- Tridentate 3-Substituted Naphthoquinone Ruthenium Arene Complexes: Synthesis, Characterization, Aqueous Behavior, and Theoretical and Biological Studies
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A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.4) intensely, whereas substituents such as halogens accelerated hydrolysis and formation of dimeric pyrazolate and hydroxido bridged dimers. The observed cytotoxic profile is unusual, as complexes exhibited much higher cytotoxicity in SW480 colon cancer cells than in the broadly chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells. This activity pattern as well as reduced or slightly enhanced ROS generation and the lack of DNA interactions indicate a mode of action different from established or previously investigated classes of metallodrugs.
- Geisler, Heiko,Westermayr, Julia,Cseh, Klaudia,Wenisch, Dominik,Fuchs, Valentin,Harringer, Sophia,Plutzar, Sarah,Gajic, Natalie,Hejl, Michaela,Jakupec, Michael A.,Marquetand, Philipp,Kandioller, Wolfgang
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p. 9805 - 9819
(2021/06/30)
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- Molecular mechanism of action of new 1,4-naphthoquinones tethered to 1,2,3-1H-triazoles with cytotoxic and selective effect against oral squamous cell carcinoma
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The oral squamous cell carcinoma (OSCC) stands out as a public health problem due to its high incidence and low survival rate, despite advances in diagnosis and treatment. Moreover, the most commonly chemotherapeutic agents for OSCC, such as carboplatin and cisplatin, generate important side effects, evidencing the urgency in developing new drugs. Naphthoquinones are an important class of natural products or synthetic compounds with cytotoxic effect demonstrated on different cancer types. In the present study, thirty-five 1,4-naphthoquinones tethered to 1,2,3-1H-triazoles were synthesized and the antitumor activity and molecular mechanisms were evaluated in several assays including in vitro and in vivo models of OSCC and normal oral human cells. Compounds 16a, 16b and 16 g were able to induce cytotoxicity in three different tumor cell lines of human OSCC (SCC4, SCC9 and SCC25) and were more toxic and selective to tumor cells (Selective Index, SI > 2) than classical and chemically similar controls (Carboplatin and Lapachol). Compound 16 g showed the higher SI value. Besides, compounds 16a, 16b and 16 g significantly reduced colony formation of SCC9 cells in the tested concentrations. Hemolytic assay using compounds 16a, 16b and 16 g at high concentrations showed no compound exhibited hemolysis higher than 5%, similar to controls. In vivo acute toxicity study showed that 16 g was the only one, among the three compounds, with no apparent limiting toxic effects on mice in the tested concentrations. Thus, the investigation of cell death mechanisms was conducted with this compound. 16 g does not trigger ROS production nor binds to DNA. On the other hand, compound 16 g induced microtubule disorganization, and molecular modeling studies suggests a potential mechanism of action related to inhibition of topoisomerases and/or hPKM2 activities. Cell morphology, pyknotic nuclei presence, cleaved caspase-3 staining and viability assays using caspase-3 inhibitors demonstrate compound 16 g induced cell death through apoptosis. Among the 35 synthesized triazole naphthoquinones, compound 16 g was the most effective compound against OSCC cells, presenting high cytotoxicity (~35 μM), selectivity (SI ~ 6) and low acute toxicity on animals, and therefore might be considered for future cancer therapy.
- Alvarez Abreu, Paula,Cardozo Paes de Almeida, Elan,Carolina Carvalho da Fonseca, Anna,Cavalcanti Chipoline, Ingrid,Francisco Ferreira, Vitor,Luiz Ferraz de Souza, Theo,Pereira de Souza, Michele,Pontes, Bruno,Ribeiro Machado da Costa, Gabriella,Robbs, Bruno K.,Won-Held Rabelo, Vitor,de Carvalho da Silva, Fernando,de Queiroz, Lucas N.
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- Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase
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Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH. The best compound identified is 17 (2-hydroxy-3-isopentylnaphthalene-1,4-dione) with IC50 = 23 ± 4 nM and selectivity index of 30.83. Some of the new compounds are useful pharmacological tools and represent new lead structures for further optimization.
