- Synthesis, Characterization, and Antileukemic Properties of Naphthoquinone Derivatives of Lawsone
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Naphthoquinones are considered privileged structures for anticancer drug molecules. The Heck reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with 1-bromo-3-methyl-2-butene offered easy access to lapachol. Several naturally occurring linear and angular heterocyclic quinoids (α-lapachone, β-lapachone, dunnione, and related analogues) were prepared from lapachol. Furthermore, we demonstrated that the synthetic naphthoquinones inhibit cell proliferation in human leukemia HL-60 cells. In particular, angular-type derivatives were found to possess moderate cytotoxicity and to elevate the levels of intracellular glutathione disulfide (GSSG). Our work highlights the significant potential of naturally occurring angular-series naphthoquinones as antileukemic agents.
- Inagaki, Ryuta,Ninomiya, Masayuki,Tanaka, Kaori,Koketsu, Mamoru
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p. 1413 - 1423
(2015/08/03)
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- Conversion of lapachol to lomatiol: Synthesis of novel naphthoquinone derivatives
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Lapachol (1), a naphthoquinone isolated mostly from the plants of the bignoniaceae family has a broad spectrum of biological activities and as a consequence it has been the object of different chemical transformations. Lomatiol (3), another naturally occurring naphthoquinone having structural similarities to lapachol, has been obtained from chemical and microbial transformations of lapachol in very low yields. In the present study, an easy approach for the synthesis of lomatiol (3) from lapachol (1) has been developed using SeO2 oxidation in 90% yield. Lomatiol, under epoxidation conditions afforded novel furano- and pyrano-naphthoquinone derivatives, which are analogues of anticancer agents, 2-acetylfuronaphthoquinone and β-lapachone. Most of the structures were unambiguously confirmed by single crystal X-ray analysis.
- Eyong, Kenneth O.,Chinthapally, Kiran,Senthilkumar, Soundararasu,Lamsh?ft, Marc,Folefoc, Gabriel N.,Baskaran, Sundarababu
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p. 9611 - 9616
(2015/12/05)
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- Biomimetic in vitro oxidation of lapachol: A model to predict and analyse the in vivo phase i metabolism of bioactive compounds
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The bioactive naphtoquinone lapachol was studied in vitro by a biomimetic model with Jacobsen catalyst (manganese(III) salen) and iodosylbenzene as oxidizing agent. Eleven oxidation derivatives were thus identified and two competitive oxidation pathways postulated. Similar to Mn(III) porphyrins, Jacobsen catalyst mainly induced the formation of para-naphtoquinone derivatives of lapachol, but also of two ortho-derivatives. The oxidation products were used to develop a GC-MS (SIM mode) method for the identification of potential phase I metabolites in vivo. Plasma analysis of Wistar rats orally administered with lapachol revealed two metabolites, α-lapachone and dehydro-α-lapachone. Hence, the biomimetic model with a manganese salen complex has evidenced its use as a valuable tool to predict and elucidate the in vivo phase I metabolism of lapachol and possibly also of other bioactive natural compounds.
- Niehues, Michael,Barros, Valeria Priscila,Emery, Flavio Da Silva,Dias-Baruffi, Marcelo,Assis, Marilda Das Dores,Lopes, Norberto Peporine
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experimental part
p. 804 - 812
(2012/09/10)
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- Natural furano naphtoquinones from lapachol: Hydroxyiso-β-lapachone, stenocarpoquinone-B and avicequinone-C
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This work describes cheap and simple methods to obtain biological active furano naphthoquinones in good yields. Hydroxyiso-β-lapachone (3) was obtained in 61% yield from the reaction of lapachol (1) and MCPBA in dichloromethane using Na2HPO4 as the base. Reaction of 1 with MCPBA, followed by the addition of KOH/DMSO furnished both stenocarpoquinone-A (2) and avicequinone-C (5) in 20% yield. Using oxone/acetone and NaHCO3, stenocarpoquinone-B (4) was obtained in 50% yield. The biological assays using tumor cell lines showed that 1 is, in general, less toxic than its derivatives. Compounds 4 and 5, on the other hand, were strongly active against the four tested tumor cells.
- Ribeiro, Carlos Magno R.,De Souza, Pablo. P.,Ferreira, Letícia L.D.M.,Pereira, Sharlene L.,Martins, Ingrid Da S.,Epifanio, Rosangela De A.,Costa-Lotufo, Letícia V.,Jimenez, Paula C.,Pessoa, Cláudia,De Moraes, Manoel O.
