- Photochemistry and photophysics of papaverine N-oxide
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The photochemistry and photophysics of papaverine N-oxide in polar aprotic and protic solvents has been studied in detail. Complex energy and charge-transfer phenomena between chromophores occur in papaverine. New photochemistry for the papaverine N-oxide system is reported. Irradiation in protic media results in the formation of an emissive charge-transfer state with ensuing intramolecular hydroxylation in high isolated yields (75-80%).
- Souto-Bachiller,Perez-Inestrosa,Suau,Rico-Gomez,Rodriguez-Rodriguez,Coronado-Perez
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- Efficient Photoinduced Electron Transfer in Papaverine N-Oxide: Regioselective Intramolecular Hydroxylation of Papaverine as an Alternative Disconnection for the Synthesis of Cularine Alkaloids
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The photochemistry of papaverine N-oxide in polar aprotic and protic solvents has been studied in detail.Complex energy and charge transfer phenomena between chromophores occur in papaverine.Irradiation in protic media results in the formation of an emissive charge transfer state with concomitant intramolecular hydroxylation.
- Suau, Rafael,Rico-Gomez, Rodrigo,Souto-Bachiller, Fernando A.,Rodriguez-Rodriguez, Lolita de los,Ruiz, Manuel L.
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- Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 Haloperidol-Maleic Acid Salt
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Papaverine HCl was successfully suspended by slurry reactive crystallization with the use of isopropyl alcohol (IPA) at 25 °C, a solid-to-liquid ratio of 0.19 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 200-400 μm, and the value for enthalpy of fusion of 154.5 J/g. The poor solubility of papaverine in IPA and better solubility of papaverine HCl in water-containing IPA had made the homogeneous nucleation of papaverine HCl dominate. Crystal size and crystallinity of papaverine HCl were time and temperature dependent. However, the 1:1 haloperidol-maleic acid salt was also successfully suspended and generated by slurry reactive crystallization with the use of water at 25 °C, a solid-to-liquid ratio of 0.18 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 500-1000 μm, and the value for enthalpy of fusion of 84.9 J/g. The poor solubility of haloperidol and 1:1 haloperidol-maleic acid salt in water had made the heterogeneous nucleation of 1:1 haloperidol-maleic acid salt dominate. Crystal size and crystallinity of 1:1 haloperidol-maleic acid salt became less sensitive to time and temperature. Comparing with grinding, solution reactive crystallization by cooling, and solution recrystallization by cooling, slurry reactive crystallization was a simple, robust, straightforward, low-constant-temperature, low-solvent-volume, and environmentally benign process giving comparable yield, particle size distribution, and crystallinity. Moreover, the use of a poor solvent in the slurry reactive crystallization enabled the recycling of the mother liquor without any significant loss in yield and crystallinity up to three cycles.
- Damayanti, Jeanne Dewi,Pratama, Dhanang Edy,Lee, Tu
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- Easy access to drug building-blocks through benzylic C-H functionalization of phenolic ethers by photoredox catalysis
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A visible light-mediated photocatalyzed C-C-bond forming method for the benzylic C-H functionalization of phenolether containing synthetic building blocks based on a radical-cation/deprotonation strategy is reported. This method allows the mild, selective generation of benzyl radicals in phenolic complex molecules and drug-like compounds, providing new entries in synthetic and medicinal chemistry.
- Brandhofer, Tobias,Derdau, Volker,García Manche?o, Olga,Méndez, María,P?verlein, Christoph,Stinglhamer, Martin
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supporting information
p. 6756 - 6759
(2021/07/13)
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- One-Pot Synthesis of Papaverine Hydrochloride and Identification of Impurities
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Abstract: A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial production.
- Qiu, Zeng-Feng,Wu, Ze-Nong,Yang, Zhe-Zhou,Yu, Wen-Shuai,Zhang, Fu-Li,Zhao, Chun-Jie
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p. 1295 - 1299
(2020/09/16)
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- 1,2,3-Triazole-Mediated Synthesis of 1-Methyleneisoquinolines: A Three-Step Synthesis of Papaverine and Analogues
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A metal-free three-step synthesis toward functionalized 1-methyleneisoquinolines from readily available substrates is reported. First, acetal-containing 1,2,3-triazoles were prepared via a high-yielding triazolization reaction and quantitatively converted into triazolo[5,1-a]isoquinolines. Next, the acid-promoted ring opening of these fused triazoles was studied in order to obtain coupling to a diverse scope of nucleophiles, including carbon nucleophiles such as veratrole. By means of non-nucleophilic strong acids under anhydrous conditions, a series of unprecedented isoquinolines and imidazo[5,1-a]isoquinolines was synthesized.
