- Access to 6a-Alkyl Aporphines: Synthesis of (±)-N-Methylguattescidine
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(-)-N-Methylguattescidine (3) is an alkaloid recently isolated from Fissistigma latifolium and assigned as a rare example of a 6a-alkyl aporphine. Herein, we report the synthesis of (±)-3 and the des-hydroxyl derivative 4 using our previously reported ortho-phenol arylation methodology mediated by the XPhos precatalyst as a key synthetic step. In addition, substituents on the aryl halide portion of the ortho-phenol arylation substrates significantly influenced the formation of an oxidized side product.
- Ku, Angela F.,Cuny, Gregory D.
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- High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- And Tricovalent Binding Modes
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The effectiveness of β-lactam antibiotics is increasingly compromised by β-lactamases. Boron-containing inhibitors are potent serine-β-lactamase inhibitors, but the interactions of boron-based compounds with the penicillin-binding protein (PBP) β-lactam targets have not been extensively studied. We used high-throughput X-ray crystallography to explore reactions of a boron-containing fragment set with the Pseudomonas aeruginosa PBP3 (PaPBP3). Multiple crystal structures reveal that boronic acids react with PBPs to give tricovalently linked complexes bonded to Ser294, Ser349, and Lys484 of PaPBP3; benzoxaboroles react with PaPBP3 via reaction with two nucleophilic serines (Ser294 and Ser349) to give dicovalently linked complexes; and vaborbactam reacts to give a monocovalently linked complex. Modifications of the benzoxaborole scaffold resulted in a moderately potent inhibition of PaPBP3, though no antibacterial activity was observed. Overall, the results further evidence the potential for the development of new classes of boron-based antibiotics, which are not compromised by β-lactamase-driven resistance.
- Newman, Hector,Krajnc, Alen,Bellini, Dom,Eyermann, Charles J.,Boyle, Grant A.,Paterson, Neil G.,McAuley, Katherine E.,Lesniak, Robert,Gangar, Mukesh,Von Delft, Frank,Brem, Jürgen,Chibale, Kelly,Schofield, Christopher J.,Dowson, Christopher G.
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- Preparation method of aporphine alkaloid
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The invention discloses a preparation method of aporphine alkaloid as shown in a formula III. The method comprises the following steps: taking a benzaldehyde compound as shown in a formula III-0 as a raw material, and sequentially carrying out Wittig reaction, Pictet-Spengler reaction, Heck reaction and palladium carbon hydrogen deprotection. A bromine-containing benzaldehyde derivative is selected as a raw material, the carbon-carbon coupling co-production rate and the reaction rate are increased through bromine atoms, and the reaction activity is improved; benzyl chloroformate is adopted for NH protection, and an electron withdrawing group is introduced, so that the reaction yield can be improved; and a styrene methyl ether derivative directly reacts with an acylated phenylethylamine derivative in an acid catalysis system by adopting a one-pot method so as to obtain benzyl tetrahydroisoquinoline. The preparation method has the advantages of mild reaction conditions, low toxicity of used reagents, easily available raw materials, convenient post-treatment and simpler reaction route compared with previous reports, and can be suitable for various reaction substrates.
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Paragraph 0055-0058; 0100-0102
(2021/06/09)
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- Design and synthesis of π-extended resveratrol analogues and in vitro antioxidant and anti-inflammatory activity evaluation
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The research on resveratrol (1) has been conducted intensively over a long time due to its proven antioxidant activity and disease-fighting capabilities. Many efforts have also been made to increase these biological effects. In the present study, six new extended aromatic resveratrol analogues containing naphthalene (2) and its bioisosteres quinoline (3 and 4), isoquinoline (5) quinoxaline (6) and quinazoline (7) scaffolds were designed and synthesized using an annulation strategy. The antioxidant and anti-inflammatory activities of these compounds were investigated. All compounds showed better antioxidant activity than resveratrol in ABTS assay. As for the anti-inflammatory test, 5 and 7 exhibited better activity than resveratrol. It is worth noting that nitrogen substitution on the extended aromatic resveratrol analogues has a significant impact on cell viability. Taking the antioxidant activities and NO inhibition activities into consideration, we conclude that isoquinoline analogue 5 may qualify for the further investigation of antioxidant and anti-inflammatory therapy. Furthermore, our study results suggest that in order to improve the biological activity of polyphenolic compounds, extended aromaticity and nitrogen substitution strategy could be a viable method for the design of future drug candidates.
- Damodar, Kongara,Gim, Ji Geun,Jeon, Seong Ho,Lee, Jeong Tae,Lee, Yeontaek,Nam, Ki Yoon,Park, Jae Phil,Park, Lee Seul
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supporting information
(2021/06/14)
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- 1,4-Palladium Shift/C(sp3)-H Activation Strategy for the Remote Construction of Five-Membered Rings
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1,n-Metal shift is an elegant alternative approach enabling the functionalization of remote C-H bonds from simple precursors. In this work, we report a novel and simple Pd0-catalyzed domino reaction involving 1,4-palladium shift and C(sp3)-H activation and leading to (fused) five-membered rings. This method allowed access to a broad range of valuable arylidene γ-lactams and indanones and was applied to the formal synthesis of (-)-pyrrolam.
