cas 2411-83-8, methyl 2,3-dihydroxybenzoate

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Diphenyl-benzo[1,3]dioxole-4-carboxylic acid pentafluorophenyl ester: A convenient catechol precursor in the synthesis of siderophore vectors suitable for antibiotic Trojan horse strategies
Catechols are components of many metal-chelating compounds, including siderophores that are naturally occurring iron(iii) chelators excreted by microorganisms. Catechol derivatives are poorly soluble in organic media and the synthesis of catechol-containing molecules requires the use of protected catechol precursors with improved organic solubility. We therefore developed 2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid pentafluorophenyl ester. This activated ester reacts with an amine functionalized scaffold to generate chelators in which the catechol functions are protected in the form of diphenyl-benzodioxole moieties. The catechol can subsequently be deprotected, at the end of the synthesis, with trifluoroacetic acid (TFA). This strategy was applied to the synthesis of two catechol compounds functionalized with a terminal propargyl extension. These two compounds were shown to promote iron uptake in Escherichia coli and Pseudomonas aeruginosa. These two compounds are suitable for use as vectors in antibiotic Trojan horse approaches, as they could be conjugated with azide-functionalized antibiotics using the Huisgen dipolar 1,3-cycloaddition.
Baco, Etienne,Hoegy, Francoise,Schalk, Isabelle J.,Mislin, Gaetan L. A.
p. 749 - 757
(2014)
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Synthesis of Protected 3,4- And 2,3-Dimercaptophenylalanines as Building Blocks for Fmoc-Peptide Synthesis and Incorporation of the 3,4-Analogue in a Decapeptide Using Solid-Phase Synthesis
3,4-Dimercaptophenylalanines and 2,3-dimercaptophenylalanines have been synthesized for the first time by nucleophilic substitution of a protected aminomalonate on 3,4- and 2,3-dimercaptobenzyl bromide derivatives. The dithiol functions were protected as thioketals, and the key precursors, diphenylthioketal-protected dimercaptobenzyl bromides, were synthesized via two distinct routes from either dihydroxy benzoates or toluene-3,4-dithiol. Racemic mixtures of the fully protected amino acids were separated by chiral HPLC into the corresponding enantiomers. The absolute configuration of both 3,4- and 2,3-analogues could be assigned based on X-ray crystallography and VCD/DFT measurements. Thioketal groups were deprotected upon reaction with mercury oxide and aqueous tetrafluoroboric acid followed by treatment with H2S gas under an argon atmosphere to obtain the corresponding dimercapto amino acids. The optically pure l-Fmoc-protected 3,4-analogue (S- enantiomer) was successfully incorporated into a decapeptide using standard solid-phase peptide synthesis. Therefore, dithiolene-functionalized peptides are now accessible from a simple synthetic procedure, and this should afford new molecular tools for research into the catalysis, diagnostic, and nanotechnology fields.
Banerjee, Isita,Ghosh, Keshab Ch.,Oheix, Emmanuel,Jean, Marion,Naubron, Jean-Valère,Réglier, Marius,Iranzo, Olga,Sinha, Surajit
supporting information
p. 2210 - 2223
(2021/02/26)

Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors
Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC50 = 12 μM), 4 (IC50 = 5.8 μM), and 10 (IC50 = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC50 = 0.082 μM) as the most potent inhibitor of PARP1 from the series.
Shao, Xuwei,Pak, Steven,Velagapudi, Uday Kiran,Gobbooru, Shruthi,Kommaraju, Sai Shilpa,Low, Woon-Kai,Subramaniam, Gopal,Pathak, Sanjai Kumar,Talele, Tanaji T.
(2020/08/10)

Practical Cleavage of Acetals by Using an Odorless Thiol Immobilized on Silica
A practical, efficient and general method was developed for the deprotection of a variety of aromatic and aliphatic acetals to their corresponding catechol or diol derivatives using thiol immobilized on silica gel. This is an application for the well-known commercial solid-supported thiol (SiliaMetS Thiol). The procedure is mild and amenable to scale-up. It does not require inert atmosphere and clean conversions were observed. This method is applicable to substituted 1,3-benzodioxole and aliphatic acetals with different functionalities. It offers the advantage of a general route with high yield, which can be undertaken at ambient temperature.
de Léséleuc, Mylène,Kukor, Andrew,Abbott, Shaun D.,Zacharie, Boulos
p. 7389 - 7393
(2019/12/03)

Dearomatization of Electron-Deficient Phenols to ortho-Quinones: Bidentate Nitrogen-Ligated Iodine(V) Reagents
Despite their broad utility, the synthesis of ortho-quinones remains a significant challenge, in particular, access to electron-deficient derivatives remains an unsolved problem. Reported here is the first general method for the synthesis of electron-deficient ortho-quinones by direct oxidation of phenols. The reaction is enabled by a novel bidentate nitrogen-ligated iodine(V) reagent, a previously unexplored class of compounds which we have termed Bi(N)-HVIs. The reaction is extremely general and proceeds with excellent regioselectivity for the ortho over para isomer. Functionalization of the ortho-quinone products was examined, resulting in a facile one-pot synthesis of catechols, as well as the incorporation of a variety of heteroatom nucleophiles. This method represents the first synthetic application of Bi(N)-HVIs and demonstrates their potential as a platform for the further development of highly reactive, but also highly tunable, I(V) reagents.
Xiao, Xiao,Greenwood, Nathaniel S.,Wengryniuk, Sarah E.
p. 16181 - 16187
(2019/11/05)