- Opsomer, Tomas,Van Hoof, Max,D'Angelo, Andrea,Dehaen, Wim
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supporting information
p. 3596 - 3600
(2020/04/21)
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- Reaction of papaverine with Baran Diversinates
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The reaction of papaverine with a series of Baran Diversinates is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C–H functionalization. Ten papaverine analogues (2–11), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the Diversinate reactions with this particular scaffold are discussed.
- Egbewande, Folake A.,Coster, Mark J.,Jenkins, Ian D.,Davis, Rohan A.
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- Preparation methods of papaverine and papaverine hydrochloride
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The invention discloses a preparation method of papaverine. The preparation method comprises 1, dissolving 3, 4-dihydropapaverine hydrochloride in water and adjusting pH of the solution to greater than 7, 2, through trimethylbenzene, carrying out extraction on the aqueous solution obtained through the step 1, and 3, adding a dehydrogenation reaction catalyst into the obtained organic phase, carrying out a dehydrogenation reaction process at a temperature of 50-180 DEG C and then treating the product to obtain papaverine. The invention also discloses a method for preparing papaverine hydrochloride from the papaverine. Through use of trimethylbenzene as a dehydrogenation reaction solvent, a dehydrogenation reaction temperature is reduced, peroxide production is avoided and production safety is greatly improved. The preparation method realizes recycle of trimethylbenzene and reduces a production cost of papaverine or papaverine hydrochloride.
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- Ruthenium-Mediated Dual Catalytic Reactions of Isoquinoline via C?H Activation and Dearomatization for Isoquinolone
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We have unraveled the ruthenium-promoted prototype reaction based on C(sp2)?C(sp3) bond formation through the reigoselective C?H activation of isoquinoline and pyridine derivatives with various alkyl halides, leading to 1-substituted isoquinoline products in good yield. This C?H catalytic reaction did not rely on chelation assistance of the directing group of the substrates. The dimer [RuCl2(p-cymene)]2in combination with an N-heterocyclic carbene ligand, adamantanecarboxylic acid and K2CO3base in N-methyl-2-pyrrolidone solution at 150 °C are the best conditions. Simultaneously, we are also able to chemically tune the reaction mode to dearomatization by adding water, leading to isoquinolone products. This reaction methodology is not suitable for other nitrogen-containing heteroarenes such as pyridazines and pyrimidines. (Figure presented.).
- Wang, Ting-Hsuan,Lee, Wei-Chih,Ong, Tiow-Gan
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supporting information
p. 2751 - 2758
(2016/09/13)
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- Rh-catalyzed sequential oxidative C-H activation/annulation with geminal-substituted vinyl acetates to access isoquinolines
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The concise synthesis of 3-substituted or non-C3-substituted isoquinolines through Rh-catalyzed sequential oxidative C-H activation/annulation with geminal-substituted vinyl acetates was developed with good functional group tolerance. The protocol was successfully applied to the total synthesis of the natural product papaverine.
- Chu, Haoke,Sun, Song,Yu, Jin-Tao,Cheng, Jiang
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p. 13327 - 13329
(2015/08/24)
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- A divergent approach to benzylisoquinoline-type and oxoaporphine alkaloids via regioselective direct ring metalation of alkoxy isoquinolines
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Methoxy- and benzyloxy-substituted isoquinolines are regioselectively metalated at C-1 with the Knochel-Hauser base, subsequent trapping with aromatic aldehydes gives aryl(isoquinolin-1-yl)carbinols as building blocks for divergent syntheses of different types of benzylisoquinoline alkaloids. Photochemical cyclization of ortho-bromo analogues under reductive conditions gives oxoaporphine alkaloids. Nine benzylisoquinoline alkaloids and two oxoaporphine alkaloids were obtained in two or three steps from appropriate isoquinolines.
- Melzer, Benedikt,Bracher, Franz
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p. 7664 - 7672
(2015/07/15)
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- C1-Benzyl and benzoyl isoquinoline synthesis through direct oxidative cross-dehydrogenative coupling with methyl arenes
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An oxidative cross-dehydrogenative coupling (CDC) of isoquinolines with methyl arenes has been developed, allowing for the facile synthesis of a broad range of structurally diverse C1-benzyl and -benzoyl isoquinolines. The direct use of readily available methyl arenes as coupling partners avoids unproductive steps for preactivating the functional group installation, and is therefore attractive. The method exhibits excellent chemoselectivity, affording exclusive benzylated products in the presence of DTBP and a catalytic amount of Y(OTf)3, and yielding benzoylated ones with TBHP and a catalytic amount of MnO2.