- Rocaboy, Ronan,Baudoin, Olivier
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supporting information
p. 1434 - 1437
(2019/02/19)
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- Preparation method for creboro intermediate
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The invention discloses a preparation method for a creboro intermediate. The preparation method for the creboro intermediate comprises the following steps that 1, 2-bromo-5-hydroxybenzaldehyde reactswith benzyl chloride or benzyl bromide in an organic solvent (i) under the existence of alkali to obtain a compound shown in a formula II; 2, the compound shown in the formula II reacts with triethylorthoformate or trimethyl orthoformate or glycol in an organic solvent (ii) under the effect of an acid catalyst to obtain a compound shown in a formula III; 3, 2-methoxyl-4, 4, 5, 5-tetramethyl-1, 3,2-boron dioxane or 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-boron dioxane or trimethyl borate or triisopropyl borate reacts with a standby solution in an organic solvent (iii) under the condition thatthe reaction temperature is 10-30 DEG C, after the reaction is completed, hydrochloric acid is added for regulating the pH value to be not larger than 3, and after a quenching reaction is performed, acompound shown in a formula IV is obtained through the reaction under the temperature of 20-100 DEG C.
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Paragraph 0046; 0090-0091
(2018/10/19)
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- Preparation method of Crisaborole intermediate
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The invention discloses a preparation method of a Crisaborole intermediate. The Crisaborole intermediate has a structure shown as the formula VI. The preparation method comprises the following steps:performing a contact reaction on a compound shown as the formula I and benzyl halide, so as to form a compound shown as the formula II; performing a contact reaction on the compound shown as the formula II and alkali metal borohydride, so as to obtain a compound shown as the formula III; performing a contact reaction on the compound shown as the formula III and a compound a, or performing a contact reaction on the compound shown as the formula III and dihydropyran, so as to obtain a compound shown as the formula IV, wherein the compound a is trimethylchlorosilane, tert-butyldimethylsilyl chloride and chloromethyl methyl ether; performing a contact reaction on the compound shown as the formula IV and an isopropylmagnesium chloride solution; adding an obtained solution into a compound b, performing a contact reaction on the mixture and fourth organic solvent mixed liquor and adding hydrochloric acid into the mixture for contact reaction, so as to obtain a compound shown as the formula V,wherein the compound b is 2-alkoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane, triisopropyl borate or trimethyl borate; performing a hydrogenation reaction on the compound shown as the formula V toobtain a compound shown as the formula VI.
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Paragraph 0052; 0053
(2019/01/08)
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- Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer
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Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure–activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.
- Crowley, Vincent M.,Huard, Dustin J. E.,Lieberman, Raquel L.,Blagg, Brian S. J.
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supporting information
p. 15775 - 15782
(2017/11/14)
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- Simple, copper(I)-catalyzed oxidation of benzylic/allylic alcohols to carbonyl compounds: Synthesis of functionalized cinnamates in one pot
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An environmentally benign [Cu(I)]-catalyzed oxidation of activated (benzylic/allylic) alcohols to the corresponding carbonyl compounds is presented. Interestingly, the reaction was also compatible with benzylic alcohols containing ortho-bromo substituents on the aromatic ring without competing with the expected intermolecular Buchwald coupling. Significantly, the catalytic system enables the synthesis of cinnamate-esters in a sequential domino one-pot fashion via oxidation followed by Wittig-Horner protocol. Copyright
- Reddy, Alavala Gopi Krishna,Mahendar, Lodi,Satyanarayana, Gedu
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supporting information
p. 2076 - 2087
(2014/07/07)
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- GPBP-1 INHIBITION AND ITS THERAPEUTIC USE
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The present invention provides compositions including anti-tumor agents and inhibitors of Goodpasture antigen binding protein, p21, and ABCC7, and their use in treating cancer.
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Page/Page column 46
(2014/01/18)
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- NOVEL CURCUMIN DERIVATIVE
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To develop a highly safe measure to treat Alzheimer's disease using a secretase-inhibiting substance, there is provided a compound represented by the following general formula (I) or a salt thereof: wherein A represents a phenyl group or the like, R1 represents a chlorine atom, a bromine atom, or a nitro group or the like, R2, R3, R4, and R5 each represent a hydrogen atom or the like, and L represents CH2—CH2 or CH═CH.
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Page/Page column 14
(2011/04/24)
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- Total synthesis of (+)-korupensamine B via an atropselective intermolecular biaryl coupling
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The asymmetric total synthesis of nonracemic korupensamine B is reported. It includes a newly designed and highly trans-diastereoselective (>20:1 dr) route to the tetrahydroisoquinoline ring and an unprecedented atropdiastereoselective Suzuki-Miyaura coupling for construction of the fully fashioned naphthylisoquinoline framework that invokes π stacking as a possible source of stereocontrol.
- Huang, Shenlin,Petersen, Tue B.,Lipshutz, Bruce H.
