- Redox Center Modification of Lapachones towards the Synthesis of Nitrogen Heterocycles as Selective Fluorescent Mitochondrial Imaging Probes
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We describe herein a synthetic strategy for the synthesis of new fluorescent imidazole and phenazine derivatives synthesized from lapachol, a naturally occurring naphthoquinone isolated from Tabebuia species (ipê tree). The photophysical properties and computational details of these compounds have been studied, aiming at gaining a complete understanding of the potential of these derivatives as probes capable of staining mitochondria selectively. Cell imaging experiments proved the capacity of the imidazole derivatives as selective fluorescent mitochondrial imaging probes. These heterocycles present the same staining patterns as MitoTracker Red, corroborating the potential of these compounds as new mitochondria markers permeable to the cell membrane.
- dos Santos, Fabíola S.,Dias, Gleiston G.,de Freitas, Rossimiriam P.,Santos, Lucas S.,de Lima, Guilherme F.,Duarte, Hélio A.,de Simone, Carlos A.,Rezende, Lidia M. S. L.,Vianna, Monique J. X.,Correa, José R.,Neto, Brenno A. D.,da Silva Júnior, Eufranio N.
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- Cytotoxic germacrane-type sesquiterpenes, pimarane-type diterpenes, and a naphthalene derivative from Wollastonia biflora
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Phytochemical investigation of the whole plants of Wollastonia biflora led to the isolation and identification of three new germacrane-type sesquiterpenes (1-3), two new pimarane-type diterpenes (4, 5), and a new naphthalene glycoside (6), along with 11 known compounds. Their structures were characterized on the basis of spectroscopic analyses and chemical methods. Compounds 1, 2, and 3 showed significant cytotoxic activity against me growth of hepatocellular carcinoma BEL-7402 cells in vitro.
- Chen, Wenliang,Tang, Weidong,Zhang, Rujun,Lou, Liguang,Zhao, Weimin
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- Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol
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A series of 5-hydroxy-1,4-naphthoquinones analogues was synthesized from juglone (6) and their antiproliferative activity against a representative panel of six human solid tumor cell lines has been investigated. The 2,5-dihydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione (4) and 2,3-dihydro-5-hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione (27) were the most potent antiproliferative agents with GI50 values of 0.42-8.1 and 0.80-2.2 μM, respectively. The results provide insight into the correlation between some structural properties of 5-hydroxynaphthoquinones and their antiproliferative activity.
- Bonifazi, Evelyn L.,Ríos-Luci, Carla,León, Leticia G.,Burton, Gerardo,Padrón, José M.,Misico, Rosana I.
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- Studies on the trypanocidal activity of semi-synthetic pyran[b-4,3] naphtho[1,2-d]imidazoles from β-lapachone
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We synthesized new naphthoimidazoles from β-lapachone with an aromatic moiety linked to the imidazole ring, using phenylic and heterocyclic aldehydes. The most active compound against Trypanosoma cruzi had a p-methyl group linked to the phenyl ring, presenting an EC50 value of 15.5 ± 2.9 μM. No reliable correlation could be established with the biological activity and the structure of in the phenylic series. For the heterocyclic series, activity was associated with a three bond-distance from nitrogen to the imidazole ring, in accordance with our previous work.
- De Moura, Kelly C.G.,Salomao, Kelly,Menna-Barreto, Rubem F.S.,Emery, Flavio S.,Pinto, Maria Do Carmo F.R.,Pinto, Antonio V.,De Castro, Solange L.
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- Electronic structure and gas-phase chemistry of protonated α- And β-quinonoid compounds: A mass spectrometry and computational study
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Rationale: The use of quinonoid compounds against tropical diseases and as antitumor agents has prompted the search for new naturally occurring and synthetic derivatives. Among these quinonoid compounds, lapachol and its isomers (α- and β-lapachone) serve as models for the synthesis of new compounds with biological activity, and the use of electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis as a tool to elucidate and characterize these products has furnished important information about these compounds. Methods: ESI-MS/MS analysis under collision-induced dissociation conditions was used to describe the fragmentation mechanisms for protonated 1,4-naphthoquinone, 1,2-naphthoquinone, α-lapachone, and β-lapachone. The B3LYP/6-31+G(d,p) model was used to obtain proton affinities, gas-phase basicities, and molecular electrostatic potential maps, thus indicating the probable protonation sites. Fragmentation pathways were suggested on the basis of the relative enthalpies of the product ions. Results: The ESI-MS signals of the cationized molecules of ortho quinonoid compounds were more intense than those of the protonated molecule. Formation of the major product ions with m/z 187 from protonated α- and β-lapachone has been attributed to a retro-Diels-Alder (RDA) reaction. Conclusions: MS/MS studies on lapachol isomers (α- and β-lapachone) will facilitate the interpretation of the liquid chromatography (LC)-MS/MS analysis of new metabolites. MS/MS data on the 1,4-naphthoquinone, 1,2-naphthoquinone, α-lapachone and β-lapachone core will help characterize new derivatives from in vitro/in vivo metabolism studies in complex matrices. The product ions revealed the major fragmentation mechanisms and these ions will serve as diagnostic ions to identify each studied compound. Copyright
- Vessecchi, Ricardo,Emery, Flávio S.,Lopes, Norberto P.,Galembeck, Sérgio E.