- Wan, Miao,Lou, Hongxiang,Liu, Lei
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supporting information
p. 13953 - 13956
(2015/09/07)
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- Acceptorless dehydrogenation of nitrogen heterocycles with a versatile iridium catalyst
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Gas up: A cyclometalated iridium complex is found to catalyze the dehydrogenation of various benzofused N-heterocycles, thus releasing H 2. Driven by as low as 0.1 mol % catalyst, the reaction affords quinolines, indoles, quinoxalines, isoquinolines, and β-carbolines in high yields. Copyright
- Wu, Jianjun,Talwar, Dinesh,Johnston, Steven,Yan, Ming,Xiao, Jianliang
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p. 6983 - 6987
(2013/07/26)
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- Characterization of a flavoprotein oxidase from opium poppy catalyzing the final steps in sanguinarine and papaverine biosynthesis
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Benzylisoquinoline alkaloids are a diverse class of plant specialized metabolites that includes the analgesic morphine, the antimicrobials sanguinarine and berberine, and the vasodilator papaverine. The two-electron oxidation of dihydrosanguinarine catalyzed by dihydrobenzophenanthridine oxidase (DBOX) is the final step in sanguinarine biosynthesis. The formation of the fully conjugated ring system in sanguinarine is similar to the four-electron oxidations of (S)-canadine to berberine and (S)-tetrahydropapaverine to papaverine. We report the isolation and functional characterization of an opium poppy (Papaver somniferum) cDNA encoding DBOX, a flavoprotein oxidase with homology to ( S)-tetrahydroprotoberberine oxidase and the berberine bridge enzyme. A query of translated opium poppy stem transcriptome databases using berberine bridge enzyme yielded several candidate genes, including an (S)-tetrahydroprotoberberine oxidase-like sequence selected for heterologous expression in Pichia pastoris. The recombinant enzyme preferentially catalyzed the oxidation of dihydrosanguinarine to sanguinarine but also converted (RS)-tetrahydropapaverine to papaverine and several protoberberine alkaloids to oxidized forms, including (RS)-canadine to berberine. The Km values of 201 and 146 μM for dihydrosanguinarine and the protoberberine alkaloid (S)-scoulerine, respectively, suggested high concentrations of these substrates in the plant. Virus-induced gene silencing to reduce DBOX transcript levels resulted in a corresponding reduction in sanguinarine, dihydrosanguinarine, and papaverine accumulation in opium poppy roots in support of DBOX as a multifunctional oxidative enzyme in BIA metabolism.
- Hagel, Jillian M.,Beaudoin, Guillaume A. W.,Fossati, Elena,Ekins, Andrew,Martin, Vincent J. J.,Facchini, Peter J.
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p. 42972 - 42983
(2013/03/13)
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- Facile synthesis of substituted isoquinolines
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A facile three-step protocol toward methoxy isoquinolines 7 starting with substituted 2-allylbenzaldehydes 9 was described. The overall synthetic process of skeleton 7 was carried out using the Grignard addition, PCC-oxidation, and one-pot oxidative cleavage of the olefinic group of skeleton 9 with OsO 4-NaIO4 followed by the condensation of the resulting 1,5-dicarbonyl compounds with NH4OAc. Skeleton 9 was prepared in high yield via the known Claisen rearrangement of skeleton 8 and O-methylation. Papaverine 2 is also synthesized via the simple three-step synthetic protocol.
- Chang, Meng-Yang,Wu, Ming-Hao,Lee, Nein-Chia,Lee, Ming-Fang
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p. 2125 - 2128
(2012/07/14)
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- Regioselective photochemical C-OMe bond formation initiated by one-electron transfer and N-OMe bond fragmentation in electron donor-acceptor systems
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Compounds that integrate electron donor-acceptor subunits with N-methoxyisoquinolinium as acceptors and substituted (methoxy)benzenes as donors were synthesized and their luminescent and photochemical properties studied. Photolysis yielded the corresponding photomethoxylation products in a two-step process that involves N-OMe bond scission followed by C-OMe bond formation. Homolysis of the N-OMe bond restores the aromatic isoquinoline nucleus and produces a methoxy radical that can couple to the required ring carbon atom in the benzene cation radical to give the products in a regioselective process controlled by the spin density of the cation radical. This photoprocess involves two different pathways: methoxylation of the acceptor (intracomponent methoxylation) or the donor (intercomponent metoxylation). Both methoxy-transfer pathways are controlled by the donoating ability (redox potential) of the donor subunit, consistent with the emission observed upon excitation of the charge-transfer state in systems that undergo intermethoxylation.
