- Insights into 6-Methylsalicylic Acid Bio-assembly by Using Chemical Probes
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Chemical probes capable of reacting with KS (ketosynthase)-bound biosynthetic intermediates were utilized for the investigation of the model type I iterative polyketide synthase 6-methylsalicylic acid synthase (6-MSAS) in vivo and in vitro. From the fermentation of fungal and bacterial 6-MSAS hosts in the presence of chain termination probes, a full range of biosynthetic intermediates was isolated and characterized for the first time. Meanwhile, in vitro studies of recombinant 6-MSA synthases with both nonhydrolyzable and hydrolyzable substrate mimics have provided additional insights into substrate recognition, providing the basis for further exploration of the enzyme catalytic activities. Chemical probes capable of reacting with KS (ketosynthase)-bound biosynthetic intermediates were utilized for the investigation of the model type I iterative polyketide synthase 6-methylsalicylic acid synthase (6-MSAS) in vivo and in vitro. From the fermentation of fungal and bacterial 6-MSAS hosts in the presence of chain termination probes, a full range of biosynthetic intermediates was isolated (see examples) and characterized.
- Parascandolo, James S.,Havemann, Judith,Potter, Helen K.,Huang, Fanglu,Riva, Elena,Connolly, Jack,Wilkening, Ina,Song, Lijiang,Leadlay, Peter F.,Tosin, Manuela
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Read Online
- Palladium-catalyzed ortho-C-H hydroxylation of benzoic acids
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A simple Pd(OAc)2 catalyzed ortho-hydroxylation of benzoic acids using TBHP as the sole oxidant has been explored. This protocol features relatively broad substrate scope and operational simplicity. The compatibility of ortho-substituted substrates is an effective complement to the previous ortho-hydroxylation reaction.
- Luo, Feihua,He, Shuhua,Gou, Quan,Chen, Jinyang,Zhang, mingzhong
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- Copper-Catalyzed One-Pot Synthesis of Dibenzofurans, Xanthenes, and Xanthones from Cyclic Diphenyl Iodoniums
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Oxygenation of cyclic diphenyl iodoniums (CDPIs) with varied medium-ring sizes has been fully investigated. This practical copper-catalyzed tandem reaction of CDPIs with water as the oxygen source enables the construction of derivatised dibenzofurans and xanthenes at moderate to good yields. Moreover, structurally important xanthones are also successfully accessed under the oxygenation conditions with additional TEMPO.
- Zhu, Daqian,Li, Min,Wu, Zhouming,Du, Yongliang,Luo, Bingling,Huang, Peng,Wen, Shijun
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supporting information
p. 4566 - 4571
(2019/07/09)
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- Direct ortho-Acyloxylation of Arenes and Alkenes by Cobalt Catalysis
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An efficient protocol for the cobalt-catalyzed acyloxylation of arenes and alkenes with the assistance of an 8-aminoquinolyl auxiliary group is reported. In this transformation, benzoic acids, alkenyl acids, and aliphatic acids could be readily involved to afford structurally diverse esters. It is worth noting that the silver sulfate (Ag2SO4) oxidant is renewable and the directing group could be removed and recycled. The strategy represents the first successful example of transition metal-catalyzed acyloxylation of alkenyl carboxamides C(sp2)?H bonds with carboxylic acids. (Figure presented.).
- Lin, Cong,Chen, Zhengkai,Liu, Zhanxiang,Zhang, Yuhong
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p. 519 - 532
(2018/02/09)
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- Valuable building block for the synthesis of lunularic acid, hydrangeic acid and their analogues
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A new functionalised sulphone-based building block has been synthesised that enabled C-C bond formation through Julia olefination. The utility of developed building block was demonstrated by successful synthesis of two natural products lunularic acid, hydrangeic acid and initial libraries of their analogues.
- Mukkamala, Ramesh,Hossain, Asik,Singh Aidhen, Indrapal
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p. 1085 - 1090
(2017/01/28)
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- Carboxylation of Phenols with CO2 at Atmospheric Pressure
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A convenient and efficient method for the ortho-carboxylation of phenols under atmospheric CO2 pressure has been developed. This method provides an alternative to the previously reported Kolbe-Schmitt method, which requires very high pressures of CO2. The addition of a trisubstituted phenol has proved essential for the successful carboxylation of phenols with CO2 at standard atmospheric pressure, allowing the efficient preparation of a broad variety of salicylic acids.
