- Synthesis and Bioactivity of a Brasilicardin A Analogue Featuring a Simplified Core
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An analogue 2 of Brasilicardin A, 1 (BraA), a potent immunosuppressive and cytotoxic agent, was synthesized in which the natural tricyclic skeleton was replaced with a synthetically more accessible substituted tetrahydronaphthalene core. BraA, this analogue (BraL), and cyclosporine A were tested for their ability to inhibit the proliferation of human T cells upon CD3/CD28 activation. Although BraL did not impact T cell activation over the dose range tested, this study shows the inhibitory activity of BraA on human T cells for the first time.
- Jung, Michael E.,Chamberlain, Brian T.,Koch, Pierre,Niazi, Kayvan R.
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- IMPROVED PROCESS FOR THE PREPARATION OF 9-ETHYL-6,6-DIMETHYL-8-[4-(MORPHOLIN-4-YL) PIPERIDIN-1-YL]-11-OXO-6,11-DIHYDRO-5H-BENZO[B]CARBAZOLE-3-CARBONITRILE HYDROCHLORIDE
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The present invention relates to novel process for the preparation of 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride compound of formula-1a, represented by the following structural formula: The present invention also provides an improved process for the preparation of tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate having the following structural formula which is useful in the preparation of Alectinib and its pharmaceutical acceptable salts.
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- Gold-Catalyzed Oxidation Terminal Alkyne: An Approach to Synthesize Substituted Dihydronaphthalen-2(1H)-ones and Phenanthrenols
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A facile gold-catalyzed oxidation terminal alkynes to synthesize substituted dihydronaphthalen-2(1H)-ones 3 and phenanthrenols 5 was realized. Various useful structures and drug precursors were generated in up to 99% yield under mild condition and low catalyst loading.
- Ling, Hui-Bo,Chen, Zi-Sheng,Yang, Fang,Xu, Bin,Gao, Jin-Ming,Ji, Kegong
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p. 7070 - 7076
(2017/07/15)
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- Synthesis and biological evaluation of 1-benzylidene-3,4-dihydronaphthalen- 2-one as a new class of microtubule-targeting agents
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A series of 1-benzylidene-3,4-dihydronaphthalen-2-one derivatives were designed and synthesized, and their biological activities in vitro and in vivo were evaluated. The results showed a number of the title compounds exhibiting potent nanomolar activity in several human cancer cell lines. Of these, compound 22b showed the strongest inhibitory activity against human CEM, MDA-MBA-435, and K562 cells (IC50 = 1 nM), displayed in vitro inhibition of tubulin polymerization (IC50 = 3.93 μM), and significantly induced cell cycle arrest in G2/M phase. In addition, compound 22b could inhibit the tumor growth in colon nude mouse xenograft tumor model significantly and seemed safer than CA-4 when achieving a similar tumor suppression. This study provided a new molecular scaffold for the further development of antitumor agents that target tubulin.
- Liu, Jia,Zheng, Can-Hui,Ren, Xiao-Hui,Zhou, Feng,Li, Wei,Zhu, Ju,Lv, Jia-Guo,Zhou, You-Jun
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experimental part
p. 5720 - 5733
(2012/07/30)
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- A concise method for the synthesis of 2-tetralone by titanium tetrachloride-promoted cyclization of 4-aryl-2-hydroxybutanal diethyl acetal
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4-Aryl-2-hydroxybutanal diethyl acetal, prepared from the reaction of benzyl Grignard reagent and glycidaldehyde diethyl acetal, was treated with titanium tetrachloride to give 2-tetralone in good yield. This highly efficient transformation involves tande
- Hon, Yung-Son,Devulapally, Rammohan
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scheme or table
p. 5713 - 5715
(2009/12/09)
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- TiCl4-promoted intramolecular cyclization of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones: an expedient method to prepare 2-tetralones
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DABCO is a very effective catalyst in the formation of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones 12 from the corresponding α-carbonatoaldehyde. Intramolecular cyclization of cyclic carbonates 12 promoted by TiCl4 affords 2-tetralones 13 contain
- Hon, Yung-Son,Devulapally, Rammohan
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experimental part
p. 2831 - 2834
(2009/09/30)
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- Discovery of a novel series of benzoic acid derivatives as potent and selective human β3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety
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We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds (10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for β3, high selectivity over β1 and β2, and good pharmacokinetic properties in rats, dogs, and monkeys.