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- Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-lapachone delivery
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β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemoglobinemia/hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated dual-model pH-responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage as the most optimal linkage. The conversion to β-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. The β-lap aryl imine prodrug conjugated ultra-pH-sensitive (UPS) polymer reached high β-lap loading density (8.3%) and exhibited dual-stage responsiveness to pH variation. In pHs under pHt, at stage I, micelles immediately dissociate and subsequently, entering stage II, micelles start to quickly release β-lap. An in vitro release study showed that the micelles constantly release β-lap (14.9 ± 0.1%) at pHs above pHt in 72 h, whereas there was a boosted release of β-lap (79.4 ± 1.2%) at pH 5.0. The micelles' intracellular distribution being predominantly in the lysosome organelle guaranteed their pH-responsive dissociation and subsequently β-lap controlled release. The M-P micelles retained NQO1-dependent cytotoxicity in A549 lung cancer cells, similar to the free drug in both efficacy and mechanism of cell death. The lysosome-oriented dual-stage ultra-pH-responsive β-lap prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung cancer, as well as other NQO1+ cancer therapies.
- Zhou, Yinjian,Dong, Ying,Huang, Gang,Wang, Yiguang,Huang, Xiaonan,Zhang, Fayun,Boothman, David A.,Gao, Jinming,Liang, Wei
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- Selective endocytic trafficking in live cells with fluorescent naphthoxazoles and their boron complexes
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Fluorescent naphthoxazoles and their boron derivatives have been synthesized and applied as superior and selective probes for endocytic pathway tracking in live cancer cells. The best fluorophores were compared with the commercially available acridine orange (co-staining experiments), showing far better selectivity.
- Dias, Gleiston G.,Rodrigues, Bernardo L.,Resende, Jarbas M.,Calado, Hállen D. R.,De Simone, Carlos A.,Silva, Valter H. C.,Neto, Brenno A. D.,Goulart, Marilia O. F.,Ferreira, Fabricia R.,Meira, Assuero S.,Pessoa, Claudia,Correa, José R.,Da Silva Júnior, Eufranio N.
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- Novel fluorescent lapachone-based BODIPY: Synthesis, computational and electrochemical aspects, and subcellular localisation of a potent antitumour hybrid quinone
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For the first time, a fluorescent lapachone-based BODIPY was synthesised and characterised by NMR and mass spectrometry. Computational and electrochemical aspects, as well as cytotoxic activity and subcellular localisation, were studied. Confocal microscopy experiments indicated that the probe was a specific mitochondria-staining agent. These in-detail analyses were useful in understanding the cytotoxic effects and mechanism of action of this novel hybrid compound. This molecule constitutes a promising prototype owing to its potential biological activities and the new strategies aimed at mechanistic investigations in cells and in vivo, and opens up an interesting avenue of research.
- Gontijo, Talita B.,De Freitas, Rossimiriam P.,De Lima, Guilherme F.,De Rezende, Lucas C. D.,Pedrosa, Leandro F.,Silva, Thaissa L.,Goulart, Marilia O.F.,Cavalcanti, Bruno C.,Pessoa, Claudia,Bruno, Marina P.,Corrêa, José R.,Emery, Flavio S.,Da Silva Júnior, Eufranio N.
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- Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition
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Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to β-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50?=?5.2?μM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000?mg/kg oral dose.
- Kumar, Balagani Sathish,Ravi, Kusumoori,Verma, Amit Kumar,Fatima, Kaneez,Hasanain, Mohammad,Singh, Arjun,Sarkar, Jayanta,Luqman, Suaib,Chanda, Debabrata,Negi, Arvind S.
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- α- and β-Lapachone Isomerization in Acidic Media: Insights from Experimental and Implicit/Explicit Solvation Approaches
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Combined experimental and mixed implicit/explicit solvation approaches were employed to gain insights into the origin of switchable regioselectivity of acid-catalyzed lapachol cyclization and α-/β-lapachone isomerization. It was found that solvating species under distinct experimental conditions stabilized α- and β-lapachone differently, thus altering the identity of the thermodynamic product. The energy profile for lapachol cyclization revealed that this process can occur with low free-energy barriers (lower than 8.0 kcal mol?1). For α/β isomerization in a dilute medium, the computed enthalpic barriers are 15.1 kcal mol?1 (α→β) and 14.2 kcal mol?1 (β→α). These barriers are lowered in concentrated medium to 11.5 and 12.6 kcal mol?1, respectively. Experimental determination of isomers ratio was quantified by HPLC and NMR measurements. These findings provide insights into the chemical behavior of lapachol and lapachone derivatives in more complex environments.
- Delarmelina, Maicon,Nicoletti, Caroline D.,de Moraes, Marcela C.,Futuro, Debora O.,Bühl, Michael,de C. da Silva, Fernando,Ferreira, Vitor F.,de M. Carneiro, José W.
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- Lewis acid mediated highly regioselective intramolecular cyclization for the synthesis of β-lapachone
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A highly regioselective intramolecular cyclization of lapachol mediated by Lewis acids including NbCl5, AlCl3, and FeCl3 was developed for synthesizing β-lapachone in excellent yields without any formation of the isomer α-lapachone. This procedure was efficient, mild, and easily scalable that avoided using highly hazardous concd H 2SO4. In the case of ZrCl4 the cyclization was found to give α-lapachone as the main product. A possible mechanism for the Lewis acid mediated cyclization was also discussed.
- Bian, Jinlei,Deng, Bang,Zhang, Xiaojin,Hu, Tianhan,Wang, Nan,Wang, Wei,Pei, Haixiang,Xu, Yu,Chu, Hongxi,Li, Xiang,Sun, Haopeng,You, Qidong
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- Fluorescent oxazoles from quinones for bioimaging applications
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This work describes a synthetic strategy for the syntheses of four new fluorescent excited state intramolecular proton transfer (ESIPT) prone oxazole derivatives synthesized from lapachol, a naturally occurring naphthoquinone isolated from the Tabebuia species (ipe tree). DFT calculations were performed to understand the ESIPT stabilizing process of these new derivatives. The new structures were designed to have improved lipophilic and balanced hydrophobic properties toward a selective cellular staining of lipid-based structures, that is, lipid inclusions in the cytosol. Cell-imaging experiments returned interesting results and showed the molecular architecture of the four derivatives had a great influence over the stabilizing processes in the excited state and over the selection of lipid inclusions inside the cells.