- Luo, Junfei,Preciado, Sara,Xie, Pan,Larrosa, Igor
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supporting information
p. 6798 - 6802
(2016/05/11)
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- Metabolically stable dibenzo[ b, e ]oxepin-11(6 H)-ones as highly selective p38 MAP kinase inhibitors: Optimizing anti-cytokine activity in human whole blood
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Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H) -ones were synthesized and tested in a p38α enzyme assay for their inhibition of tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown that the additional introduction of hydrophilic residues at position 9 leads to a substantial improvement of the inhibitory potency and metabolic stability. Using protein X-ray crystallography, the binding mode of the disubstituted dibenzoxepinones and the induction of a glyince flip in the hinge region were confirmed. The most potent compound of this series, 32e, shows an outstanding biological activity on isolated p38α, with an IC50 value of 1.6 nM, extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and low ATP competitiveness. The ability to inhibit the release of TNF-α from human whole blood was optimized down to an IC50 value of 125 nM. With the promising dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.
- Baur, Benjamin,Storch, Kirsten,Martz, Kathrin E.,Goettert, Marcia I.,Richters, André,Rauh, Daniel,Laufer, Stefan A.
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p. 8561 - 8578
(2013/12/04)
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- CARBAZOLE CARBOXAMIDE COMPOUNDS USEFUL AS KINASE INHIBITORS
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Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, thereof, are useful as kinase modulators, including Btk modulation.
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Page/Page column 33-34
(2010/07/04)
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- Enediyne antitumor antibiotic maduropeptin biosynthesis featuring a C-methyltransferase that acts on a COA-Tethered aromatic substrate
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The enediyne antitumor antibiotic maduropeptin (MDP) is produced by Actinomadura madurae ATCC 39144. The biosynthetic pathway for the 3,6-dimethylsalicylic acid moiety of the MDP chromophore is proposed to be comprised of four enzymes: MdpB, MdpB1, MdpB2, and MdpB3. Based on the previously characterized biosynthesis of the naphthoic acid moiety of neocarzinostatin (NCS), we expected a biosynthetic pathway featuring carboxylic acid activation by the MdpB2 CoA ligase immediately before its coupling to an enediyne core intermediate. Surprisingly, the MDP aromatic acid biosynthetic pathway employs an unusual logic in which MdpB2-catalyzed CoA activation occurs before MdpB1-catalyzed C-methylation, demonstrating that MdpB1 is apparently unique in its ability to C-methylate a CoA-tethered aromatic acid. MdpB2 is a promiscuous CoA ligase capable of activating a variety of salicylic acid analogues, a property that could be potentially exploited to engineer MDP analogues.
- Ling, Jianya,Horsman, Geoffrey P.,Huang, Sheng-Xiong,Luo, Yinggang,Lin, Shuangjun,Shen, Ben
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supporting information; experimental part
p. 12534 - 12536
(2010/11/04)
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- COMPOUNDS WITH 7-MEMBER CYCLE AND THE PHARMACEUTICAL USE THEREOF FOR PREVENTING AND TREATING DIABETES AND METABOLISM SYNDROME
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The invention discloses a new use of a class of heptacyclic compounds in the preparation of formulations for the prevention and treatment of diabetes and metabolic syndromes; the present invention also discloses a new class of heptacyclic compounds; the present invention also discloses a process for preparing the heptacyclic compounds and a composition containing the same. The heptacyclic compounds of the present invention can be used to effectively preventing or treating diseases such as diabetes and metabolic syndromes.
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Page/Page column 33
(2010/07/06)
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- Titanocene(III) chloride mediated radical-induced synthesis of 3,4-dihydroisocoumarins: synthesis of (±)-hydrangenol, (±)-phyllodulcin, (±)-macrophyllol and (±)-thunberginol G
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A radical-promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp2TiCl) as the radical initiator. The total synthesis of four naturally occurring dihydrocoumarins hydrangenol, phyllodulcin, macrophyllol and thunberginol G has been accomplished using the radical technology. Cp2TiCl was prepared in situ from commercially available titanocene dichloride (Cp2TiCl2) and Zn-dust in THF under argon.
