the lineages evaluated (Table 1). In comparison of these structures with the imines, previously obtained from β-lapachone COMPOUND LINKS
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Download mol file of compound26,37 the simple insertion of the NH-bond was enough to provoke the suppression of the activity. As suggested by Burton and coworkers,37 the change in the redox centre does not affect the overall activity and selectivity of the lapachone imine derivatives and it was described as an alternative in the search for new anticancer agents considering the high cytotoxicity of the β-lapachone COMPOUND LINKS
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Download mol file of compound26 in normal cell lines. On the basis of this principle, we considered the redox centre modification of lapachone derivatives as an important strategy to obtain novel antitumor drugs despite the lack of activity of the compounds described herein.
The third group of compounds was strategically planned by C-ring modification16 of nor-β-lapachone COMPOUND LINKS
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Download mol file of compound34 and molecular hybridization19 with chalcone moieties (Scheme 7).
Chalcones are recognized by their biological activities, for instance, antitumor,38 leishmanicidal39 and antimalarial.40 Considering the potential of the chalcones, naphthoquinoidal compounds 10–15 were prepared and evaluated against cancer and normal cell lines (Table 1). The selectivity index was considered to establish the potential of these structures (Table 2).
For the insertion of COMPOUND LINKS
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Explore further on Open PHACTSchalcone in the naphthoquinoidal moiety, compounds 1–6 were prepared. The structures 1–3 were also evaluated and showed activity against HL-60, HCT-116 and OVCAR-8 with IC50 values in the range of 0.46 to 15.35 μM. Compound COMPOUND LINKS
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Download mol file of compound4 was not active and the structures COMPOUND LINKS
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Download mol file of compound6 presented activity only for HL-60 with IC50 values = 10.5 and 10.0 μM, respectively.
After evaluating nor-β-lapachone based chalcone 10–15, the data confirmed the success of our approach. As previously described,8 the compounds were classified according to their activity as highly active (IC50 < 2 μM), moderately active (2 μM < IC50 < 10 μM), or inactive (IC50 > 10 μM). The structures 10–15 were considered highly active against HL-60 and HCT-116 with IC50 values between 0.04 to 2.2 μM. Compounds COMPOUND LINKS
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Download mol file of compound3, 10–12, COMPOUND LINKS
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Download mol file of compound15 were considered very promising against HL-60 after assaying these structures against peripheral blood mononuclear cells (PBMC). The selectivity index (SI), which is an excellent parameter to determine the efficiency of the compounds in cancer cells with low cytotoxicity in normal cell lines is expressed by the ratio of cytotoxicities between normal cell (PBMC) and different cancer cell lines. For compounds COMPOUND LINKS
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Download mol file of compound15 the values of SI (considering HL-60) were 45.8, 55.0, 32.5, 79, 13.3 and 16.2 (Table 2), respectively. For COMPOUND LINKS
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Explore further on Open PHACTSdoxorubicin, the drug used clinically against several types of cancer, the SI value is 12.0. In comparison with the positive control, COMPOUND LINKS
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Explore further on Open PHACTSdoxorubicin, nor-β-lapachone-based chalcone COMPOUND LINKS
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Download mol file of compound12 is more active and this structure could be considered as an important prototype for further studies. To the best of our knowledge, COMPOUND LINKS
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Download mol file of compound12 can be considered as one of the most active substances for HL-60 cancer cell line with a high selectivity index obtained from lapachol COMPOUND LINKS
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Another important characteristic that points to the success of the strategy herein employed was the increase of the activity of nor-β-lapachone COMPOUND LINKS
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Download mol file of compound34 after the insertion of the chalcone moieties (IC50 values for COMPOUND LINKS
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Download mol file of compound34 in the range of 1.25–1.75 μM), Table 1. The hybrid compounds were also more active than the non-hybridized chalcones 1–4.
Finally, compound COMPOUND LINKS
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Download mol file of compound13 was not active against HCT-116, OVCAR-8 and SF295, but this molecule presented selective activity for HL-60 with IC50 value = 2.20 μM. In terms of selectivity index this structure was not promising, but further modifications in this prototype are under investigation in our research group to develop drugs with selectivity against a certain type of cancer. Compounds COMPOUND LINKS
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Download mol file of compound14 and COMPOUND LINKS
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Download mol file of compound15 were highly active against all the cancer cell lines evaluated, but these compounds were more cytotoxic than the other derivatives of this class.
In general terms, lapachone-based COMPOUND LINKS
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Explore further on Open PHACTSchalcone hybrids presented important activity against cancer cell lines with low cytotoxicity in normal cancer cell lines. This manuscript represents the first report on this class of compounds with promising activity, and based on our experience with lapachone derivatives, the compounds herein described deserve further subsequent studies.
The last class of compounds herein evaluated has been chosen because of the intrinsic ability of these structures to generate ROS. In fact, the compounds 41–43 were considered highly active (IC50 < 2 μM) against all the cancer lineages evaluated with some exceptions. The main problem observed for these compounds was the high cytotoxicity observed in normal cell lines (PBMC). For instance, compound COMPOUND LINKS
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Download mol file of compound41 was highly active against HL-60 cell lines with IC50 = 0.45 μM, but it presented IC50 value = 0.27 μM for normal cells. In general, 41–43 are more cytotoxic for normal cell than cancer cell lines.
Lately, microencapsulation aimed controlled release is an important strategy to increase the efficiency of antitumor drugs.41 Recent studies using β-lapachone were described to try to diminish the cytotoxicity of this important antitumor quinone.42 Considering the promising results observed for 41–43, in four types of cancer cell lineage, studies aiming controlled delivery systems, could be an interesting possibility to solve the problem of cytotoxicity.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1018940. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4md00371c |
This journal is © The Royal Society of Chemistry 2015 |