- Dias, Gleiston G.,Pinho, Pamella V. B.,Duarte, Hélio A.,Resende, Jarbas M.,Rosa, Andressa B. B.,Correa, José R.,Neto, Brenno A. D.,Da Silva Júnior, Eufranio N.
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- Nanocomposite gels of poloxamine and Laponite for β-Lapachone release in anticancer therapy
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Nano-hybrid systems have been shown to be an attractive platform for drug delivery. Laponite RD (LAP), a biocompatible synthetic clay, has been exploited for its ability to establish of strong secondary interactions with guest compounds and hybridization with polymers or small molecules that improves, for instance, cell adhesion, proliferation, and differentiation or facilitates drug attachment to their surfaces through charge interaction. In this work, LAP was combined with Tetronics, X-shaped amphiphilic PPO-PEO (poly (propylene oxide)–poly (ethylene oxide) block copolymers. β-Lapachone (BLPC) was selected for its anticancer activity and its limited bioavailability due to very low aqueous solubility, with the aim to improve this by using LAP/Tetronic nano-hybrid systems. The nanocarriers were prepared over a range of Tetronic 1304 concentrations (1 to 20% w/w) and LAP (0 to 3% w/w). A combination of physicochemical methods was employed to characterize the hybrid systems, including rheology, particle size and shape (DLS, TEM), thermal analysis (TG and DSC), FTIR, solubility studies and drug release experiments. In vitro cytotoxicity assays were performed with BALB/3T3 and MCF-7 cell lines. In hybrid systems, a sol-gel transition can occur below physiological temperature. BLPC exhibits the most significant increase in solubility in formulations with a high concentration of T1304 (over 10% w/w) and 1.5% w/w LAP, or systems with only LAP (1.5%), with a 50 and 100-fold increase in solubilisation, respectively. TEM images showed spherical micelles of T1304, which elongated into wormlike micelles with concentration (20%) and in the presence of LAP, a finding that has not been reported before. A sustained release of BLPC over 140 hours was achieved in one of the formulations (10% T1304 with 1.5% laponite), which also showed the best selectivity index towards cancer cells (MCF-7) over BALB/3T3 cell lines. In conclusion, BLPC-loaded T1304/LAP nano-hybrid systems proved safe and highly effective and are thus a promising formulation for anticancer therapy.
- Camara, Gabriel Bezerra Motta,Barbosa, Raquel de Melo,García-Villén, Fátima,Viseras, César,Almeida Júnior, Renato Ferreira de,Machado, Paula Renata Lima,Camara, Celso Amorim,Farias, Kleber Juvenal Silva,de Lima e Moura, Tulio Flavio Accioly,Dreiss, Cécile A.,Raffin, Fernanda Nervo
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- Novel N,N-di-alkylnaphthoimidazolium derivative of β-lapachone impaired Trypanosoma cruzi mitochondrial electron transport system
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Trypanosoma cruzi is a protozoan parasite that causes Chagas disease, a neglected tropical disease that is endemic in Latin America and spreading worldwide due to globalization. The current treatments are based on benznidazole and nifurtimox; however, these drugs have important limitations and limited efficacy during the chronic phase, reinforcing the necessity of an alternative chemotherapy. For the last 30 years, our group has been evaluating the biological activity of naphthoquinones and derivatives on T. cruzi, and of the compounds tested, N1, N2 and N3 were found to be the most active in vitro. Here, we show the synthesis of a novel β-lapachone-derived naphthoimidazolium named N4 and assess its activity on T. cruzi stages and the mechanism of action. The new compound was very active on all parasite stages (IC50/24 h in the range of 0.8–7.9 μM) and had a selectivity index of 5.4. Mechanistic analyses reveal that mitochondrial ROS production begins after short treatment starts and primarily affects the activity of complexes II-III. After 24 h treatment, a partial restoration of mitochondrial physiology (normal complexes II-III and IV activities and controlled H2O2 release) was observed; however, an extensive injury in its morphology was still detected. During treatment with N4, we also observed that trypanothione reductase activity increased in a time-dependent manner and concomitant with increased oxidative stress. Molecular docking calculations indicated the ubiquinone binding site of succinate dehydrogenase as an important interaction point with N4, as with the FMN binding site of dihydroorotate dehydrogenase. The results presented here may be a good starting point for the development of alternative treatments for Chagas disease and for understanding the mechanism of naphthoimidazoles in T. cruzi.
- Bomba?a, Ana Cristina S.,Silva, Leonardo A.,Chaves, Otávio Augusto,da Silva, Lorrainy S.,Barbosa, Juliana M.C.,da Silva, Ari M.,Ferreira, Aurélio B.B.,Menna-Barreto, Rubem F.S.
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- Benzo[a]phenazine derivatives: Promising scaffolds to combat resistant Mycobacterium tuberculosis
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The continuous emergence of resistant Mycobacterium tuberculosis keeps tuberculosis (TB) treatment options still insufficient, and new therapeutic alternatives are urgently needed. Considering the antimycobacterial activity of phenazine derivatives previously reported by our research group, we aimed to explore possible applications to circumvent the resistance in M. tuberculosis. Firstly, we evaluated the antimicrobial activity of seven benzo[a]phenazine derivatives against eleven M. tuberculosis strains: ten resistant and one susceptible (H37Rv). Then, we determined the cytotoxicity of benzo[a]phenazine derivatives and investigated the possible mechanism of action of the most promising compound. Among them, compound 10 was the only one active against all strains evaluated, with a minimum inhibitory concentration between 18.3 and 146.5?μM. For some resistant strains, this compound showed antimicrobial activity higher than rifampicin and it was also active against MDR strains, indicating an absence of cross-resistance with anti-TB drugs. Also, 10 showed a pharmacological safety for further in vivo studies and its mechanism of action seems to be related to oxidative stress. Thus, our findings indicate that benzo[a]phenazine derivatives are promising scaffolds for the development of new anti-TB drugs, mainly focusing on the treatment of resistant TB cases.