- Mandal, Samir Kumar,Roy, Subhas Chandra
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experimental part
p. 11050 - 11057
(2009/04/11)
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- Towards EPC-syntheses of the structural class of cochleamycins and macquarimicins. Part 3: EPC-syntheses of the β-keto lactone subunits and first attempts towards the syntheses of the pentacyclic antibiotics of this group
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Practical EPC-syntheses of δ-substituted-β-keto δ-lactones, subunits of the cochleamycins and macquarimicins, are presented. In consequence Tietze's tandem reaction is employed to combine δ-allyl-β-keto δ-lactone with a hydrindene derivative, the second subunit of these acetogenic antibiotics. Model reactions for the final oxidative radical tandem cyclization reveal that the electrophilic radical cyclizes exclusively in exo-trig fashion. However, with the intended precursor of macquarimicin C allylic hydrogen abstraction thwarted the oxidative radical tandem cyclization.
- Chrobok,G?ssinger,Grünberger,K?hlig,White,Wuggenig
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p. 8336 - 8350
(2008/02/05)
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- PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF COMPLEX DISEASES AND THEIR DELIVERY BY INSERTABLE MEDICAL DEVICES
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The present invention relates to polyphenol-like compounds that are useful for inhibiting VCAM-1 expression, MCP-1 expression and/or SMC proliferation in a mammal. The disclosed compounds are useful for regulating markers of inflammatory conditions, including vascular inflammation, and for treatment and prevention of inflammatory and cardiovascular diseases and related disease states.
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Page/Page column 108-112
(2008/06/13)
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- Vitamin E metabolites: Synthesis of [D2]- and [D 3]-γ-CEHC
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Deuterated analogues of α- and γ-CEHC, main urinary and plasma metabolites of vitamin E, can be traced and accurately determined quantitatively by MS in complex matrices. In that regard, here we report the first synthesis of rac-[D3]-γ-CEHC together with a simple route to 7a,8a-[D2]-γ-CEHC through the set up of efficient procedures for the preparation of the corresponding deuterated hydroquinone building blocks. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Mazzini, Francesco,Galli, Francesco,Salvadori, Piero
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p. 5588 - 5593
(2008/02/04)
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- Salicylate activity. 3. Structure relationship to systemic acquired resistance
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Salicylic acid (2-hydroxybenzoic acid; SA) is a primary signal inducing plant defenses against pathogens. This plant disease resistance, known as systemic acquired resistance (SAR), is an attractive target for the development of new plant protection agents. SAR induction is a multistep process that includes accumulation of pathogenesis-related (PR) proteins. The structure-activity profile of salicylates and related compounds has been evaluated using an inducible PR protein (PR-1a) and plant resistance to tobacco mosaic virus (TMV) as markers. Among the 47 selected monosubstituted and multiple-substituted salicylate derivatives tested, all 8 derivatives that induced more PR-1a protein than SA were fluorinated or chlorinated in the 3- and/or 5-position (3,5-difluorosalicylate > 3-chlorosalicylate > 5-chlorosalicylate > 3,5-dichlorosalicylate > 3-chloro-5-fluorosalicylate > 3-fluorosalicylate > 3-fluoro-5-chlorosalicylate > 3,5-dichloro-6-hydroxysalicylate > SA). In general, substitutions for or on the 2-hydroxyl group or at the 4-position of the ring reduced or eliminated PR-1a protein induction. In contrast, substitutions in positions ortho (3-position) or para (5-position) to the hydroxyl group with electron-withdrawing groups other than chlorine or fluorine decreased induction, and electron-donating groups in these positions also had a deleterious effect on PR-1a induction. PR-1a protein accumulation and reduction in TMV lesion diameter exhibited a log-linear relationship. The seven salicylate derivatives that were the most active TMV resistance inducers were all halogenated in the 3- and/or 5-position (3-chlorosalicylate > 3,5-difluorosalicylate > 3,5-dichloro-6-hydroxysalicylate > 3,5,6-trichlorosalicylate > 5-chlorosalicylate > 5-fluorosalicylate > 3,5-dichlorosalicylate > 4-fluorosalicylate > 3-fluorosalicylate > 3-chloro-5-fluorosalicylate > 4-chlorosalicylate > SA). The correlation between PR-1a protein induction and resistance to TMV confirms the value of using PR-1a induction as a screening tool for developing new plant disease control agents.
- Silverman, F. Paul,Petracek, Peter D.,Heiman, Daniel F.,Fledderman, Christina M.,Warrior, Prem
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p. 9775 - 9780
(2007/10/03)
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- Lobatamide C: Total synthesis, stereochemical assignment, preparation of simplified analogues, and V-ATPase inhibition studies
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The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a β-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.