- Collado, Daniel,Perez-Inestrosa, Ezequiel
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p. 1800 - 1808
(2012/05/04)
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- Catalyst and base controlled site-selective sp2 and sp3 direct arylation of azine N-oxides
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Site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner. The sp3 arylation reaction is applied to the synthesis of the natural products, papaverine and crykonisine, and a rationale for low reactivity of electron-deficient aryl halides is provided. Mechanistic investigations point toward the intimate involvement of the base in the mechanism of these reactions.
- Schipper, Derek J.,Campeau, Louis-Charles,Fagnou, Keith
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experimental part
p. 3155 - 3164
(2009/08/15)
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- Combination of benzyl-4, 5-dihydro-1H-imidazole derivative and an opioid receptor ligand
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The present invention refers to a combination of a Compound A, a benzyl-4,5-dihydro-1 H-imidazole derivative according to formula (I) and a Compound B, an opioid receptor ligand; especially of xylometazoline or oxymetazoline and a μ-opioid receptor agonist, most preferably of xylometazoline or oxymetazoline and morphine; a medicament comprising this combination; a pharmaceutical formulation for nasal application comprising this combination; or the use of this combination for the treatment of the symptoms of pain, or the prevention or the prophylaxis of the symptoms of pain, whereas pain particularily encompasses visceral pain, chronic pain, cancer pain, acute pain or neuropathic pain, specifically involving also breakthrough pain.
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- Orthogonal synthesis of indolines and isoquinolines via aryne annulation
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Described in this report is the development of two unique methodologies exploiting the reactivity of arynes. Reaction of N-carbamoyl-functionalized enamine derivatives with benzyne affords substituted indolines. An orthogonal reactivity is uncovered when related enamine derivatives are modified as amides, such that isoquinolines are formed as the product of condensation with benzyne. This latter transformation is applied to a concise total synthesis of the opiate alkaloid papaverine. Copyright
- Gilmore, Christopher D.,Allan, Kevin M.,Stoltz, Brian M.
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p. 1558 - 1559
(2008/09/17)
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- LiCl-mediated preparation of highly functionalized benzylic zinc chlorides
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In the presence of zinc dust (1.5-2.0 equiv) and LiCI(1.5-2.0 equiv), various benzylic chlorides bearing functional groups (iodide, cyanide, ester, ketone) are smoothly converted at 25°C to the corresponding zinc reagents without homo-coupling (≤5%). The utility of these benzylic zinc reagents is demonstrated by a short synthesis of papaverine.
- Metzger, Albrecht,Schade, Matthias A.,Knochel, Paul
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supporting information; experimental part
p. 1107 - 1110
(2009/04/06)
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- Drugs for incontinence
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Use in the incontinence of one or more of the following classes of drugs selected from the following: B) salified and non salified nitric oxide-donor drugs, of formula: A-X1—N(O)z, B′) nitrate salts of drugs used for the incontinence, and which do not contain in the molecule a nitric oxide donor group; C) organic or inorganic salts of compounds inhibiting phosphodiesterases.
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- New, simple total syntheses of benzo[b]naphtho[2,3-d]furan-6,11-diones and benzo[b]naphtho[2,1-d]furans
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Here we account the transformation of 2-[(2'- bromophenyl)acetyl]phenylacetic acids and 1-benzylisoquinolines into benzo[b]naphtho[2,3-d]furan-6,11-diones. Synthesis of benzo[b]naphtho[2,1- d]furans from 1-benzylisoquinolines is also described.