- Calil, Felipe A.,David, Juliana S.,Chiappetta, Estela R.C.,Fumagalli, Fernando,Mello, Rodrigo B.,Leite, Franco H.A.,Castilho, Marcelo S.,Emery, Flavio S.,Nonato, M.Cristina
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p. 357 - 366
(2019/02/19)
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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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p. 1364 - 1373
(2017/02/18)
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- Discovery of quinone-directed antitumor agents selectively bioactivated by NQO1 over CPR with improved safety profile
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In this work, we mainly focused on discovering compounds with good selectivity for NQO1 over CPR. The NQO1-mediated two-electron reduction of compounds would kill cancer cells selectively, while CPR-mediated one-electron reduction would induce potential hepatotoxicity. Several novel quinone-directed antitumor agents were discovered as specific NQO1 substrates through structure-activity relationship studies. Among them, compound 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione (12b) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by CPR. It afforded the highest selectivity between NQO1/CPR (selectivity ratio = 6.37), much higher than the control β-lapachone (selectivity ratio = 1.36), indicated 12b may possess superior safety profile. The electrochemical studies provided a reasonable explanation to the good selectivity toward NQO1. Molecular docking studies supported that 12b was capable of forming additional C-H … π interactions with Trp105 and Phe178 residues compared to the control β-lap. In addition, compound 12b was shown to kill cancer cells efficiently both in vitro and in vivo model. This work gave us a promising and novel scaffold for further investigation.
- Bian, Jinlei,Li, Xiang,Wang, Nan,Wu, Xingsen,You, Qidong,Zhang, Xiaojin
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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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p. 13200 - 13207
(2017/09/26)
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- Palladium(II)-Catalyzed C-H Bond Activation/C-C Coupling/Intramolecular Tsuji-Trost Reaction Cascade: Facile Access to 2 H -Pyranonaphthoquinones
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An efficient one-pot synthesis of 2H-pyranonaphthoquinone was achieved via a palladium-catalyzed C-H bond activation/C-C bond formation/intramolecular Tsuji-Trost reaction cascade. The unprecedented procedure exhibits excellent functional group tolerance, giving the target naphthoquinones in moderate to good isolated yields (40-88%) under mild reaction conditions. Scalable production of the product can make this reaction a method of choice for the synthesis of 2H-pyranonaphthoquinones.
- Bian, Jinlei,Qian, Xue,Wang, Nan,Mu, Tong,Li, Xiang,Sun, Haopeng,Zhang, Lianshan,You, Qidong,Zhang, Xiaojin
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supporting information
p. 3410 - 3413
(2015/07/28)
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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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- Synthesis and biological evaluation of lipophilic 1,4-naphthoquinone derivatives against human cancer cell lines
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To examine the effect of hydrophobicity on the anticancer activity of 1,4-naphthoquinone derivatives, a series of compounds bearing a 2-O-alkyl-, 3-C-alkyl- or 2/3-N-morpholinoalkyl group were synthesized and evaluated for their anticancer activity against five human cancer cell lines in vitro. The cytotoxicity of these derivatives was assayed against HT-29, SW480, HepG2, MCF-7 and HL-60 cells by the MTT assay. Among them, 2-hydroxy-3-farnesyl-1,4-naphthoquinone (11a) was found to be the most cytotoxic against these cell lines. Our results showed that the effectiveness of compound 11a may be attributed to its suppression of the survival of HT-29. Secondly, in the Hoechst 33258 staining test, compound 11a-treated cells exhibited nuclear condensation typical of apoptosis. Additionally, cell cycle analysis by flow cytometry indicated that compound 11a arrested HT-29 cells in the S phase. Furthermore, cell death detected by Annexin V-FITC/propidium iodide staining showed that compound 11a efficiently induced apoptosis of HT-29 in a concentration-dependent manner. Taken together, compound 11a effectively inhibits colon cancer cell proliferation and may be a potent anticancer agent.