Amide derivatives and their medical use
The invention relates to novel amide derivatives shown in a structural formula I in the specification or a pharmaceutically acceptable salt thereof, a medicine composition which takes the compounds as active components, and an application of the derivatives or the pharmaceutically acceptable salt of the derivatives to preparation of analgesia medicines. In the structural formula I, R1 and R2 are a hydrogen atom and a C1-C3 alkyl; R3 is hydrogen atom, C1-C3 alkyl, phenyl or a hydroxyl-substituted alkyl.
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Paragraph 0064; 0066; 0067

(2018/04/21)

CHELATING PLATFORM FOR DELIVERY OF RADIONUCLIDES
Siderocalin-metal chelator combinations that bind metallic radioisotopes used in nuclear medicine with high affinity are described. The high affinity siderocalin-metal chelator combinations include a number of chelator backbone arrangements with functional groups that coordinate with metals. The siderocalin-metal chelator combinations can be used to deliver radionuclides for imaging and therapeutic purposes.
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Paragraph 0236

(2018/03/25)

A heterocyclic compound and use thereof
The invention discloses a compound of a general formula I and application of the compound serving as a plant disease-resistance activator. In the formula, a substituent group R1 and 0-3 substituent groups R2 exist on the 4th, 5th, 6th and 7th sites; R1 is independently selected from -R3OOH, -R4OOR5, -R6OH and -R7-O-R8; R2 is independently selected from C1-C6 alkyl, C1-6 halogenated alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy, hydroxyl, halogen, nitro, amino and C1-C6 alkylamino; R3, R4, R5, R6, R7 and R8 are independently selected from C1-C6 alkyl and C1-6 halogenated alkyl. The compound induces plants to generate disease resistance so as to inhibit pathogens instead of directly killing or inhibiting the pathogens. The compound has the advantages of systematicness, durability, broad spectrum, high safety and the like, so the amount of highly toxic pesticides can be reduced, and the compound is environmentally friendly and has huge industrialized and commercial prospects and market values.
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Paragraph 0084-0090

(2018/05/24)

Quinazoline heterocyclic compounds as well as preparation method and application thereof
The invention provides quinazoline heterocyclic compounds as well as a preparation method and an application thereof and belongs to the field of medicinal chemistry. The structural formula is shown as a formula (I) in the specification, wherein R represents -H and -CH3; R is defined in the specification, 8,10-dichloro-2,3-dihydro-[1,4] dioxane [2,3-f] quinazoline (IX) is prepared firstly, and then R and R substitution are performed. The compounds can be applied as PI3K (phosphoinositide 3-kinase) inhibitors for treating cancer.
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Paragraph 0078; 0079; 0080; 0081; 0082; 0083

(2017/07/19)

Catechol-Based Ligands as Potential Metal Chelators Inhibiting Redox Activity in Alzheimer's Disease
The loss of homeostasis of redox metal ions, namely, copper and iron, has been considered to be an important contributing factor in neuronal death observed in the brain of patients affected by Alzheimer's disease (AD). Specific ligands able to regulate the homeostasis of copper and, to a lesser extent, iron ions in the brain have therefore been considered to be potential drugs for the treatment of AD. Herein, the synthesis and metal coordination properties of a series of ligands based on a bis(2,3-dihydroxyalkylbenzamide) scaffold, which are potentially able to regulate the homeostasis of redox metal ions, are reported. These catechol-based ligands exhibit high specific affinities for CuII and FeIII, and a lower affinity for ZnII, which indicates that they may interact with redox metal ions without disturbing the structural and dynamic role of zinc chelation in many proteins. These ligands inhibit the reduction of dioxygen induced by CuII–Aβ1–16, and this suggests that they may be able to efficiently reduce the oxidative stress induced by metal-loaded amyloids in the AD brain.
Nguyen, Michel,Meunier, Bernard,Robert, Anne
p. 3198 - 3204
(2017/07/22)

Synthesis and antioxidant activity of 1,3,4-oxadiazoles and their diacylhydrazine precursors derived from phenolic acids
Eight 1,3,4-oxadiazole derivatives containing phenolic acid moieties (7a-h) and eight of their diacylhydrazine precursors (6a-h) were synthesized, characterized using spectroscopic methods and examined by scavenging of stable DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals. The most potent phenolic 1,3,4-oxadiazoles showed better DPPH scavenging activity in comparison with their corresponding diacylhydrazine precursors as a result of participation of both aromatic rings and a 1,3,4-oxadiazole moiety in resonance stabilization of the formed phenoxyl radical. Four diacylhydrazines (6d, 6e, 6g, and 6h) and four 1,3,4-oxadiazoles (7d, 7e, 7g and 7h) with the best DPPH scavenging activity, were chosen for further evaluation of their antioxidant potential through various assays. The investigated compounds exerted pronounced ABTS radical scavenging capacity, moderate to good H2O2 scavenging properties and strong ferric ion reducing capacity. Further in vitro evaluation of the antioxidant properties of the most active compounds demonstrated their protective effects in normal lung fibroblasts MRC-5 against hydrogen peroxide induced oxidative stress. Diacylhydrazine 6h increased two times the activity of glutathione peroxidase in treated cells in comparison with a control sample and did not affect the superoxide dismutase activity.
Mihailovi?, Nevena,Markovi?, Violeta,Mati?, Ivana Z.,Stanisavljevi?, Nemanja S.,Jovanovi?, ?ivko S.,Trifunovi?, Sne?ana,Joksovi?, Ljubinka
p. 8550 - 8560
(2017/02/10)

