Synthesis and anti-inflammatory evaluations of β-lapachone derivatives
Graphical abstract
The inhibitory effect of 6b on LPS-stimulated inflammatory mediator production in Raw 264.7 cell is associated with the suppression of the NF-κB and MAPK signaling pathways.
Introduction
Inflammation is a central feature of many pathophysiological conditions in response to tissue injury and host defenses against microbial challenge. Pro-inflammatory cells, mainly activated macrophages, mediate most of the cellular and molecular pathophysiology of inflammation by producing cytokines and other pro-inflammatory molecules, including prostaglandins, enzymes, and free radicals such as NO.1, 2 Three isoforms of NOS exist, constitutively expressed neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible isoform (iNOS).3 Activated macrophages transcriptionally express inducible nitric oxide synthase (iNOS), which is responsible for the prolonged and profound production of NO.4, 5, 6 The aberrant release of NO can lead to amplification of inflammation as well as tissue injury.7 Therefore, inhibition of neutrophils and/or macrophages activation and the following release of inflammatory mediators provide a promising strategy for the development of potential anti-inflammatory agents.
Many efforts had been devoted to the discovery of novel anti-inflammatory agents for the past few years.8, 9, 10, 11, 12, 13 The natural quinones include lapachol, α-lapachone and β-lapachone (β-LAPA) (Fig. 1) were isolated from the heartwood of the Bignoniaceae family (Tabebuia sp) and evaluated for their biological activities. Among them, β-LAPA was found to be able to inhibit the expression of nitric oxide (NO) and PGE2 in alveolar macrophages.14 In order to discover novel drug candidates, we have synthesized certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives and evaluated for their anti-inflammatory activities. Our results indicated that (E)-2-(2-(5-nitrofuran-2-yl)vinyl)furo[3′,2′:3,4]naphtho[1,2-d]imidazole (1) was capable of inhibiting iNOS expression, with an IC50 value of 0.52 μM while 2-(4-methoxyphenyl)-furo[3′,2′:3,4]naphtho[1,2-d]imidazole (2) exhibited a strongly inhibitory activity on LPS-induced PGE2 production, with an IC50 value of 0.047 μM.15, 16 We have also demonstrated that certain quinolin-2(1H)-one derivatives such as (E)-4-[2-cyclohex-2-enylidene]hydrazinyl]quinolin-2(1H)-one (3) significantly suppressed LPS-induced NO production and iNOS gene expression in macrophages.17 The present study intends to explore novel β-LAPA derivatives which possess significant anti-inflammatory potency and lower cytotoxicity. In addition to the quinone (naphthalene-1,2-dione) pharmacophores, their hydroxylamine-condensed derivatives have also been synthesized and evaluated on the ground that many hydroxylamine-condensed derivatives exhibited more potent biological activities than that of their respective ketone precursors.18, 19, 20, 21
Section snippets
Chemistry
Treatment of sodium 3,4-dioxo-3,4-dihydronaphthalene-1-sulfonate (4) with aniline afforded 4-(phenylamino)naphthalene-1,2-dione (5a) in 81% yield as described in Figure 2. The 1H NMR spectrum of compound 5a showed a total of 11 proton signals, which included ten aromatic methynes (δH 5.87 (3-H), 7.29–7.33 (3 Ar-H), 7.49–7.53 (2 Ar-HH), 7.75 (7-H), 7.87 (6-H), 8.05 (5-H), 8.33 (8-H)) and one broad amino-proton (δH 9.89), and the 13C NMR spectrum of 5a showed two carbonyl carbons (δC 175.92,
Conclusion
In summary, we have synthesized certain β-LAPA derivatives and evaluated for their anti-inflammatory activities. Results indicated that 4-(4-methoxyphenoxy)-naphthalene-1,2-dione (6b) and β-LAPA significantly attenuated the release of inflammatory mediators (NO and TNF-α, MMP-9) in a concentration-dependent manner. These data indicated that 6b and β-LAPA target p38 kinase and NF-κB. These compounds inhibit iNOS, COX-2, and the formation of pro-inflammatory cytokine NO, TNF-α, MMP-9. Although
General
TLC: Precoated (0.2 mm) silica gel 60 F254 plates from EM Laboratories, Inc.; detection by UV light (254 nm). Mp: electrothermal IA9100 digital melting-point apparatus; uncorrected. The ultraviolet–visible (UV–VIS) absorption spectra were recorded on a Jasco V570 spectrometer. IR spectra were measured on PERKIN ELMER System 2000 FT-IR spectrophotometer. 1H and 13C NMR spectra: Varian-Unity-400 spectrometer at 400 and 100 MHz or Varian-Gemini-200 spectrometer at 200 and 50 MHz, chemical shifts δ in
Acknowledgments
Financial support of this work by the National Science Council of the Republic of China (NSC 99-2320-B-037-0-18-MY2) is gratefully acknowledged. We also thank the National Center for High-Performance Computing for providing computer resources and chemical database services.
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2020, Advanced Synthesis and CatalysisAssessment of various formulation approaches for the application of beta-lapachone in prostate cancer therapy
2020, International Journal of PharmaceuticsCitation Excerpt :Beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol-[1,2-b]pyran-5,6-dione, β-Lap) is an ortho-naphthoquinone extracted from the bark of Tabebuia avellanedae. It has drawn strong interest for its wide variety of potential pharmacological effects including anti-tumor activity (Abreu et al., 2005; Kung et al., 2008; Tseng et al., 2013; Ma et al., 2015; Moreno et al., 2015). It has been suggested that β-Lap enters the cancer cells in its oxidized form and is activated after reduction by the NAD(P)H:quinone oxidoreductase (NQO1), a multifunctional antioxydant enzyme predominately located in the cytoplasm.
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These two authors contributed equally to this work.