- Imanishi, Masashi,Nakajima, Yutaka,Tomishima, Yasuyo,Hamashima, Hitoshi,Washizuka, Kenichi,Sakurai, Minora,Matsui, Shigeo,Imamura, Emiko,Ueshima, Koji,Yamamoto, Takao,Yamamoto, Nobuhiro,Ishikawa, Hirofumi,Nakano, Keiko,Unami, Naoko,Hamada, Kaori,Matsumura, Yasuhiro,Takamura, Fujiko,Hattori, Kouji
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experimental part
p. 4804 - 4822
(2009/07/11)
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- Synthesis and antifungal activities of novel 2-aminotetralin derivatives
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Novel 2-aminotetralin derivatives were synthesized as antifungal agents. The 2-aminotetralin scaffold was chemically designed to mimic the tetrahydroisoquinoline ring of the lead molecule described before. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 10a, 12a, 12c, 13b, and 13d are more potent than fluconazole against seven testing human fungal pathogens. Compound 10b exhibits much higher antifungal activities against all of the four fluconazole-resistant clinic Candida albicans strains than the control drugs including amphotericin B, terbinafine, ketoconazole, and itraconazole. The mode of action of some compounds to the potential receptor lanosterol 14α-demethylase (CYP51) was investigated by molecular docking. The studies presented here provide a new structural type for the development of novel antifungal compounds. Furthermore, 10b was evaluated in vivo by a rat vaginal candidiasis model, and it was found that 10b significantly decreases the number of fungal colony counts.
- Yao, Bin,Ji, Haitao,Cao, Yongbin,Zhou, Youjun,Zhu, Jü,Lü, Jiaguo,Li, Yaowu,Chen, Jun,Zheng, Canhui,Jiang, Yuanying,Liang, Rongmei,Tang, Hui
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p. 5293 - 5300
(2008/03/18)
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- A convenient strategy for the total synthesis of pisiferic acid type diterpenes
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A practical method for the total synthesis of pisiferic acid type diterpenoids is described. This involves Robinson annulation of the keto ester for the key intermediate.
- Zhu, Hui,Tu, Pengfei
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- New platelet fibrinogen receptor glycoprotein IIb-IIIa antagonists: Orally active series of N-alkylated amidines with a 6,6-bicyclic template
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The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholino-formimidoyl)benzamido]-3,4-dihydro-2H-1-benzopyran-3- yl]acetate hydrochloride ((S)-4·HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4- tetrahydronaphthalene or 3,4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4·HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral administration of MS-180 ((S)4·HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4·HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.
- Okumura, Kunio,Shimazaki, Toshiyuki,Aoki, Yoji,Yamashita, Hiroyuki,Tanaka, Eishi,Banba, Shinichi,Yazawa, Kouhei,Kibayashi, Kenji,Banno, Hitoshi
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p. 4036 - 4052
(2007/10/03)
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- New Intramolecular α-Arylation Strategy of Ketones by the Reaction of Silyl Enol Ethers to Photosensitized Electron Transfer Generated Arene Radical Cations: Construction of Benzannulated and Benzospiroannulated Compounds
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Efficient intramolecular α-arylation of ketones is achieved by the reaction of silyl enol ethers to photosensitized electron transfer (PET) generated arene radical cations. The arene radical cations are generated by one-electron transfer from the excited state of the methoxy-substituted arenes to ground-state 1,4-dicyanonaphthalene (DCN). This arylation strategy has provided the unique opportunity of constructing five- (23), six- (18), seven- (25) and eight-membered (27) benzannulated as well as benzospiroannulated (34) compounds. The explanation for the formation of 27 has been advanced by considering the proximity between the arene radical cation and silyl enol ether due to the self-coiling in the aqueous environment.
- Pandey, Ganesh,Karthikeyan,Murugan
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p. 2867 - 2872
(2007/10/03)
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- Synthesis of 2-tetralones via a novel 1,2-carbonyl transposition of 1-tetralones
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Simple acidic hydrolysis of epoxyamides 4, derived from 1-tetralones, furnishes the corresponding 2-tetralones in good yield.
- Pryde, David C.,Henry, Steven S.,Meyers
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p. 3243 - 3246
(2007/10/03)
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- 2-Amido-8-methoxytetralins: A Series of Nonindolic Melatonin-like Agents
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A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a-q) was prepared and evaluated for their ability to complete for 2-iodomelatonin binding to chicken retinal membranes and for their potency to inhibit the calcium-dependent release of dopamine from rabbit retina.The lead compound, 2-acetamido-8-methoxytetralin (4j), showed a moderate affinity (Ki = 46 nM) and potency (IC50 = 1.4 nM) at the melatonin receptor.The structural requirements necessary for optimal agonistic activity at the melatonin receptor are as follows.First, the amido group, which should have a small, nonbranched alkyl group, is essential for affinity, and second, the methoxy substituent at the 8-position of the 2-amidotetralin ring is essential for optimal agonistic activity at the melatonin receptor.We concluded that this series of unsubstituted and methoxy-substituted 2-amidotetralins constitutes a class of nonindolic melatonin-like agents that can be used as pharmacological tools to further characterize melatonin receptors and to elucidate the mode of action of melatonin.
- Copinga, Swier,Tepper, Pieter G.,Grol, Cor J.,Horn, Alan S.,Dubocovich, Margarita L.