Chasing Weak Forces: Hierarchically Assembled Helicates as a Probe for the Evaluation of the Energetics of Weak Interactions
London dispersion forces are the weakest interactions between molecules. Because of this, their influence on chemical processes is often low, but can definitely not be ignored, and even becomes important in cases of molecules with large contact surfaces. Hierarchically assembled dinuclear titanium(IV) helicates represent a rare example in which the direct observation of London dispersion forces is possible in solution even in the presence of strong cohesive solvent effects. Hereby, the dispersion forces do not unlimitedly support the formation of the dimeric complexes. Although they have some favorable enthalpic contribution to the dimerization of the monomeric complex units, large flexible substituents become conformationally restricted by the interactions leading to an entropic disadvantage. The dimeric helicates are entropically destabilized.
Van Craen, David,Rath, Wolfgang H.,Huth, Marina,Kemp, Laura,R?uber, Christoph,Wollschl?ger, Jan M.,Schalley, Christoph A.,Valkonen, Arto,Rissanen, Kari,Albrecht, Markus
supporting information
p. 16959 - 16966
(2017/11/30)

Engineered recognition of tetravalent zirconium and thorium by chelator-protein systems: Toward flexible radiotherapy and imaging platforms
Targeted α therapy holds tremendous potential as a cancer treatment: it offers the possibility of delivering a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic α-generating radioisotopes 225Ac and 227Th are promising radionuclides for therapeutic use, provided adequate chelation and targeting. Here we demonstrate a new chelating platform composed of a multidentate high-affinity oxygen-donating ligand 3,4,3-LI(CAM) bound to the mammalian protein siderocalin. Respective stability constants log β110 = 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the EuIII (a lanthanide surrogate for AcIII), ZrIV, and ThIV complexes of 3,4,3-LI(CAM) through spectrophotometric titrations, reveal this ligand to be one of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. The resulting metal-ligand complexes are also recognized with extremely high affinity by the siderophore-binding protein siderocalin, with dissociation constants below 40 nM and tight electrostatic interactions, as evidenced by X-ray structures of the protein:ligand:metal adducts with ZrIV and ThIV. Finally, differences in biodistribution profiles between free and siderocalin-bound 238PuIV-3,4,3-LI(CAM) complexes confirm in vivo stability of the protein construct. The siderocalin:3,4,3-LI(CAM) assembly can therefore serve as a "lock" to consolidate binding to the therapeutic 225Ac and 227Th isotopes or to the positron emission tomography emitter 89Zr, independent of metal valence state.
Captain, Ilya,Deblonde, Gauthier J.-P.,Rupert, Peter B.,An, Dahlia D.,Illy, Marie-Claire,Rostan, Emeline,Ralston, Corie Y.,Strong, Roland K.,Abergel, Rebecca J.
supporting information
p. 11930 - 11936
(2016/12/03)

SULFONYLUREAS AND RELATED COMPOUNDS AND USE OF SAME
ABSTRACT The present invention provides for certain sulfonyl ureas and related compounds which have advantageous properties and show useful activity in the inhibition of activation of the NLRP3 inflammasome. Such compounds are useful in the treatment of a wide range of disorders in which the inflammation process, or more specifically the NLRP3 inflammasome, have been implicated as being a key factor.
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Page/Page column 167; 168

(2016/09/15)

Algidisides I and II, New Iridoid Glycosides from Gentiana algida
Two new iridoid glycosides, algidiside I [2′-(2′′,3′′-dihydroxybenzoyl)loganic acid] (1) and algidiside II [6′-(2′′,3′′-dihydroxybenzoyl)loganic acid] (2), and 14 known iridoids including for the first time from the aerial part of Gentiana algida Pall. 2′
Olennikov,Chirikova
p. 637 - 641
(2016/09/03)

Arene cis-Diol Dehydrogenase-Catalysed Regio- and Stereoselective Oxidation of Arene-, Cycloalkane- and Cycloalkene-cis-diols to Yield Catechols and Chiral α-Ketols
Benzene cis-diol dehydrogenase and naphthalene cis-diol dehydrogenase enzymes, expressed in Pseudomonas putida wild-type and Escherichia coli recombinant strains, were used to investigate regioselectivity and stereoselectivity during dehydrogenations of arene, cyclic alkane and cyclic alkene vicinal cis-diols. The dehydrogenase-catalysed production of enantiopure cis-diols, α-ketols and catechols, using benzene cis-diol dehydrogenase and naphthalene cis-diol dehydrogenase, involved both kinetic resolution and asymmetric synthesis methods. The chemoenzymatic production and applications of catechol bioproducts in synthesis were investigated.
Boyd, Derek R.,Sharma, Narain D.,Berberian, M. Victoria,Cleij, Marcel,Hardacre, Christopher,Ljubez, Vera,McConville, Gareth,Stevenson, Paul J.,Kulakov, Leonid A.,Allen, Christopher C. R.
p. 1881 - 1894
(2015/06/02)

Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity
A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC 50 value of 3.11 μM and Hela with IC50 value of 2.54 μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50 = 0.45 μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.
Duan, Yong-Tao,Yao, Yong-Fang,Huang, Wei,Makawana, Jigar A.,Teraiya, Shashikant B.,Thumar, Nilesh J.,Tang, Dan-Jie,Tao, Xiang-Xiang,Wang, Zhong-Chang,Jiang, Ai-Qin,Zhu, Hai-Liang
p. 2947 - 2954
(2014/05/20)

Synthesis and antibacterial activity of catecholate-ciprofloxacin conjugates
The development of an efficient route to obtain artificial siderophore-antibiotic conjugates active against Gram-negative bacteria is crucial. Herein, a practical access to triscatecholate enterobactin analogues linked to the ciprofloxacin along with their antibacterial evaluation are described. Two series of conjugates were obtained with and without a piperazine linker which is known to improve the pharmacokinetics profile of a drug. A monocatecholate-ciprofloxacin conjugate was also synthesized and evaluated. The antibacterial activities against Pseudomonas aeruginosa for some conjugates are related to the iron concentration in the culture medium and seem to depend on the bacterial iron uptake systems.
Fardeau, Sylvain,Dassonville-Klimpt, Alexandra,Audic, Nicolas,Sasaki, Andre,Pillon, Marine,Baudrin, Emmanuel,Mullie, Catherine,Sonnet, Pascal
p. 4049 - 4060
(2014/08/18)

Rigenolide A, a new secoiridoid glucoside with a cyclobutane skeleton, and three new acylated secoiridoid glucosides from Gentiana rigescens Franch
Rigenolide A (1), a new secoiridoid glucoside with a cyclobutane skeleton and three new acylated secoiridoid glucosides, 2′-(2,3-dihydroxybenzoyl)- gentiopicroside (2), 2′-(2,3-dihydroxybenzoyl)-swertiamarin (3), 3′-(2,3-dihydroxybenzoyl)-sweroside (4), along with two noriridoids (7 and 8) and two known secoiridoid glucosides (5 and 6), were isolated from Gentiana rigescens Franch. The structures of new compounds were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for DPPH free-radical scavenging activity.
Suyama, Yoshihiro,Kurimoto, Shin-Ichiro,Kawazoe, Kazuyoshi,Murakami, Kotaro,Sun, Han-Dong,Li, Shun-Lin,Takaishi, Yoshihisa,Kashiwada, Yoshiki
p. 166 - 172
(2013/10/21)

Synthesis and characterization of a novel prostate cancer-targeted phosphatidylinositol-3-kinase inhibitor prodrug
The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a substantial proportion of prostate tumors and is considered a key mechanism supporting progression toward an androgen-independent status, for which no effective therapy is available. Therefore, PI3K inhibitors, alone or in combination with other cytotoxic drugs, could potentially be used to treat cancer with a constitutive activated PI3K/Akt pathway. To selectively target advanced prostate tumors with a constitutive activated PI3K/Akt pathway, a prostate cancer-specific PI3K inhibitor was generated by coupling the chemically modified form of the quercetin analogue LY294002 (HO-CH2-LY294002, compound 8) with the peptide Mu-LEHSSKLQL, in which the internal sequence HSSKLQ is a substrate for the prostate-specific antigen (PSA) protease. The result is a water-soluble and latent PI3K inhibitor prodrug (compound 11), its activation being dependent on PSA cleavage. Once activated, the L-O-CH2-LY294002 (compound 10) can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with a potency comparable to that of the original LY294002 compound.
Baiz, Daniele,Hassan, Sazzad,Karpova, Yelena,Kulik, George,Pinder, Tanya A.,Welker, Mark E.,Salsbury, Freddie
p. 8038 - 8046,9
(2020/09/15)

Identification of novel matrix metalloproteinase inhibitors by screening of phenol fragments library
In the last 20 years, a great variety of synthetic, low molecular weight MMP inhibitors (MMPIs) have been synthesized and tested, although none has reached clinical utility. Exploration of novel ZBGs and development of non-hydroxamate MMPI has become a focus in current research. It's well-known that polyphenols can produce beneficial effects on human health by their antioxidant properties as well as they have the ability to block gelatinase activity. In this work we tested a series of selected phenols as MMP inhibitors. The most interesting hit (B6) shows sub-micromolar activity against MMP-2 (IC50 0.59 ± 0.05 μM, LE = 1.07) and a fairly good selectivity spectrum. A screening of selected phenols against four matrix metalloproteinases is reported. Eight phenols showed a very interesting activity and selective profile. The most interesting hit (B6) presents a sub-micromolar activity against MMP-2 (IC50 0.59±0.05μM). Copyright
Rubino, Maria Teresa,Maggi, Dariana,Laghezza, Antonio,Loiodice, Fulvio,Tortorella, Paolo
experimental part
p. 557 - 563
(2012/06/30)

Facile synthesis of salmochelin S1, S2, MGE, DGE, and TGE
Salmochelin S1, S2, MGE, DGE, and TGE were prepared through amide bond connection of an aryl C-glucosyl acyl chloride (Ar1COCl) and serine ester amines, followed by hydrogenolysis of the per-benzylated precursors. Each synthesis employed a highly diastereoselective Ni-catalyzed Negishi approach to the aryl C-glycoside subunit.
Yu, Xiaolong,Dai, Yijing,Yang, Tao,Gagné, Michel R.,Gong, Hegui
supporting information; scheme or table
p. 144 - 151
(2011/03/17)