- Halicki, Priscila Cristina Bartolomeu,da Silva, Eufranio Nunes,Jardim, Guilherme Augusto de Melo,Almeida, Renata Gomes de,Vicenti, Juliano Rosa de Menezes,Gon?alves, Bruna Lisboa,da Silva, Pedro Eduardo Almeida,Ramos, Daniela Fernandes
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p. 352 - 362
(2021/06/30)
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- Naphthoquinone-based hydrazone hybrids: Synthesis and potent activity against cancer cell lines
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Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio-and hepatotoxicity, and the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α-and βlapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Methods: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Results: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, compounds 3 and 4 being the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.
- Gonsalves, Arlan de Assis,Pessoa, Claudia,Silva, Maria Francilene Souza,Silva, Thaissa Lucio,Araújo, Cle?nia Roberta Melo,Araújo, Edigênia Cavalcante,Goulart, Marília Oliveira Fonseca,Guimar?es, Délis Galv?o,Rolim, Larissa Araújo,Santos, Danyelle Candido,Santos, Victória Laysna Dos Anjos,da Costa, Marcília Pinheiro,de Oliveira, Fátima de Cássia Evangelista
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p. 945 - 955
(2021/11/30)
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- Antiproliferative activity of naphthoquinones and indane carboxylic acids from lapachol against a panel of human cancer cell lines
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Lapachol (1) is a well-studied natural product isolated from plants of the Bignoniaceae family and demonstrates diverse biological effects. Historically, chemical transformation of the lapachol scaffold has yielded new derivatives with impressive biological activity and rich chemical diversity. β-lapachone (2), α-lapachone (3), and 2-acetylfuronaphthoquinone (4) are examples of analogs derived from lapachol that show superior antitumor activity compared with the natural product. In the present study, novel indane carboxylic acid: 2,2-dimethyl-2,3-dihydroindeno[1,2-b]pyran-4,5-dione (9) and methyl 5-hydroxy-2,2-dimethyl-2,3,4,5-tetrahydroindeno[1,2-b]pyran-5-carboxylate (10) and naphthoquinone derivatives were synthesized from lapachol with structural similarities to the antitumor lapachol derivatives. The synthesized compounds were evaluated for antiproliferative activities against a panel of human cancer cell lines including in vitro models for neuroblastoma, melanoma, glioblastoma, and non-small cell lung cancer. As expected, the most potent derivatives were those incorporating β-naphthoquinone and α-naphthoquinono[2,3-b]furan skeletons. Many of these compounds possessed nanomolar to single digit micromolar antiproliferative potency. However, the most interesting analog evaluated was the dione 9 with an indeno[1,2-b]pyran skeleton, which demonstrated potent cytotoxic activity. The current investigation identified several new lead compounds that could be used as starting points for anticancer drug discovery.
- Baskaran, Sundarababu,Du, Liqin,Eyong, Kenneth O.,Folefoc, Gabriel N.,Hull, Kenneth G.,Ingels, Aude,Ketsemen, Herve L.,Kornienko, Alexander,Mathieu, Veronique,Romo, Daniel,Zhao, Zhenze
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- Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish
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During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.
- Foulkes, Matthew J.,Tolliday, Faith H.,Henry, Katherine M.,Renshaw, Stephen A.,Jones, Simon
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- ALBUMIN NANOPARTICLES, THE MAKING METHOD, AND USES THEREOF
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An albumin nanoparticle comprises a core consisting of at least one diester derivative of β-lapachone and a shell consisting of at least one albumin. Further, a preparation method and use thereof. The albumin nanoparticle has a significantly longer in vivo half-life, markedly reduced toxicity and side effects, and an observably widened therapeutic window, and thus can treat cancer associated with KRAS mutations.
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- Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis
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Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H37Rv) strain and two isoniazid-resistant strains (INHR1 and INHR2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H37Rv and INHR1 (katG S315T) or INHR2 (inhA C(?5)T) strains. Compounds 1a, 2a, and 8a were effective against the INHR1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INHR2 strain, with MICs in the range of 3.12–6.25 μg/mL. Compounds 1b and 5b were the most active against H37Rv, with MIC of 0.78 μg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains.
- Reis, Wallace J.,Bozzi, ícaro A.O.,Ribeiro, Matheus F.,Halicki, Priscila C.B.,Ferreira, Laís A.,Almeida da Silva, Pedro E.,Ramos, Daniela F.,de Simone, Carlos A.,da Silva Júnior, Eufranio N.
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p. 4143 - 4150
(2019/08/06)
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- 5-LIPOXYGENASE ANTAGONISTS
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This invention relates to the treatment of conditions, such as cancer, associated with 5-lipoxygenase (5-LO) expression using β-lapachone compounds that inhibit 5-lipoxygenase (5-LO), such as β- lapachone and derivatives thereof. Methods of treatment of conditions associated with 5-lipoxygenase (5-LO) expression as well as medical uses of β-lapachone compounds in such methods are provided, as well as methods of selecting or prognosing cancer patients.
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(2019/04/10)
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- Lawsone, Juglone, and β-Lapachone Derivatives with Enhanced Mitochondrial-Based Toxicity
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Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS), and inhibition of proteins. Here, we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone, and β-lapachone. We have found that (i) the free hydroxyl group of lawsone and juglone modulates toxicity; (ii) lawsone and juglone derivatives differ in their mechanisms of action, with ROS generation being more important for the former; and (iii) a subset of derivatives possess the capability to disrupt mitochondrial function, with β-lapachones being the most potent compounds in this respect. In addition, we have cross-compared yeast results with antibacterial and antitumor activities. We discuss the relationship between the mechanistic findings, the antiproliferative activities, and the physicochemical properties of the naphthoquinones.