- Martinez, Elena,Martinez, Luis,Estevez, Juan C.,Estevez, Ramon J.,Castedo, Luis
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p. 2175 - 2176
(2007/10/03)
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- Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons
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DNA topoisomerases are nuclear enzymes responsible for modifying the topological state of DNA. The development of agents capable of poisoning topoisomerases has proved to be an attractive approach in the search for novel cancer chemotherapeutics. Coralyne, an antileukemic alkaloid, has appreciable structural similarity to the potent topoisomerase I and II poison, nitidine. Analogues of coralyne were synthesized and evaluated for their activity as topoisomerase I and topoisomerase II poisons. These analogues were also evaluated for cytotoxicity in the human lymphoblast cell line, RPMI 8402, and its camptothecin-resistant variant, CPT-K5. The pharmacological activity of these analogues exhibited a strong dependence on the substitution pattern and the nature of substituents. Several 1- benzylisoquinolines and 3-phenylisoquinolines were also synthesized. These compounds, which incorporate only a portion of the ring structure of coralyne, were evaluated as topoisomerase poisons and for cytotoxicity. These structure-activity studies indicate that the structural rigidity associated with the coralyne ring system may be critical for pharmacological activity. The presence of a 3,4-methylenedioxy substituent on these coralyne analogues was generally associated with enhanced activity as a topoisomerase poison. 5,6-Dihydro-3,4-methylenedioxy-10,11-dimethoxydibenzo[a,g]quinolizinium chloride was the most potent topoisomerase I poison among the coralyne analogues evaluated, having similar activity to camptothecin. This analogues also possessed exceptional potency as a topoisomerase II poison. Despite the pronounced activity of several of these coralyne derivatives as topoisomerase I poisons, mine of these compounds had cytotoxic activity similar to camptothecin. Possible differences in cellular absorption between these coralyne analogs, which possess a quaternary ammonium group, and camptothecin may be responsible for the differences observed in their relative cytotoxicity.
- Makhey, Darshan,Gatto, Barbara,Yu, Chiang,Liu, Angela,Liu, Leroy F.,LaVoie, Edmond J.
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p. 781 - 791
(2007/10/03)
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- Short-cut in the pomeranz-fritsch synthesis of 1-benzyl-isoquinolines; short and efficient syntheses of norrecticuline derivatives and of papaverine
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A new methodology for the Pomeranz-Fritsch synthesis of 1-benzyl-1,2-dihydroisoquinolines avoiding pavine or isopavine troubles, has been developed. These intermediates could be reduced to their 1,2,3,4-tetrahydro congeners or aromatized to give isoquinolines, as it was demonstrated by the synthesis of some norrecticuline derivatives 4-7 and of papaverin 8.
- Hirsenkorn, Rolf
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p. 1775 - 1778
(2007/10/02)
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- BERBIN-8-ONES FROM 2'-HALOGENO-1-BENZYLISOQUINOLINES AND METAL CARBONYLS
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The title compounds were synthesised from 2'-halogeno-1-benzylisoquinolines, their 3,4-dihidro- or 1,2,3,4-tetrahydro-derivatives and metal carbonyls under mild conditions.
- Trifonov, Latchezar S.,Orahovats, Alexander S.
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p. 3159 - 3162
(2007/10/02)
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- THE REACTION OF HETEROAROMATIC AMINE OXIDES WITH TiCl4/NaBH4
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Treatment of 2-, 3-, 4-picoline N-oxides and 2,6-dimethylpyridine N-oxide with TiCl4/NaBH4 in dimethoxyethane afforded the corresponding picolines and 2,6-dimethylpyridine in acceptable yields.The same reaction of quinaldine N-oxide and benzoquinoline N-oxide succesfully gave quinaldine and benzoquinoline, respectively.In the case of quinoline N-oxide, 1,2,3,4-tetrahydroquinoline and quinoline were obtained.On the other hand, lepidine N-oxide and isoquinoline N-oxide afforded the corresponding 1,2-dihydro derivatives.Similarly, papaverine N-oxide gave 1,2-dihydropapaverine as major product accompanying with papaverine.
- Kano, Shinzo,Tanaka, Yasuyuki,Hibino, Satoshi
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- New structural analogs of papaverine: 3 benzyl 6,7 dimethoxy (di and tetrahydro) isoquinolines
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Syntheses of 3 benzyl 3,4 dihydroisoquinolines by cyclisation of a N acyl α benzylhomoveratrylamine by means of polyphosphoric acid ester, in boiling toluene, gave yields between 60 and 90%. While the hydrogenation of these dihydroisoquinolines to tetrahydroisoquinolines with an alkaline borohydride gave satisfactory result, their dehydrogenation into isoquinolines could not be accomplished. Pharmacological properties of the hydrobromides or hydrochlorides of the bases of the two series of the aforementioned 3 benzylisoquinolines and comparison of their activities with those of papaverine and the analogues 1 and 4 benzylisoquinolines are reported.
- Prudhommeaux,Ernouf,Foussard Blanpin,Viel
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