Synthesis, crystal structures, insecticidal activities, and structure-activity relationships of novel N ′- Tert -Butyl- N ′-substituted-benzoyl- N -[di(octa)hydro]benzofuran{(2,3-dihydro)benzo[1, 3]([1,4])dioxine}carbohydrazide derivatives
Several series of novel N′-tert-butyl-N′-substituted-benzoyl-N- [di(octa)hydro]benzofuran{(2,3-dihydro)benzo[1,3]([1,4])dioxine}carbohydrazide derivatives Ia, Ib, IIa-IIg, IIIa, IIIb, and Va-Vc were designed and synthesized. Their structures were confirmed by 1H NMR spectra, HRMS, and X-ray single-crystal structures. The larvicidal activities against oriental armyworm, beet armyworm, diamond-back moth, and corn borer of these compounds were evaluated and contrasted with those of RH-2485, JS-118, and ANS-118. The larvicidal activities against oriental armyworm indicate that monosubstituent or multisubstituents and the substituting group position cannot promote increasing activities and that the cycle region in the general structure of IIa-IIg is much more sensitive to activity than that in the general structure of Ia and Ib. The space volume of the A ring in the structure of Va cannot be too large; if it is, the activity will be decreased significantly. Stomach toxicities against beet armyworm, diamond-back moth, and corn borer of compounds Ia, Ib and IIg indicate that benzoheterocyclic analogues of N-tert-butyl-N,N′- diacylhydrazines show significant selectivities to different lepidopterous pests.
Huang, Zhiqiang,Liu, Yuxiu,Li, Yongqiang,Xiong, Lixia,Cui, Zhipeng,Song, Hongjian,Liu, Hongli,Zhao, Qiqi,Wang, Qingmin
experimental part
p. 635 - 644
(2011/10/02)

Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates
The lantibiotic gallidermin was modified at lysine residues by regioselective attachment of derivatives of pyochelin, agrobactin and desferrioxamine B with the objective of having siderophore receptors of Gram-negative bacteria transport the antibiotic-iron chelator conjugate through the outer membrane. All of the conjugates retained activity against the Gram-positive indicator strain, Lactococcus lactis subsp. cremoris HP. However, testing of the conjugates against several Gram-negative strains yielded unexpected results. Bacteria treated with 100 μM of the conjugates complexed with Fe3+ grew better than bacteria grown in iron-free media but worse than bacteria grown in the same media supplemented with 10 μM FeCl 3. Although these findings indicate that the conjugates are unable to inhibit the growth of Gram-negative bacteria, they indicate penetration of the outer membrane and provide structure-activity information for design of other lantibiotic conjugates. The synthetic strategy is applicable for linking biomarkers or fluorescence probes to gallidermin for studies on its localization and mode of action. As there are many lantibiotics that operate with unknown mechanisms of action, this chemical approach provides a means to modify such peptides with biomarkers for biological investigations.
Yoganathan, Sabesan,Sit, Clarissa S.,Vederas, John C.
experimental part
p. 2133 - 2141
(2011/05/14)

Synthesis of carbon-11-labeled casimiroin analogues as new potential PET agents for imaging of quinone reductase 2 and aromatase expression in breast cancer
Carbon-11-labeled casimiroin analogues were first designed and synthesized as new potential PET agents for imaging of quinone reductase (QR) 2 and aromatase expression in breast cancer. [11C]casimiroin (6-[ 11C]methoxy-9-methyl-[1,3]dioxolo[4,5-h]quinolin-8(9H)-one, [ 11C]11) and its carbon-11-labeled analogues 5,6,8-trimethoxy-1-[ 11C]methyl-4-methylquinolin-2(1H)-one ([11C]17), 8-methoxy-1-[11C]methyl-4-methylquinolin-2(1H)-one ([ 11C]21a), 6,8-dimethoxy-1-[11C]methyl-4-methylquinolin- 2(1H)-one ([11C]21b), and 5,8-dimethoxy-1-[11C]methyl-4- methylquinolin-2(1H)-one ([11C]21c), were prepared from their corresponding precursors with [11C]methyl triflate ([ 11C]CH3OTf) under basic conditions (NaH) through either O- or N-[11C]methylation and isolated by semi-preparative HPLC method in 40-50% radiochemical yields decay corrected to end of bombardment (EOB), based on [11C]CO2, and 111-185 GBq/μmol specific activity at the end of synthesis (EOS).
Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.,Zheng, Qi-Huang
experimental part
p. 967 - 973
(2010/10/05)

SYNTHESIS OF 2-AMINO-SUBSTITUTED 4-OXO-4H-CHROMEN-8.YL-TRIFLUORO-METHANESULFONIC ACID ESTERS
A method of synthesising a compound of formula (I): wherein RN1 and RN2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocyclyl group, or C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; from a compound of formula (III): comprising the steps of: (a) removing the allyl group from the compound of formula (III) with appropriate reaction conditions to yield a compound of formula (II):; and (b) reacting the compound of formula (II) with a triflating agent to yield a compound of formula (I).
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Page/Page column 30

(2008/06/13)