- Anaissi-Afonso, Laura,Oramas-Royo, Sandra,Ayra-Plasencia, Jessel,Martín-Rodríguez, Patricia,García-Luis, Jonay,Lorenzo-Castrillejo, Isabel,Fernández-Pérez, Leandro,Estévez-Braun, Ana,Machín, Félix
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p. 1950 - 1957
(2018/06/18)
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- A Photoactivatable Probe for Super-Resolution Imaging of Enzymatic Activity in Live Cells
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A dual-Activatable, fluorogenic probe was developed to sense esterase activity with single-molecule resolution. Without enzymatic pre-Activation, the diazoindanone-based probe has an electron-poor core and, upon irradiation, undergoes Wolff rearrangement to give a ring-expanded xanthene core that is nonemissive. If the probe is pre-Activated by carboxylesterases, the tricyclic core becomes electron-rich, and the photoinduced Wolff rearrangement produces a highly emissive rhodol dye. Live-cell and solution studies confirmed the selectivity of the probe and revealed that the photoactivated dye does not diffuse away from the original location of activation because the intermediate ketene forms a covalent bond with surrounding macromolecules. Single-molecule localization microscopy was used to reconstruct a super-resolved image of esterase activity. These single-molecule images of enzymatic activity changed significantly upon treatment of the cells with inhibitors of human carboxylesterase I and II, both in terms of total number of signals and intracellular distribution. This proof-of-principle study introduces a sensing mechanism for single-molecule detection of enzymatic activity that could be applied to many other biologically relevant targets.
- Halabi, Elias A.,Thiel, Zacharias,Trapp, Nils,Pinotsi, Dorothea,Rivera-Fuentes, Pablo
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supporting information
p. 13200 - 13207
(2017/09/26)
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- Cyclometalated ruthenium complexes from naturally occurring quinones: studies on their photophysical features, computational details and trypanocidal activity
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Phenazinic ligands and Ru(ii)-based complexes were synthesized from natural products lapachol and lawsone and evaluated against T. cruzi, the etiological agent of Chagas disease. These new ruthenium compounds could provide promising trypanocidal drugs. Besides synthesis and trypanocidal activity, this paper reports photophysical features and computational details of the compounds. The fluorescent trypanocidal substances are promising derivatives for further studies aiming to find molecules active against parasites associated with neglected diseases.
- De Souza, Clayton M.,Silva, Rafaela C.,Fernandes, Philipe O.,De Souza Filho, José D.,Duarte, Hélio A.,Araujo, Maria H.,De Simone, Carlos A.,De Castro, Solange L.,Menna-Barreto, Rubem F. S.,Demicheli, Cynthia P.,Da Silva Júnior
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p. 3723 - 3731
(2017/07/12)
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- On the search for potential antimycobacterial drugs: Synthesis of naphthoquinoidal, phenazinic and 1,2,3-triazolic compounds and evaluation against Mycobacterium tuberculosis
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Fifteen naphthoquinones, sixteen phenazines and fifteen aryl triazoles were synthesized and evaluated against Mycobacterium tuberculosis. Twenty five substances are reported here for the first time and, among all of the compounds evaluated, six presented MIC (minimal inhibitory concentration) values ≤ 6.25 μg mL-1. These substances are promising antimycobacterial prototypes.
- Jardim, Guilherme A. M.,Cruz, Eduardo H. G.,Valen?a, Wagner O.,Resende, Jarbas M.,Rodrigues, Bernardo L.,Ramos, Daniela F.,Oliveira, Ronaldo N.,Silva, Pedro E.A.,Da Silva Júnior, Eufranio N.
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p. 1013 - 1027
(2015/05/20)
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- 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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- Naphthoquinone-based chalcone hybrids and derivatives: Synthesis and potent activity against cancer cell lines
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Novel naphthoquinone-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. This journal is
- Jardim, Guilherme A. M.,Guimares, Tiago T.,Pinto, Maria Do Carmo F.R.,Cavalcanti, Bruno C.,De Farias, Kaio M.,Pessoa, Claudia,Gatto, Claudia C.,Nair, Divya K.,Namboothiri, Irishi N. N.,Da Silva Jnior, Eufrnio N.
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p. 120 - 150
(2015/02/02)
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- Synthesis of β-lapachone, a potential anticancer agent from the lapacho tree
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A pharmaceutically important natural product, β-lapachone, was efficiently synthesized in four steps in 70% overall yield starting from commercially available 1, 4-naphthoquinone. The key step of the synthesis was the direct conversion of 2-prenyl-1, 4-naphthoquinone into β-lapachone through an advantageous cyclization/hydration/oxidation cascade process.
- Katoh, Tadashi,Katoh, Takeru,Monma, Hiromitsu,Wakasugi, Jun,Narita, Koichi
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p. 7099 - 7103
(2015/02/05)
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- A mechanistic study on the Hooker oxidation: Synthesis of novel indane carboxylic acid derivatives from lapachol
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The Hooker oxidation is one of the most intriguing transformations wherein lapachol (1) is readily converted to norlapachol (2) in very good yield. This one-pot reaction involves a very intricate mechanism in which the alkyl side chain of lapachol is shortened by one carbon unit. Previous studies have unequivocally established the involvement of an indane carboxylic acid derivative 3, as a key intermediate (Hooker intermediate), and its simultaneous conversion to norlapachol (2) via the oxidative cleavage of vicinol diol and subsequent intramolecular aldol reaction of the resulting keto acid. However, the formation of the key Hooker intermediate 3 from lapachol (1) remains ambiguous. The present study has thrown some light on the formation of the key intermediate 3 from lapachol (1) via benzilic acid rearrangement of the corresponding labile o-diquinone intermediate 8 derived from lapachol. The involvement of o-diquinone intermediate 8 in the Hooker oxidation has been further established by trapping of this labile intermediate as the corresponding phenazine derivative 9. The involvement of benzilic acid rearrangement as a key step in the Hooker oxidation is further shown with a variety of o-quinones prepared from lapachol (1). The Royal Society of Chemistry 2013.
