- Studies on quinones. Part 43: Synthesis and cytotoxic evaluation of polyoxyethylene-containing 1,4-naphthoquinones
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A series of naphthoquinones 2,3-disubstituted with chlorine and oxyethylene groups have been prepared from 2,3-dichloro- and 2,3-dimethoxy-1,4-naphthoquinone. The members of these series were tested on normal human fibroblasts and on a panel of four human cancer cell lines. Antitumor activities, which were in the range of IC50 1.3-89.5 μM, discussed in terms of LUMO energy, lipophilicity and size of the polyoxyethylene moiety.
- Valderrama, Jaime A.,Leiva, Hilda,Rodriguez, Jaime A.,Theoduloz, Cristina,Schmeda-Hirshmann, Guillermo
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- Plumbagin-Serum Albumin Interaction: Spectral, Electrochemical, Structure-Binding Analysis, Antiproliferative and Cell Signaling Aspects with Implications for Anticancer Therapy
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Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule with potent anticancer activity. Like other 1,4-naphthoquinones, it exhibits electrophilic reactivity towards biological nucleophiles. We demonstrate that plumbagin and structurally related 1,4-naphthoquinones with at least one unsubstituted quinoid carbon (C2 or C3) bind to albumin, an ubiquitously present nucleophile, with minimum recovery of free drug. Extraction recovery of plumbagin from albumin in solution showed one-phase exponential decline with a half-live of 9.3 min at 10 μmol/L. In the presence of albumin, plumbagin exhibited instant changes in UV/Vis absorption bands. Electrochemical analysis using cyclic voltammetry showed a decrease in redox peak currents over time until electro-inactivity, thus suggesting the formation of a supramolecular adduct inaccessible for electron transfer. The adduct inhibited cell growth and caused cell-cycle arrest of prostate cancer cells, in part by decreasing levels of the cell-cycle regulator RBBP. The conjugate displayed similar cellular effects to those described for plumbagin, such as decreased levels of androgen receptor and protein kinase C epsilon. The effect of plumbagin-albumin on cancer cells was species-specific, suggesting a receptor-mediated mechanism. Furthermore, it was blocked by cathepsin inhibitor pepstatin A, indicating that lysosomal degradation is involved in the processing of plumbagin-albumin adduct. The spontaneously formed adduct of plumbagin with serum albumin is likely to mediate the biological activities of plumbagin in vivo and to fundamentally influence its pharmacodynamics.
- Chrastina, Adrian,Welsh, John,Rondeau, Gaelle,Abedinpour, Parisa,Borgstr?m, Per,Baron, Véronique T.
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- A new 2,3-dimethoxy-1,4-naphthoquinone redox anolyte for non-aqueous organic static redox battery
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Redox flow batteries (RFB) are the choice for grid-level large-scale energy storage applications. Especially, the non-aqueous variant of RFB is considered for its unique advantages such as low cost, diverse engineering possibility of redox molecules, and
- Ramanujam, Kothandaraman,Sankararaman, Sethuraman,Vallayil, Priya
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- Ruthenium-catalyzed C-H oxygenation of quinones by weak O-coordination for potent trypanocidal agents
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Ruthenium-catalysis enabled the C-5 selective C-H oxygenation of naphthoquinones, and also sets the stage for the site-selective introduction of a hydroxyl group into anthraquinones. A-ring modified naphthoquinoidal compounds represent an important class of bioactive quinones for which the present study encompasses the first C-H oxygenation strategy by weak O-coordination.