Synthesis and investigation of a chiral enterobactin analogue based on a macrocyclic peptide scaffold
A chiral C3-symmetric enterobactin analogue (1) has been synthesized by attachment of three 2,3-dihydroxybenzoyl units to a chiral oxazole-containing macrocyclic peptide scaffold. Complex formation kinetics and stoichiometry with various metal ions were investigated by spectrophotometric methods. In the cases of AlIII, InIII and FeIII complexes, UV absorption and CD kinetics showed nonlinearity, which results from slow conformational changes of the octahedral complexes. Virtual binding constants were determined from UV absorption data and showed selective binding of GaIII in preference to FeIII, by two orders of magnitude. CD spectroscopy revealed highly diastereoselective binding of Al III, GaIII, InIII, FeIII and Ge IV ions at room temperature, corresponding to the helical chirality opposite to that of the analogous enterobactin complexes. Ab initio calculations confirmed the energetic stabilization of the A isomers relative to the A isomers.
Pinter, Aron,Haberhauer, Gebhard
scheme or table
p. 11061 - 11068
(2009/11/30)

Vesicles to concentrate iron in low-iron media: An attempt to mimic marine siderophores
Amphiphilic catechol-type iron chelators were studied with the aim of mimicking the properties of marine bacterial siderophores. The FeIII complexation constants and aqueous solution speciation of LS10, a sulfonated catechol unit that has a C10 lipophilic carbon chain connected by an amide linkage, were determined by spectrophotometric titration. The calculated value of pFe3+ is 18.1 at pH 7.4. Cryogenic transmission electron microscopy showed that the tris(catecholate) ferric complex formed at physiological pH initially assembles into micelles, in which the catecholate-iron units stay on the exterior of the micelle. The average diameter of these micelles was estimated to be 4.2 nm. The micelles then slowly rearrange into clusters of different sizes, which leads to the formation of unilamellar and bilamellar vesicles. The reorganization processes are comparable to those observed by Butler et al. for the marinobactin siderophores produced by marine bacteria, but in contrast to the marinobactins, vesicles of the Fe3+-LS10 complex form without an excess of iron relative to ligand concentration. The time-dependent micelle-to-vesicle transition is discussed herein.
Bednarova, Lucie,Brandel, Jeremy,Du Moulinet D'Hardemare, Amaury,Bednar, Jan,Serratrice, Guy,Pierre, Jean-Louis
experimental part
p. 3680 - 3686
(2009/04/11)

Synthesis and biological activity of analogues of vanchrobactin, a siderophore from Vibrio anguillarum serotype O2
Several analogues of vanchrobactin, a catechol siderophore isolated from the bacterial fish pathogen Vibrio anguillarum serotype O2 strain RV22, have been synthesized. The biological evaluation of these novel compounds showed that most of them are active as siderophores, as determined by growth promotion assays using the producer strain, as well as V. anguillarum serotype O1, Salmonella enterica, and Erwinia chrysanthemi. These compounds also gave a positive chrome azurol-S (CAS) test. On the basis of these results, we were able to deduce some structure-activity relationships. Furthermore, we found an analogue with siderophore activity that has appropriate functionality (an amino group) for use as an antibiotic vector to be employed in a "Trojan horse strategy". This journal is The Royal Society of Chemistry.
Soengas, Raquel G.,Larrosa, Marta,Balado, Miguel,Rodriguez, Jaime,Lemos, Manuel L.,Jimenez, Carlos
scheme or table
p. 1278 - 1287
(2008/10/09)

Convergent total syntheses of fluvibactin and vibriobactin using molybdenum(vi) oxide-catalyzed dehydrative cyclization as a key step
Efficient total syntheses of fluvibactin and vibriobactin have been achieved via molybdenum(vi) oxide-catalyzed dehydrative cyclization, Sb(OEt)3-catalyzed ester-amide transformation, and WSCI and HOAt-promoted dehydrative amide formation. The Royal Society of Chemistry.
Sakakura, Akira,Umemura, Shuhei,Ishihara, Kazuaki
supporting information; experimental part
p. 3561 - 3563
(2009/02/05)

Vanchrobactin: absolute configuration and total synthesis
The stereochemistry of vanchrobactin, a siderophore produced by the bacterial fish pathogenVibrio anguillarum serotype O2, was elucidated by chiral capillary electrophoresis analysis and total synthesis as N-[N′-(2,3-dihydroxybenzoyl)-d-arginyl]-l-serine.
Soengas, Raquel G.,Anta, Cristina,Espada, Alfonso,Nieto, Rosa M.,Larrosa, Marta,Rodríguez, Jaime,Jiménez, Carlos
p. 3021 - 3024
(2008/02/06)

Ortho-substituted catechol derivatives: The effect of intramolecular hydrogen-bonding pathways on chloride anion recognition
(Chemical Equation Presented) This paper reports a series of chloride anion receptors containing two catechol head groups connected through their ortho-positions via a spacer chain. The linking group chosen to attach the spacer chain to the catechol units has a major impact on the anion-binding potential of the receptor. Linking groups that are capable of forming stable six-membered intramolecular hydrogen-bonded rings with the catechol O-H groups significantly inhibit the ability of the catechol units to hydrogen bond to chloride anions. However, where the linking groups are only capable of forming five- or seven-membered intramolecular hydrogen-bonded rings, then anion binding via hydrogen bonding through the catechol O-H groups becomes a possibility. This process is solvent dependent; the presence of competitive solvent (e.g., DMSO-d6) disrupts the intramolecular hydrogen-bonding pattern and enhances anion binding relative to simple unfunctionalized catechol. The most effective receptor is that in which the hydrogen-bonding linker (-CH 2CONH-) is most distant from the catechol units and can only form a seven-membered intramolecular hydrogen-bonded ring. In this case, the receptor, which contains two catechol units, is a more effective chloride anion binder than simple unfunctionalized catechol, demonstrating that the two head groups, in combination with the N-H groups in the linker, act cooperatively and enhance the degree of anion binding. In summary, this paper provides insight into the hydrogen-bonding patterns in orthofunctionalized catechols and the impact these have on the potential of the catechol O-H groups to hydrogen bond to a chloride anion.
Winstanley, Keith J.,Smith, David K.
p. 2803 - 2815
(2008/02/01)