- Eyong, Kenneth O.,Puppala, Manohar,Kumar, Ponminor Senthil,Lamsh?ft, Marc,Folefoc, Gabriel N.,Spiteller, Michael,Baskaran, Sundarababu
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p. 459 - 468
(2013/02/25)
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- Potent antileukemic action of naphthoquinoidal compounds: Evidence for an intrinsic death mechanism based on oxidative stress and inhibition of DNA repair
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The current study describes that nor-β-lapachone and its arylamino derivatives, iodinated and methylated naphthoquinones and nor-β-lapachone- based 1,2,3-triazoles exhibited pronounced cytotoxic effects against four human leukemia cell lines (HL-60, K562, Molt-4 and Jurkat). Nor-β-lapachones arylamino substituted with potent activity were identified, revealing themselves as potential prototypes against tumor cell lines. Moreover, cells treated with these compounds showed DNA damage according to the standard comet assay, a finding that was, at least in part, due to increased intracellular levels of ROS. HL-60 cells were chosen to study the underlying molecular mechanisms of cytotoxicity. Drug-induced apoptosis in HL-60 cells was observed by flow cytometry analyses. Strains of Saccharomyces cerevisiae were used for a preliminary investigation into the mechanism of drug action on DNA topoisomerases. These results suggested that the cytotoxicity of these compounds apparently does not involve topoisomerase inhibition, but that treatment impairs DNA repair activity, thus triggering cell death. Considering their pro-oxidant properties, we investigated the ability of these compounds to induce apoptosis and chromosomal aberrations as micronuclei in Chinese hamster lung fibroblasts (V79 cells). Morphological apoptotic nuclei and micronuclei induction following drug treatment were observed, suggesting a correlation between DNA damage and apoptosis.
- Cavalcanti, Bruno C.,Cabral, Igor O.,Rodrigues, Felipe A. R.,Barros, Francisco W. A.,Rocha, Danilo D.,Magalha?es, Hemerson I. F.,Moura, Dinara J.,Saffi, Jenifer,Henriques, Joa?o A. P.,Carvalho, Tatiane S. C.,Moraes, Manoel O.,Pessoa, Cla?udia,De Melo, Isadora M. M.,Da Silva Jr., Eufra?nio N.
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p. 145 - 163
(2013/05/08)
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- Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones against oesophageal cancer cells
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Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, α- and β-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC50 1.6-11.7 μM) compared to the current drug of choice cisplatin (IC 50 = 16.5 μM). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3.0 and 7.3 μM) and the previously reported compound 11a (IC50 = 3.9 μM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds.
- Sunassee, Suthananda N.,Veale, Clinton G.L.,Shunmoogam-Gounden, Nelusha,Osoniyi, Omalaja,Hendricks, Denver T.,Caira, Mino R.,De La Mare, Jo-Anne,Edkins, Adrienne L.,Pinto, Antonio V.,Da Silva Junior, Eufranio N.,Davies-Coleman, Michael T.
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- β-Lapachone analogs with enhanced antiproliferative activity
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In this study, we describe the synthesis of a series of α- and β-lapachone containing hydroxyl or methoxyl groups on the benzene ring, by means of the selective acid promoted cyclization of the appropriate lapachol analog. The evaluation of the antiproliferative activity in human solid tumor cell lines provided 7-hydroxy-β-lapachone as lead with enhanced activity over the parent drug β-lapachone. Cell cycle studies, protein expression experiments, and reactive oxygen species analysis revealed that, similarly to β-lapachone, ROS formation and DNA damage are critical factors in the cellular toxicity of 7-hydroxy-β-lapachone.
- Rios-Luci, Carla,Bonifazi, Evelyn L.,Leon, Leticia G.,Montero, Juan C.,Burton, Gerardo,Pandiella, Atanasio,Misico, Rosana I.,Padron, Jose M.
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experimental part
p. 264 - 274
(2012/08/28)
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- Concise synthesis of (±)-rhinacanthin A, dehydro α-lapachone, and β-lapachone, and pyranonaphthoquinone derivatives
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A concise synthesis of (±)-rhinacanthin A is achieved in two steps by epoxidation of dehydro-α-lapachone, followed by chemo-and regioselective reduction. Dehydro-α-lapachone was also synthesized in two steps starting from 4-methoxy-1-naphthol by ethylenediamine diaetate (EDDA)-catalyzed benzopyran formation and a CAN-mediated oxidation reaction. β-Lapachone was synthesized in three steps from 4-methoxy-1-naphthol by benzopyran formation, catalytic hydrogenation, and Jones oxidation. As additional reactions, synthesis of pyranonaphthoquinone derivatives with the pyranokunthone B skeleton has been achieved in a single step from readily available 2-hydroxy-6-methoxy-1,4-naphthoquinone and 2-hydroxy-7-methoxy-1,4- naphthoquinone.
- Wang, Xue,Chen, Ye,Lee, Yong Rok
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experimental part
p. 153 - 156
(2011/11/01)
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- Synthesis and evaluation of quinonoid compounds against tumor cell lines
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Thirty two compounds were synthesized in moderate to high yields and showed activity against cancer cells HL-60 (leukemia), MDA-MB435 (melanoma), HCT-8 (colon) and SF295 (central nervous system), with IC50 below 2 μM for some compounds. The β-lapachone-based 1,2,3-triazoles showed the best cytoxicity profile and emerge as promising anticancer prototypes. Insights about the reactive oxygen species (ROS) mechanism of anticancer action for some compounds were obtained by addition of 1-bromoheptane that deplete reduced glutathione (GSH) content and by using N-acetylcysteine that protects cells against apoptotic cellular death, as well by analysis of thiobarbituric acid reactive substances (TBARS) formation, and oxidative DNA damage after treatment detected by the comet assay with the bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (ENDOIII).