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p. 2891 - 2898
(2007/10/02)
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- Intramolecular nucleophilic addition of silylenol ether to photosensitized electron transfer (PET) generated arene radical cations: A novel non-reagent based carboannulation reaction
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A new carboannulation strategy by intramolecular addition of silylenol ether to PET generated arene radical cation is reported.
- Pandey,Krishna,Girija,Karthikeyan
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p. 6631 - 6634
(2007/10/02)
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- Enantioselective approach to morphinans
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Enantioselective synthesis of morphinan derivative 20 from 2,7-dimethoxynaphthalene has been achieved in twelve steps (11% overall yield).
- Sdassi, Hamid,Revial, Gilbert,Pfau, Michel,D'Angelo, Jean
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p. 875 - 878
(2007/10/02)
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- The Intramolecular Buchner Reaction of Aryl Diazoketones. Substituent Effects and Scope in Synthesis
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Rhodium(II) acetate-catalysed cyclisation of α-diazoketones derived from 3-arylpropionic acid produces bicyclodecatrienones or 2-tetralones depending on the substitution pattern of the aryl ring in the precursor; the former products are transformed into the latter catalytically with trifluoroacetic acid.Precursors with methyl, methoxy, and acetoxy substituents have been examined, efficient cyclisation occurring in all cases.When the precursor contains a meta-methoxy substituent, 2-tetralones are obtained directly.The efficient conversion of 3-phenylpropionicacid into trans-1-methylbicyclodecan-2-one is also described, partial asymmetric synthesis having been realised through the use of rhodium (S)-mandelate as the cyclisation catalyst.Cyclisations of diazoketones derived from 4-phenylbutyric acid and 5-phenylpentanoic acid have also been studied; the former provides a new entry into the bicycloundecane system whereas the latter produces a 2,3-disubstituted cyclopentanone via C-H insertion.Aspects of the cycloheptatriene-norcaradiene equilibrium in fused ring systems are discussed.
- Kennedy, Michael,McKervey, M. Anthony,Maguire, Anita R.,Tuladhar, Sarbajna M.,Twohig, M. Fiona
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p. 1047 - 1054
(2007/10/02)
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- Pharmacologically active amino-5,6,7,8-tetrahydronaphtho [2,3-B] furan compounds
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Compounds of general formula I, STR1 in which: R1 denotes a hydrogen atom or, with the proviso, however, that the amino radical is at the 7-position, a linear or branched alkyl radical containing 1 to 4 carbon atoms, R2 denotes a hydrogen atom or, with the proviso, however, that the amino radical is at the 6-position, a linear or branched alkyl radical containing 1 to 4 carbon atoms, R3 and R4, which may be identical or different, each denote a hydrogen atom, a benzyl radical, a cyclohexylmethyl radical, a linear or branched alkylene radical containing from 1 to 5 carbon atoms, a linear or branched alkyl radical containing from 1 to 10 carbon atoms (optionally substituted with a hydroxy radical, with a carboxy radical or with an alkoxy radical having 1 to 5 carbon atoms, with an alkoxycarbonyl radical having 2 to 6 carbon atoms, with an anlkyphenyl radical or with an alkyl-2-theinyl radical), a halogenated alkyl radical containing from 1 to 5 carbon atoms, or form, together with the nitrogen to which they are attached, a 2-oxo-1-pyrrolidinyl radical, A-B denotes, with the oxygen to which it is attached, an ethyleneoxy radical, an ethynyleneoxy, a 2-oxo-1-oxyethylene radical or a 2-hydroxy-1-oxyethylene radical. The compounds of the formula I possess antidepressant, antiaggressive, and dopaminergic properties.
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- Synthesis and Dopaminergic Activity of 2-Substituted Octahydrobenzoquinolines
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A series of 2-substituted octahydrobenzoquinolines has been synthesized and assayed for dopamine agonist activity.Only the compounds corresponding to the β-rotameric conformation of dopamine showed biphasic activity in competition binding studies with the radioligand spiroperidol.These findings suggest that the congeners possessing the β-rotamer conformation show receptor-binding characteristics that resemble those of the ergolines more closely than do those of the corresponding α-rotamer congeners.
- Craig, J. Cymerman,Torkelson, Steven M.,Findell, Paul R.,Weiner, Richard I.
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p. 961 - 968
(2007/10/02)
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- Efficient Synthesis of Bicyclodecatrienones and of 2-Tetralones via Rhodium(II) Acetate-catalysed Cyclisation of α-Diazoketones derived from 3-Arylpropionic Acids
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Rhodium(II) acetate-catalysed cyclisation of α-diazoketones derived from 3-arylpropionic acids produces bicyclodecatrienones or 2-tetralones depending on the substitution pattern of the aryl ring; the former products are transformed into the latter by catalytic amounts of trifluoroacetic acid.
- McKervey, M. Anthony,Tuladhar, Sarbajna M.,Twohig, M. Fiona
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p. 129 - 130
(2007/10/02)
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