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experimental part
p. 347 - 351
(2012/05/31)
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- Chemistry of lapachol - Syntheses of some new biogenetically related naphthoquinones, naphthoquinone dimers, naphthaquinoxaline and naphtha-azaquinoxaline derivatives from lapachol
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The present short review focus on chemical transformations of lapachol to a large number of biogenetically related lapachol conegeners, dimers and heterocyclic analogues that have been achieved in our laboratory during more than two decades. Conversion of lapachol to stenocarpoquinone-B, rhinacanthin-A, β-(l-hydroxyisopropanyl)-dihydrofurano-1,2-naphthoquinone, stenocarpoquinone-A, dehydro-α-lapachone and dehydro-β-lapachone by the reaction with m-chloroperbenzoic acid; dehydroiso-α-lapachone, dehydroiso-β-lapachone, dehydro-α-lapachone, α-lapachone and β-lapachone by the reaction with aqueous NaNO2 and glacial AcOH; adenophyllone, quadrllone and dehydro-α-lapachone by the reaction with boiling pyridine; naphthaquinoxaline and naphtha-azaquinoxaline derivatives by the reaction with 1,2-diamines and dialkyltin dilapacholates by the reaction with dialkyltin diisopropoxides have been accomplished. Notably the syntheses of rhinacanthin-A, β-(1-hydroxyisopropanyl)-dihydrofurano-1,2-naphthoquinone, dehydroiso-α-lapachone, dehydroiso-β-lapachone, adenophyllone and quadrllone have been reported for the first time from our group starting from lapachol. The synthesis of novel naphthaquinoxaline and azaquinoxaline derivatives from lapachol has been additional interesting results of this investigation.
- Singh, Pahup,Krishna, Vivek,Khandelwal, Poonam,Sharma, Kuldeep K.,Sharma
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experimental part
p. 85 - 95
(2011/07/30)
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- Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line
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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 β-cycled-pyran-1,2-naphthoquinones [0.1 μM 50 0.6 μM] 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.
- Pérez-Sacau, Elisa,Díaz-Peńate, Raquel G.,Estévez-Braun, Ana,Ravelo, Angel G.,García-Castellano, Jose M.,Pardo, Leonardo,Campillo, Mercedes
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p. 696 - 706
(2008/02/01)
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- Conversion of lapachol to array of furano and pyranonaphthoquinone congeners
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Chemical conversion of lapachol to α-lapachone, β-lapachone, dehydro-α-lapachone, dehydroiso-α-lapachone and dehydroiso-β- lapachone by reaction with aqueous NaNO2 and glacial AcOH; rhinacanthin-A, stenocarpoquinone-A, stenocarpoquinone-B and its isomer by reaction with meta-chloroperbenzoic acid at 0° for 30 min and dehydro-α-lapachone and dehydro-β-lapachone at 25° for 4 h respectively and di- and tribromo derivatives by reaction with Br2 in chloroform has been reviewed. In most of these reactions prenyl chain cyclises into an oxygen function to give a number of furano and pyrano-naphthoquinone derivatives. Some of these naphthoquinones co-occur with lapachol in the same plant species.
- Krishna, Vivek,Lamba, Jyoti,Singh, Pahup
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p. 1039 - 1044
(2007/10/03)
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- Inhibitory effects of lapachol derivatives on epstein-barr virus activation
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Sixteen derivatives (2-17) synthesized from the naphthoquinone lapachol (1), were tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), as a test for potential cancer chemopreventive agents. They exhibited a variety of inhibitory activities from very high to moderate, which allow us to suggest structure-activity relationships. Ten of these derivatives are reported for the first time, their structures being thoroughly determined by spectroscopic methods.
- Sacau, Elisa Perez,Estevez-Braun, Ana,Ravelo, Angel G.,Ferro, Esteban A.,Tokuda, Harunkuni,Mukainaka, Teruo,Nishino, Hoyoku
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p. 483 - 488
(2007/10/03)
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- Chemical constituents of Avicennia alba. Isolation and structural elucidation of new naphthoquinones and their analogues
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Three new naphthoquinones and their analogues, named avicequinone-A (1), -B (2), -C (3), and avicenol-A (4), -B (5), -C (6), respectively, were isolated from the stem hark of Avicennia alba (Avicenniaceae) collected in Singapore, and their structures were elucidated by means of spectral methods. Gillan and co-workers have proposed that the structures of the new phytoalexins isolated from Avicennia marina are 1,2-naphthoquinones 8 and 9. Our synthetic and spectrometric studies showed that these structures should be revised respectively to 1,4-naphthoquinones 2 and 3, named avicequinone-B and -C by us.
- Ito, Chihiro,Katsuno, Shinya,Kondo, Yuichi,Tan, Hugh T.-W.,Furukawa, Hiroshi
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p. 339 - 343
(2007/10/03)
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- Conversion of Lapachol to Rhinacanthin-A and other Cyclized Products
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A facile synthesis of rhinacanthin-A is achieved by the side chain cyclization of lapachol with meta-chloroperbenzoic acid long with stenocarpoquinone-A, stenocarpoquinone-B and its isomer.Keywords: Lapachol, Rhinacanthin-A, Stenocarpoquinone-A, Stenocarpoquinone-B, Dehydro-β-lapachone
- Singh, P.,Pardasani, R. T.,Suri, A.,Pokharna, C. P.
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p. 1031 - 1033
(2007/10/02)
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