- Da Silva Jr., Eufranio N.,Cavalcanti, Bruno C.,Guimar?es, Tiago T.,Pinto, Maria Do Carmo F.R.,Cabral, Igor O.,Pessoa, Cláudia,Costa-Lotufo, Letícia V.,De Moraes, Manoel O.,De Andrade, Carlos K.Z.,Dos Santos, Marcelo R.,De Simone, Carlos A.,Goulart, Marilia O.F.,Pinto, Antonio V.
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body text
p. 399 - 410
(2011/02/27)
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- The evaluation of quinonoid compounds against Trypanosoma cruzi: Synthesis of imidazolic anthraquinones, nor-β-lapachone derivatives and β-lapachone-based 1,2,3-triazoles
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In continuing our screening program of naphthoquinone activity against Trypanosoma cruzi, the aetiological agent of Chagas' disease, new β-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-β-lapachones, 3-alkoxy-nor-β-lapachones and imidazole anthraquinones were synthesised and evaluated against bloodstream trypomastigote forms of the parasite. Compounds 2,2-dimethyl-3-(2,4-dibromophenylamino)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, IC50/24 h 24.9 ± 7.4 and 4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione with 23.4 ± 3.8 μM showed a trypanosomicidal activity higher than benznidazole. These results demonstrate the potential of naphthoquinone derivatives as novel structures for the development of alternative drugs for Chagas' disease.
- da Silva Júnior, Eufranio N.,Guimar?es, Tiago T.,Menna-Barreto, Rubem F.S.,Pinto, Maria do Carmo F.R.,de Simone, Carlos A.,Pessoa, Claudia,Cavalcanti, Bruno C.,Sabino, José R.,Andrade, Carlos Kleber Z.,Goulart, Marilia O.F.,de Castro, Solange L.,Pinto, Ant?nio V.
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scheme or table
p. 3224 - 3230
(2010/07/08)
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- Complex diazaazulenones from the reaction of ortho -naphthoquinones with ammonium acetate
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Complex diazaazulenones compounds were obtained from ortho-naphthoquinones by reaction with ammonium acetate. Georg Thieme Verlag Stuttgart.
- Emery, Flavio S.,Pinto, Maria Do Carmo F.R.,De Simone, Carlos A.,Malta, Valéria R.S.,Da Silva Júnior, Eufranio N.,Pinto, Antonio V.
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scheme or table
p. 1931 - 1934
(2010/10/02)
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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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scheme or table
p. 85 - 95
(2011/07/30)
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- Synthesis of naturally occurring naphthoquinone epoxides and application in the synthesis of β-lapachone
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Optimized epoxidation conditions of mono- and dialkylated naphthoquinones are presented. Based on the epoxidation protocol making use of H 2O2/Na2CO3, naphthoquinone epoxides are obtained in high yields. The optimized epoxidation conditions are applied in a short and high yielding synthesis of the pharmaceutically important β-lapachone.
- Claessens, Sven,Habonimana, Pascal,De Kimpe, Norbert
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experimental part
p. 3790 - 3795
(2010/09/05)
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- A macrolactone from benzo[a]phenazine with potent activity against Mycobacterium tuberculosis
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We report here an alternative to the MCPBA or ozonolysis-based oxidation methods of quinoxaline-featuring compounds prepared from beta-lapachones. The use of peracetic acid allowed a simple preparation of the corresponding macrolactones by cleavage of the ring system. These lactones were evaluated for their antimycobacterial potential and compound 4 turned out to have an MIC of 0.62 μg per mL on Mycocabteriumtuberculosis H37Rv. These results justify further research into its value as a potential lead for an original treatment of tuberculosis.
- Silva, Raphael S.F.,Pinto, Maria do Carmo F.R.,Goulart, Marilia O.F.,de Souza Filho, Jose D.,Neves Jr., Ivan,Lourenco, Maria Cristina S.,Pinto, Antonio V.
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scheme or table
p. 2334 - 2337
(2009/09/05)
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- Unexpected transformation of quinones to spirolactones and to naturally occurring naphthalenic compounds
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In the last few years, natural quinones of the lapachol group have been used as starting points for the preparation of several bioactive heterocyclic compounds. Herein, we announce that lapachones, derivatives of lapachol, under certain conditions in the presence of inorganic reagents give unexpected products, spirolactones and naphthalenic derivatives, nordihydrolapachenone and tetrahydrotectol, both naturally occurring compounds. Nordihydrolapachenone was identified by X-ray analysis. Lapachol itself can also be converted to tetrahydrotectol.
- da Silva Júnior, Eufranio N.,de Simone, Carlos A.,de Souza, Adolfo C.B.,Pinto, Cleverson N.,Guimar?es, Tiago T.,Pinto, Maria do Carmo F.R.,Pinto, Ant?nio V.
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scheme or table
p. 1550 - 1553
(2009/06/21)
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- PHARMACEUTICAL COMPOSITION CONTAINING NAPHTHOQUINONE-BASED COMPOUND FOR INTESTINE DELIVERY SYSTEM
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Provided is an oral pharmaceutical composition with improved bioavailability and pharmacokinetic properties of a drug, by increasing a bioabsorption rate and an in vivo retention time of an active ingredient via intestine-targeted formulation of a particular naphthoquinone-based compound, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient.
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Page/Page column 15
(2008/12/06)
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- COMPOUND FOR TREATMENT OR PREVENTION OF PROSTATE-RELATED DISEASES AND PHARMACEUTICAL COMPOSITION OF COLON DELIVERY SYSTEM CONTAINING THE SAME
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Provided is a naphthoquinone-based compound represented by Formula 1 or 2 having therapeutic effect on the treatment and/or prevention of prostate and/or testicle (seminal glands)-related diseases, and to a pharmaceutical composition of intestinal delivery system containing the same.