- Dias, Gleiston G.,Rogge, Torben,Kuniyil, Rositha,Jacob, Claus,Menna-Barreto, Rubem F. S.,Da Silva Júnior, Eufranio N.,Ackermann, Lutz
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supporting information
p. 12840 - 12843
(2018/11/30)
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- Method for inhibiting Trypanosoma cruzi
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Methods are provided to inhibit proliferation of Trypanosoma cruzi with imido-substituted 1,4-naphthoquinones, including novel compounds. Administering an imido-substituted 1,4-naphthoquinone can be used to provide prophylaxis or treatment to a patient in
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Page/Page column 24
(2016/09/26)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF PROSTATE CARCINOMA
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Disclosed herein are 1,4-naphthoquinone analogs, pharmaceutical compositions that include one or more of such 1,4-naphthoquinone analogs, and methods of treating and/or ameliorating diseases and/or conditions associated with a cancer, such as prostate can
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Paragraph 0287-0288
(2016/06/01)
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- Synthesis and characterization of novel unsymmetrical and symmetrical 3-halo- or 3-methoxy-substituted 2-dibenzoylamino-1,4-naphthoquinone derivatives
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Symmetrical and unsymmetrical 3-halo- or 3-methoxy- substituted 2-dibenzoylamino- 1,4-naphthoquinone analogs were synthesized with an average yield of 45% via sodium hydride promoted bis-acylation of 2-amino-3-chloro-1,4- naphthoquinone, 2-amino-3-bromo- 1,4-naphthoquinone and 2-amino-3-methoxy-1,4- naphthoquinone.
- Brandy, Yakini,Brandy, Nailah,Akinboye, Emmanuel,Lewis, Malik,Mouamba, Claudia,MacK, Seshat,Butcher, Ray J.,Anderson, Alan J.,Bakare, Oladapo
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p. 1973 - 1984
(2013/04/10)
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- METHOD FOR INHIBITING TRYPANSOMA CRUZI
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In its broadest aspect, a method for treating a mammalian patient at risk or suffering from a disease caused by a kinetoplastid parasite comprises administering to such subject an effective kinetoplasticidal amount of an imido-substituted 1,4- naphthoquin
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Page/Page column 30
(2013/03/26)
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- New insights into cyclobutenone rearrangements: A total synthesis of the natural ROS-generating anti-cancer agent cribrostatin 6
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Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σI providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.
- Mohamed, Mubina,Gon?alves, Théo P.,Whitby, Richard J.,Sneddon, Helen F.,Harrowven, David C.
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experimental part
p. 13698 - 13705
(2012/01/05)
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- Chemoselective reactions of 2,3-dichloro-1,4-naphthoquinone
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The reaction of 2,3-dichloro-1,4-naphthoquinone with alkoxides, primary amines, and phenols was shown to proceed chemoselectively rather to the corresponding 2-substituted 3-chloro-naphthoquinones or 2,3-disubstituted quinones than to brazanquinone deriva
- Sarhan, Abd El-Wareth A. O.,Kamal El-Dean, Adel M.,Abdel-Monem, Maisa I.
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p. 205 - 212
(2007/10/03)
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- Synthesis and antiplatelet, antiinflammatory and antiallergic activities of 2,3-disubstituted 1,4-naphthoquinones
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Modification of 2-acetamido-3-chloro-1,4-naphthoquinone, which has potent antiplatelet, antiallergic and antiinflammatory activities, led to a series of 2,3-disubstituted 1,4-naphthoquinones. Some of these compounds showed significant antiplatelet, antiallergic and antiinflammatory activities. Among them, 2-methoxy-3-chloro-1,4-naphthoquinone (15) and 2- ethoxy-3-chloro-1,4-naphthoquinone (17) exhibited potent inhibitory effects on neutrophil and mast cell degranulation. 2-Methoxy-1,4-naphthoquinone (20) and 2-ethoxy-1,4-naphthoquinone (21) exhibited potent inhibitory effect on neutrophil superoxide formation. These four compounds were thus selected for further evaluation.