- Wang, Shao-Hung,Lo, Chih-Yu,Gwo, Zhong-Heng,Lin, Hong-Jhih,Chen, Lih-Geeng,Kuo, Cheng-Deng,Wu, Jin-Yi
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p. 11994 - 12015
(2015/08/18)
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- A new method to prepare 3-alkyl-2-hydroxy-1,4-naphthoquinones: Synthesis of lapachol and phthiocol
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In this article a mild, simple, safe, and chemoselective synthesis and reduction of o-quinone methides to the corresponding 3-alkyl-2-hydroxy-1,4- naphthoquinones, compounds with interesting biological activity, mediated by the formic acid-water system is described. This new one-pot methodology was applied to the synthesis of lapachol and constitutes an efficient and inexpensive alternative for the preparation of this natural bioactive compound Georg Thieme Verlag Stuttgart ? New York.
- Ferreira, Sabrina Baptista,Rodriguesdarocha, David,Carneiro, José Walkimar M.,Santos, Wilson Costa,Ferreira, Vitor Francisco
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supporting information; experimental part
p. 1551 - 1554
(2011/08/04)
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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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- 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 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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- 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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- 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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p. 567 - 570
(2008/02/13)
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- Palladium-catalyzed allylation of 2-hydroxy-1,4-naphthoquinone: Application to the preparation of lapachol
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The Pd(PPh3)4-catalyzed reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with allyl alcohols and allyl esters offers an easy access to 3-allyl-2-hydroxy-1,4-naphthoquinones, compounds with interesting biological activity. The reaction finds application in the preparation of lapachol. Other 2-hydroxy-1,4-benzoquinones give allylation products in low yields. Georg Thieme Verlag Stuttgart.
- Kazantzi, Georgia,Malamidou-Xenikaki, Elizabeth,Spyroudis, Spyros
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p. 427 - 430
(2008/01/03)
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- SYNTHESIS OF BETA-LAPACHONE AND ITS INTERMEDIATES
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A novel process for synthesizing β-lapachone (beta-lapachone), an agent that has demonstrated significant antineoplastic activity against human cancer lines. The process comprises the conversion of starting material, 2-hydroxy-1,4-naphothoquinone into β-lapachone intermediate, lapachol. The lapachol is then converted to β-lapachone by treatment with sulfuric acid and purified by recrystallization from ethanol. This novel process is extremely simple and provides β-lapachone in excellent quality and high yield.
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- Ortho-quinone derivatives novel synthesis therefor and their use in the inhibition of neoplastic cell growth
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The invention relates to β-lapachone derivatives of formula II and compositions containing said compounds: STR1 wherein, R5, R6 and R7 are as defined in the specification. The compounds are potent inhibitors of neoplastic cell growth and proliferation.
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- A preparative synthesis of lapachol and related naphthoquinones
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The lithium salt of 2-hydroxy-1,4-naphthoquinone was prepared in situ by addition of lithium hydride to the frozen solution of the quinone in dimethyl sulfoxide. As the solution thawed, the lithium quinone was slowly formed and was then alkylated with 3,3-dimethylallyl bromide. Lapachol was thus obtained in 40% yield. When treated with m-chloroperoxybenzoic acid it was converted into its epoxide, that was cyclized with boron trifluoride etherate to 3- hydroxy-β-lapachone in 67% overall yield. Esters of the latter were prepared by condensation with carboxylic acid derivatives using 1,1 '- carbonyldiimidazole and DBU as condensing agents.
- Sun, Jerry S.,Geiser, Andrew H.,Frydman, Benjamin
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p. 8221 - 8224
(2007/10/03)
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- Prenylation of Quinonoid Compounds with Prenyl Bromide Using Lead Bromide/Aluminium Powder as Catalyst
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An efficient method for the prenylation at quinonoid position using prenyl bromide in the presence of catalytic amount of lead bromide and aluminium powder in acetonitrile has been carried out.