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Page/Page column 23
(2008/12/06)
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- Semisynthesis and antitumoral activity of 2-acetylfuranonaphthoquinone and other naphthoquinone derivatives from lapachol
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Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), β-lapachone (10) and dehydro-β-lapachone diacetate (11) showed 100% inhibition at 25 μg/ml. All the tested samples showed dose-dependent activity.
- Eyong, Kenneth O.,Kumar, Ponminor S.,Kuete, Victor,Folefoc, Gabriel N.,Nkengfack, Ephriam A.,Baskaran, Sundarababu
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supporting information; experimental part
p. 5387 - 5390
(2009/05/26)
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- Trypanosoma cruzi: Activities of lapachol and α- and β-lapachone derivatives against epimastigote and trypomastigote forms
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Derivatives of natural quinones with biological activities, such as lapachol, α- and β-lapachones, have been synthesized and their trypanocidal activity evaluated in vitro in Trypanosoma cruzi cells. All tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity as compared with current trypanocidal drugs, nifurtimox and benznidazole. The results presented here show that the anti-T. cruzi activity of the α-lapachone derivatives can be increased by the replacement of the benzene ring by a pyridine moiety. Free radical production and consequently oxidative stress through redox cycling or production of electrophilic metabolites are the potential biological mechanism of action for these synthetic quinones.
- Salas, Cristian,Tapia, Ricardo A.,Ciudad, Karina,Armstrong, Veronica,Orellana, Myriam,Kemmerling, Ulrike,Ferreira, Jorge,Maya, Juan Diego,Morello, Antonio
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p. 668 - 674
(2008/09/17)
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- Studies on novel polycyclic heterocycles: Synthesis of new naphthaquinoxaline and naphthazaquinoxaline derivatives from naturally occurring quinones
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A facile synthesis of novel polycyclic heterocycles namely naphthaquinoxaline and naphthazaquinoxaline derivatives is carried out by the reaction of lapachol and β-lapachone, naturally occurring naphthoquinones with o-phenylene diamine and 2,3-diaminopyridine. Regioselectivity in the reaction of β-lapachone with 2,3-diaminopyridine is confirmed by single crystal X-ray diffraction of a representative compound 6,7-dihydro-8,8-dimethyl- 8//-pyrano[3',2':4]-naphtha[2,l-e]pyrido[2,3-b]pyrazine; C20H 17N3O, crystallizes as orthorhombic in the space group Pbca with cell parameters a =9.793(3)A, b=17.514(6)A, c=18.334(6)A, V=3144.5(17) A3, Z=8,1.332 mg/m 3, R1=0.3076, WR2=0.3595.
- Singh, Pahup,Dandia, Anshu,Khandelwal, Poonam
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p. 427 - 433
(2008/09/20)
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- PHARMACEUTICAL COMPOSITION FOR TREATMENT AND PREVENTION OF RESTENOSIS
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Provided is a pharmaceutical composition for the treatment and/or prevention of restenosis including (a) a therapeutically effective amount of a particular compound represented by Formula 1 and 2, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, and (b) a pharmaceutically acceptable carrier, a diluent or an excipient, or any combination thereof.
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Page/Page column 50-52
(2008/12/06)
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- ANTICANCER COMPOSITION CONTAINING NAPHTHOQUINONE-BASED COMPOUND FOR INTESTINE DELIVERY SYSTEM
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Provided is an oral pharmaceutical composition with improved bioavailability and pharmacokinetic properties of a drug, by increasing a bioabsorption rate and an in vivo retention time of an active ingredient via intestine-targeted formulation of a certain naphthoquinone-based compound or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient having therapeutic effects on prevention or treatment of i) cancer, or treatment of ii) bacterial, fungal or parasitic infectious diseases and/or iii) dermatological diseases.
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Page/Page column 48-50
(2008/12/06)
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- PHARMACEUTICAL COMPOSITION FOR THE TREATMENT AND PREVENTION OF DISEASES INVOLVING IMPOTENCE
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Disclosed is a pharmaceutical composition for the treatment and/or prevention of erectile dysfunction, comprising (a) a therapeutically effective amount of a compound represented by Formula 1 or 2, and (b) a pharmaceutically acceptable carrier, a diluent or an excipient, or any combination thereof.
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Page/Page column 50; 51
(2008/12/06)
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- Radermachol and naphthoquinone derivatives from Tecomella undulata: Complete 1H and 13C NMR assignments of radermachol with the aid of computational 13C shift prediction
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Petroleum ether extract of the heartwood of Tecomella undulata affords radermachol, an unusual rare pigment and 2-isopropenylnaphtho[2,3-b]furan-4,9- quinone along with lapachol, tecomaquinone-I, dehydro-α-lapachone, α-lapachone, β-lapachone, cluytyl ferulate, stigmasterol and β-sitosterol. Radermachol and 2-isopropenylnaphtho [2,3-b]furan-4,9-quinone are being reported for the first time from genus Tecomella. Complete assignments of 1H and 13C NMR signals of polyketide, radermachol 1, have been achieved by the 13C NMR chemical shift prediction using ab initio MO and DFT/GIAO methods in addition to 2D-NMR techniques.
- Singh, Pahup,Khandelwal, Poonam,Hara, Noriyuki,Asai, Teigo,Fujimoto, Yoshinori
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experimental part
p. 1865 - 1870
(2009/05/27)
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- HYDROXY SULFONATE OF QUINONE COMPOUNDS AND THEIR USES
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The present invention provides sodium 6-hydroxy-2,2-dimethyl-5-oxo-3,4,5,6-tetrahydro-2H- benzo(h)chromene-6-sulfonate, and its synthesis and uses in the treatment of cancer.
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Page/Page column 21-22
(2008/12/08)
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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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