- Lien, Jin-Cherng,Huang, Li-Jiau,Wang, Jih-Pyang,Teng, Che-Ming,Lee, Kuo-Hsiung,Kuo, Sheng-Chu
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p. 1181 - 1187
(2007/10/03)
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- METHOD FOR TREATING DISEASE STATES IN MAMMALS WITH NAPHTHALENE LIPOXYGENASE-INHIBITTNG AGENTS
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Psoriasis in mammals is relieved by topically administering naphthalenes of the formula: wherein: R1 is lower alkoxy or optionally substituted phenoxy, R2 is the same as R1, or R2 is hydrogen, lower alkyl, optionally substituted phenyl or optionally substituted phenylalkyl, R3 is hydrogen, lower alkyl, lower alkoxy, halo, optionally substituted phenyl, optionally substituted phenyl-lower-alkyl or optionally substituted phenyl-lower-alkoxy, and m is 1 or 2; both X groups are the same and X is either -C(O)OR4 or -C(O)NR5R6 , wherein R4 is alkyl, phenyl or benzyl optionally substituted with one or two lower alkyl groups, lower alkoxy groups or halo; and R5 and R6 are independently hydrogen, lower alkyl, cycloalkyl or phenyl optionally substituted with one or two lower alkyl groups, lower alkoxy groups or halo. The compounds of this invention are also useful for the treatment of disease-states caused by lipoxygenase activity in mammals, particularly 5-lipoxygenase activity, when administered systemically.
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- Naphthalene anti-psoriatic agents
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Psoriasis in mammals is relieved by topically administering naphthalenes of the formula: STR1 wherein: R1 and R2 are the same and are lower alkoxy or optionally substituted phenoxy, R3 is lower alkyl, lower alkoxy, or halo
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- General Regiospecific Synthesis of Annulated Quinones
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A general regiospecific synthesis of annulated hydroquinones/quinones is presented.This specifically involves the thermal rearrangement of the 4-aryl-4-hydroxycyclobutenones 1a-k to the corresponding annulated hydroquinones.The synthetic scope and mechani
- Moore, Harold W.,Perri, Steven T.
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p. 996 - 1003
(2007/10/02)
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- Topical Nonsteroidal Antipsoriatic Agents. 1. 1,2,3,4-Tetraoxygenated Naphthalene Derivatives
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On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay.Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179,lonapalene, 11a).An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, eth er and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors.Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity.Lonapalene (11a) is currently in clinical development as a topical applied nonsteroidal antipsoriatic agent.
- Jones, Gordon H.,Venuti, Michael C.,Young, John M.,Murthy, D.V. Krishna,Loe, Brad E.,et al.
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p. 1504 - 1511
(2007/10/02)
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- Product and mechanistic studies of the anodic oxidation of methoxylated naphthalenes. The EECrCp mechanism
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The anodic oxidations of 1- and 2-methoxy- and 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 2,3-, 2,6-, and 2,7-dimethoxynaphthalenes have been studied in methanolic potassium hydroxide. At lower temperatures (0-20°C) the major process in 1-methoxynaphthalene and 1,5-, 1,6-, and 1,7-dimethoxynaphthalenes is two-electron oxidation resulting in addition of methoxy groups across the 1,4-positions followed by loss of methanol on workup to afford the methoxylated naphthalene. In contrast, 2-methoxynaphthalene and 1,3-, 2,3-, 2,6-, and 2,7-dimethoxynaphthalenes give major amounts of products derived from four-electron oxidation under these conditions. When the anodic oxidation of this first class of compounds was conducted in refluxing methanol, increased amounts of four-electron oxidation products were isolated. While 1-methylnaphthalene and naphthalene also undergo anodic oxidation under these conditions, these unactivated systems react less selectively and efficiently. Mechanistic studies are most consistent with the key step of the anodic oxidation under these conditions being the reaction of methoxy radical with the aromatic radical cation. This reaction sequence is termed the EECrCp mechanism, and the results of the oxidation of the methoxylated naphthalenes above are discussed in this format.
- Dolson, Mark G.,Swenton, John S.
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p. 2361 - 2371
(2007/10/21)
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