- Khanna, R.N.,Singh, Prem Kumar
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p. 1743 - 1749
(2007/10/02)
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- Annulation Reactions Leading to Naphtalene Derivatives. New Syntheses of Natural 1,2- and 1,4-Naphthoquinones
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1-(Phenylsulfonyl)-2-oxo-3-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene derivatives with various C-3 substituents were effectively prepared by a one-step cyclization involving 1--2-(bromomethyl)benzene derivatives and monosubstituted malonic esters.A high yield one-step decarboxylation-desulfonylation of the above products by lithium iodide led to C-3-substituted 2-naphthalenols 7a-g whereas prior C-1 alkylation of the cyclization products provided 1,3-dialkylated 2-naphthalenols 6s,b.Oxidations of compounds 7 to o-naphthoquinones 8a-f further oxidations of the above products to substituted 2-hydroxy-1,4-naphthoquinones provided a new pathway to naturally occuring naphthoquinones like phthiocol (9), droserone methyl ether (10), and lapachol (15).
- Ghera, Eugene,Ben-David, Yoshua
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p. 3355 - 3359
(2007/10/02)
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- β-Lapachone: Synthesis of Derivatives and Activities in Tumor Models
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In order to find a 3,4-dihydro-2H-naphthopyran-5,6-dione more potent than the naturally occurring 2,2-dimethyl derivative , we synthesized a series of analogous compounds with modifications at position 2 of the pyran ring or at positions 8 and 9 of the benzene ring.Of the compounds tested in vitro for inhibition of RNA-dependent DNA polymerase and in mice infected with Rauscher leukemia, all retained good enzyme activity.Inhibition of the reverse transcriptase activity of the 2,2-substituted derivatives 10b-e was as strong as 10a.However, only the 2-methyl-2-phenyl derivative 10e proved to be about as potent as 2,2-dimethyl reference compound 10a in prolonging the mean survival time of mice with Rauscher leukemia virus induced leukemia.
- Schaffner-Sabba, Karl,Schmidt-Ruppin, Karl H.,Wehrli, Walter,Schuerch, ALfred R.,Wasley, Jan W. F.
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p. 990 - 994
(2007/10/02)
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- Synthesis of Naturally Occuring Naphthoquinones: Deoxylapachol, 2,3-Di-(3-methyl-but-2-enyl)-1,4-naphthoquinone, 2-Methyl-3-(3-methyl-but-2-enyl)-1,4-naphthoquinone and Lapachol
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Deoxylapachol (I), 2,3-di-(3-methyl-but-2-enyl)-1,4-naphthoquinone (II), 2-methyl-3-(3-methyl-but-2-enyl)-1,4-naphthoquinone (III) and lapachol (IV) have been synthesised by the prenylation of 1,4-naphthoquinone (V) (for I and II), 2-methyl-1,4-naphthoquinone (VII) (for III) and 2-hydroxy-1,4-naphthoquinone (IX) (for IV) by prenyl bromide.
- Kapoor, N. K.,Gupta, R. B.,Khanna, R. N.
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p. 189 - 191
(2007/10/02)
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- Reaction of Lapachol with Lead Tetraacetate and N-Bromosuccinimide
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Reaction of lapachol (II) with N-bromosuccinimide and lead tetraacetate yields 3-bromo-α-lapachone (III) and 4-bromo-iso-α-lapachone (V), characterised on the basis of spectral and chemical studies.
- Kapoor, N. K.,Gupta, R. B.,Khanna, R. N.
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p. 508 - 509
(2007/10/02)
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- Bromination with N-Bromosuccinimide : Part III - Formation of 3'-Bromo-β-lapachone, Dehydro-iso-β-lapachone and 4'-Bromo-iso-β-lapachone from Lapachol
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Lapachol (I), on bromination with N-bromosuccinimide, affords three ortho-naphthoquinone derivatives which have been characterized to be 3'-bromo-β-lapachone (IV), dehydro-iso-β-lapachone (V) and 4'-bromo-iso-β-lapachone (X) on the basis of spectral and chemical studies.
- Gupta, R. B.,Khanna, R. N.
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