- Shen, Ruichao,Lin, Cheng Ting,Bowman, Emma Jean,Bowman, Barry J.,Porco Jr., John A.
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p. 7889 - 7901
(2007/10/03)
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- Total synthesis and stereochemical assignment of the salicylate antitumor macrolide lobatamide C
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The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C is reported. The synthesis involves Cu(I)-mediated enamide formation and Na2CO3-mediated esterification of a β-hydroxy acid and a salicylate cyanomethyl ester. Macrolactonization was accomplished using a Mitsunobu protocol. The stereochemical assignment of lobatamide C was achieved by Mosher ester analysis and comparison with prepared stereoisomers. Copyright
- Shen, Ruichao,Lin, Cheng Ting,Porco Jr., John A.
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p. 5650 - 5651
(2007/10/03)
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- Regioselective dealkylation of 2-alkoxybenzoic acid and its amide derivatives with aliphatic amines
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The methoxy group of o-anisic acid was cleaved with aliphatic amines in aprotic dipolar solvents. This cleavage reaction was especially smooth when piperazine in dimethylacetamide was used. This method was applicable to a variety of dealkylations of o-alkoxybenzoic acid and ist amide derivatives with high regio-selectivity.
- Nishioka, Hiroyasu,Nagasawa, Masaaki,Yoshida, Kiyoshi
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p. 243 - 246
(2007/10/03)
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- Synthesis of Saturated Anacardic Acids, and Alkenyl and Alkynyl Analogues
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The C-alkylation of esters of 2-methoxy-6-methylbenzoic acid and of the 4-methyl isomers affords a route to homologous compounds including in the former case members of the natural anacardic acids from Anacardium occidentale and ω-alkynyl compounds suitable for synthesising other natural phenolic lipids or for structure/activity studies.
- Tyman, John H. P.,Visani, Naina
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p. 228 - 240
(2007/10/03)
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- Efficient total synthesis of AI-77-B, a gastroprotective substance from Bacillus pumilus AI-77
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First total synthesis of AI-77-B (1), a gastroprotective substance from Bacillus pumilus AI-77, was achieved in a stereoselective and convergent manner. In this synthesis, the dihydroisocoumarin part 2 was constructed in one step through 1,2-addition of the benzylic anion 17b to Boc-L-leucinal 7b. The hydroxy amino acid 4 was elaborated from (R)-glutamic acid in a highly stereoselective manner. Condensation of 2·HCl and 4, intramolecular Pinner reaction, followed by mild hydrolysis afforded AI-77-B (1).
- Hamada,Hara,Kawai,Kohno,Shioiri
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p. 8635 - 8652
(2007/10/02)
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- Synthesis of Gerberinol-I
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The synthesis of 4-hydroxy-5-methylcoumarin (II) is described.The compound (II) affords gerberinol-I (I) on treatment with formaldehyde.The synthetic sample of I is identical (m.m.p. and co-IR) with an authentic I.
- Chatterjea, J. N.,Singh, K. R. R. P.,Jha, I. S.,Prasad, Y.,Shaw, S. C.
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p. 796 - 798
(2007/10/02)
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- SELECTIVE SYNTHESES USING CYCLODEXTRINS AS CATALYSTS. 2. PARA-ORIENTED CARBOXYLATION OF PHENOLS.
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4-Hydroxybenzoic acid and 4-hydroxy-3-methylbenzoic acid are synthesized in virtually 100% selectivities and high yields from the corresponding phenols and carbon tetrachloride by using beta -cyclodextrin ( beta -CD) as catalyst. The selective syntheses are successfully achieved by a small molar ratio, even 0. 03, of beta -CD to phenols and are hardly suppressed by oxygen. Kinetic study shows that the selective catalyses by beta -CO originate from both promotion of the para carboxylation and almost complete inhibition of the ortho carboxylation. Heptakis(2,6-di-0-methyl) beta -cyclodextrin in contrast decreases the para selectivity, showing the importance of the hydroxyl groups of beta -CD in its selective catalysis. The selective catalysis by beta -CD proceeds via formation of a molecular complex with the active species, probably the trichloromethyl cation.
- Komiyama,Hirai
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p. 174 - 178
(2007/10/02)
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