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supporting information; experimental part
p. 14021 - 14023
(2011/01/04)
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- TRICYCLIC HETEROCYCLIC DERIVATIVES
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The present invention relates to a tricyclic heterocyclic derivative of Formula (I) wherein the variables are as defined in the specification. The present invention further relates to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular for the treatment of serotonin-mediated disorders such as obesity, schizophrenia and cognitive dysfunction.
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Page/Page column 52
(2009/04/25)
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- NOVEL CURCUMIN DERIVATIVE
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The present invention provides a novel compound that is structurally similar to curcumin and has a suppressive effect on Aβ aggregation, a degradative effect on Aβ aggregates, an inhibitory effect on β-secretase, and a protective effect on neurons. The novel compound is a compound represented by the following general formula (Ia) or a salt thereof: wherein R1 represents a 4-hydroxy-3-methoxyphenyl group or the like, and R2 represents a 1H-indol-6-yl group or the like.
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Page/Page column 110
(2009/12/07)
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- Total synthesis of bulbophylol-B
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The first total synthesis of bulbophylol-B (1) has been achieved with the longest linear sequence of 12 steps and an overall yield of 17.9% via a new and practical approach to construct the dihydrodibenz[b,f]oxepin skeleton employing Wittig, selective reduction, and intramolecular Ullmann reactions as key steps.
- Lin, Jinshun,Zhang, Weige,Jiang, Nan,Niu, Zeyu,Bao, Kai,Zhang, Liang,Liu, Dailin,Pan, Chao,Yao, Xinsheng
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experimental part
p. 1938 - 1941
(2009/09/25)
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- Survivin inhibitors
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Compounds that inhibit survivin, compositions containing the compounds and methods of treating diseases in which survivin is unregulated or overexpressed are disclosed.
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Page/Page column 19
(2010/11/26)
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- Unforeseen formation of 2-bromo-3-hydroxybenzaldehyde by bromination of 3-hydroxybenzaldehyde
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Contrary to literature reports, bromination of 3-hydroxybenzaldehyde can afford both 2-bromo-5-hydroxybenzaldehyde and 2-bromo-3-hydroxybenzaldehyde, but 4-bromo-3-hydroxybenzaldehyde was not detected. 2-Bromo-3-hydroxybenzaldehyde was converted into 2-(benzyloxy)-1-bromo-5-methoxy-7-methylnaphthalene. X-ray crystallographic analysis supports the identity of 2-bromo-3- hydroxybenzaldehyde.
- Van Otterlo, Willem A. L.,Michael, Joseph P.,Fernandes, Manuel A.,De Koning, Charles B.
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p. 5091 - 5094
(2007/10/03)
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- Total syntheses of plagiochins A and D, macrocyclic bis(bibenzyls), by Pd(0) catalyzed intramolecular Stille-Kelly reaction
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Total syntheses of plagiochins A (1) and D (4), the former of which exhibits a significant neurotrophic activity, have been accomplished. The key 16-membered ring closure in 4 has been achieved directly from the dibromoperrottetin derivative (7) by Pd(0)
- Fukuyama, Yoshiyasu,Yaso, Hideyuki,Mori, Takashi,Takahashi, Hironobu,Minami, Hiroyuki,Kodama, Mitsuaki
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p. 259 - 274
(2007/10/03)
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- Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy- 2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands
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The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10- hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D1-like and D2-like subtypes. All compounds showed very low D1 affinities. This could be ascribed to the absence of a catechol nucleus or of the β-phenyldopamine pharmacophore. Only the N-methyl-5- hydroxy- (5a), N-methyl-10-hydroxy-(6a), and N-methyl-4-bromo-10-methoxy- 2,3,12,12a-tetrahydro-1H-[1]-benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D2 receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)-ethylamine moiety does not meet the requirements of the D2 agonist pharmacophore: namely, the 2-(3- hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D4 receptors, and only 5a showed low affinity for rat recombinant D3 receptors. Analysis of the influence of Na+ on [3H]spiperone binding showed that 5a displays a potential dopamine D2 agonist profile, whereas 6a probably has a dopamine D2 antagonist activity. The D2 agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.
- Claudi, Francesco,Di Stefano, Antonio,Napolitani, Fabrizio,Cingolani, Gian Mario,Giorgioni, Gianfabio,Fontenla, Josè A.,Montenegro, Gisela Y.,Rivas, Maria E.,Rosa, Elizabeth,Michelotto, Barbara,Orlando, Giustino,Brunetti, Luigi
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p. 599 - 608
(2007/10/03)
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- Total synthesis of plagiochins C, and D, macrocyclic bis(bibenzyl) constituents of plagiochila acantophylla
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Plagiochins C (3) and D (4) were synthesized by convergent schemes. Rings C and B were joined by Ullman ether synthesis, the aryl-aryl bond between rings A and D was formed by Pd(0)-catalysed coupling of an arylboronic acid (ring D) and a bromobenzoic ester (ring A). Rings C and D were linked by the Wittig reaction, while final ring closure was effected by tetraphenylethene assisted Wurtz reaction.
- Keseru,Mezey-Vandor,Nogradi,Vermes,Kajtar-Peredy
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p. 913 - 922
(2007/10/02)
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