Nanomolar inhibition of the enterobactin biosynthesis enzyme, EntE: Synthesis, substituent effects, and additivity
2,3-Dihydroxybenzohydroxamoyl adenylate (I) was prepared as a potential product analog inhibitor of EntE (EC# 2.7.7.58), a 2,3-dihydroxybenzoate AMP ligase from Escherichia coli that is required for the biosynthesis of enterobactin. This compound, obtained by the aqueous reaction of imidazole-activated adenosine 5′-phosphate and 2,3-dihydroxybenzohydroxamic acid, is a competitive inhibitor with a Ki value of 4.5 × 10-9 M. Deletion of the catecholic 3-OH group of (I), in compound (II), reduced inhibitory activity by a factor of 3.5, whereas, removal of both the 3-OH and 2-OH groups, in (III), reduced inhibitory activity by a factor of ～2000. Acetohydroxamoyl adenylate (IV), in which the entire catechol moiety of (I) is replaced by a hydrogen atom, gave {less-than or slanted equal to}10% inhibition at 6 × 10-4 M, indicating a reduction in affinity by more than 105. The binding free energy of (I) is nearly equivalent to the sum of the corresponding values for adenosine 5′-phosphate and 2,3-dihydroxybenzoate.
Callahan, Brian P.,Lomino, Joseph V.,Wolfenden, Richard
p. 3802 - 3805
(2008/12/22)

Judicious application of allyl protecting groups for the synthesis of 2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate, a key precursor of DNA-dependent protein kinase inhibitors
(Chemical Equation Presented) 2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl 2,2,2-trifluoromethanesulfonate is a key intermediate for the synthesis of the DNA-dependent protein kinase (DNA-PK) inhibitor 8-dibenzothiophen-4-yl-2- morpholin-4-yl-chromen-4-one (NU7441). Two improved methods for the synthesis of this triflate have been developed: (A) in 35% overall yield, through modification of the published route, and (B) in 15% overall yield, by a new route employing a Baker-Venkataraman rearrangement to enable generation of the chromenone scaffold. Both syntheses depend on the judicious use of allyl protecting groups.
Aristegui, Sonsoles Rodriguez,El-Murr, Marine Desage,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.
p. 5927 - 5929
(2007/10/03)

1-AMINO-2-OXY-SUBSTITUTED TETRAHYDRONAPHTALENE DERIVATIVES, METHODS FOR THE PRODUCTION THEREOF, AND THEIR USE AS ANTIPHLOGISTICS
The invention relates to polysubstituted tetrahydronaphtalene derivatives of formula (I), to methods for the production thereof, and to their use as antiphlogistics. The substituents are defined in Claim 1.
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Page/Page column 76

(2010/02/11)

New COMT inhibitors for the treatment of depression and impaired cognition
The present invention relates to compounds of formula I wherein R1 is as defined in the specification and to esters thereof which are hydrolyzable under physiological conditions and to the pharmaceutically acceptable salts thereof. The compounds of the invention are inhibitors of COMT and, thus, are useful for the treatment of diseases for which COMT inhibition is beneficial. The invention further relates to the treatment, control, or prevention of diseases such as depression, schizophrenia, Parkinson's disease, and to improve cognition.
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Page/Page column 6

(2010/02/12)

Structure-based design: Synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors
The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitors are described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor 1 (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acid-derived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs' catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S 1-S2 active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a Ki value of 0.7 nM and an antiviral IC50 value of 0.3 μM. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway.
Ghosh, Arun K.,Swanson, Lisa M.,Cho, Hanna,Leshchenko, Sofiya,Hussain, Khaja Azhar,Kay, Stephanie,Walters, D. Eric,Koh, Yasuhiro,Mitsuya, Hiroaki
p. 3576 - 3585
(2007/10/03)

Hydroxy-methoxybenzoic methyl esters: Synthesis and antifeedant activity on the pine weevil, Hylobius abietis
The pine weevil Hylobius abietis (L.) (Coleoptera: Curculionidae) feeds on the bark of coniferous seedlings and is the economically most important forestry restocking pest in large parts of Europe. Substances with an antifeedant effect may offer an environmentally friendly alternative to insecticides for the protection of planted seedlings. Bioassays were performed on commercial and synthetic methyl hydroxy-methoxybenzoates in order to determine their possible antifeedant activity. Two methyl hydroxy-methoxybenzoates were synthesized by esterification and mono-O-methylation of two dihydroxybenzoic acids. A regioselective protection-deprotection strategy was used in the synthetic pathway of the other non-commercial esters, esterification and selective pivaloylation of the less-hindered hydroxyl group of other commercial dihydroxybenzoic acids gave diester intermediates, which then were O-methylated before methanolysis of the pivaloyl group which yielded the desired non-commercial methyl hydroxy-methoxybenzoates. The five synthesized methyl hydroxy-methoxybenzoic esters were complemented with commercial samples of the five other isomers of methyl hydroxy-methoxybenzoate and spectrometric data were collected for the complete set of isomers. All ten isomers were tested for their antifeedant effect on the pine weevil. The effect varied considerably among the hydroxy-methoxybenzoic esters. Methyl 2-hydroxy-3-methoxybenzoate showed the highest effect and may thus be a candidate for practical use in pine weevil pest management.
Legrand, Sacha,Nordlander, G?ran,Nordenhem, Henrik,Borg-Karlson, Anna-Karin,Unelius, C. Rikard
p. 829 - 835
(2007/10/03)

Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src
Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.
Plé, Patrick A.,Green, Tim P.,Hennequin, Laurent F.,Curwen, Jon,Fennell, Michael,Allen, Jack,Lambert-Van Der Brempt, Christine,Costello, Gerard
p. 871 - 887
(2007/10/03)

QUINAZOLINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
The invention concerns quinazoline derivatives of Formula (I) wherein each of Z, m, R1, n, R3,Z2 and R14 have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive or anti-proliferative agent in the containment and/or treatment of solid tumour disease.
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Page/Page column 65

(2008/06/13)

SUBSTITUTED 3-CYANOQUINOLINES AS MEK INHIBITORS
The invention concerns quinoline derivatives of Formula (I) wherein each of Z1, m, R1, n, R3, Z2 and R14 have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive or anti-proliferative agent in the containment and/or treatment of solid tumour disease.
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Page 68

(2010/11/30)

Quinazoline derivatives
The invention concerns quinazoline derivatives of Formula (I) wherein each of m, R1, n, R2 and R3 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
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(2008/06/13)

Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
Compounds that are dual aP2/k-FABP inhibitors are provided having the formula wherein A, B, X, Y, R1, R2 and R3 are as described herein. A method is also provided for treating diabetes and related diseases, especially Type II diabetes, employing dual aP2/k-FABP inhibitors alone or in combination with at least one other antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin.
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Page 59

(2010/02/06)

AMINOETHANOL DERIVATIVES
The present invention provides a pharmaceutical agent having cholesteryl ester transfer protein inhibitory action and useful as a blood lipid lowering agent and the like. The present invention relates to a compound represented by the formula wherein Ar1 is an aromatic ring group optionally having substituents, Ar2 is an aromatic ring group having substituents, OR'' is an optionally protected hydroxyl group, R is an acyl group, R' is a hydrogen atom or a hydrocarbon group optionally having substituents, or a salt thereof, and a pharmaceutical composition containing a compound of the formula (I) or a salt thereof or a prodrug thereof.
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Page/Page column 86

(2010/11/30)

Synthetic studies of the phosphatidylinositol 3-kinase inhibitor LY294002 and related analogues
Synthetic methodologies have been developed for the direct and high-yielding preparation of the phosphatidyl-inositol 3-kinase inhibitor LY294002. These methods are readily amenable to the efficient generation of analogues, which will facilitate a detailed investigation of this important family of enzymes.
Abbott, Belinda,Thompson, Philip
p. 1099 - 1106
(2007/10/03)

Antidiabetic agents
A compound of the formula wherein n, m, Z, R1, R5, R8, R9, R10 and R11 are as defined above, useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia.
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(2008/06/13)

Therapeutic morpholino-substituted compounds
Morpholino-substituted pyridopyrimidine, quinolone, and benzopyranone derivatives inhibit phosphoinositide (PI) 3-kinase, an enzyme that regulates platelet-adhesion processes. As a consequence, the compounds in question have anti-thrombotic activity, as well as other pharmaceutical properties. The compounds claimed are represented by formula (I), (II) and (III). PI 3-kinase generates 3-phosphorylated PI second messengers which stimulate platelet adhesion under blood-flow conditions. Because platelet adhesion is a necessary step in the formation of a thrombus, inhibition by these compounds of PI 3-kinase under such conditions inhibits or prevents thrombus formation. The compounds are useful in treating PI 3-kinase-dependent conditions including cardiovascular diseases such as coronary artery occlusion, stroke, acute coronary syndrome, acute myocardial infarction, vascular restenosis, atherosclerosis, and unstable angina; respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD), and bronchitis; inflammatory disorders; neoplasms including cancers such as glioma, prostate cancer, small cell lung cancer, and breast cancer, and diseases linked to disordered white blood cell function, such as autoimmune and inflammatory diseases.
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(2008/06/13)

ALKYLOXYAMINO SUBSTITUTED FLUORENONES AND THEIR USE AS PROTEIN KINASE C INHIBITORS
The present invention describes certain alkyloxyamino-substituted fluorenones which inhibit protein kinase C, as well as pharmaceutical compositions including these compounds and methods of using these compounds to control protein kinase C activity in mammals, including humans. More specifically, the present compounds are useful for the treatment of neoplastic disease states, disorders associated with abnormal blood flow (including hypertension, ischemia, atherosclerosis, coagulation disorders), and inflammatory diseases (including immune disorders, asthma, lung fibrosis, and psoriasis).
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(2008/06/13)

Tricyclic compounds, their production and use
A compound of the formula: wherein R1 is H or a substituent; m is 1-3; Ar is an aromatic group which may be substituted; X is a bond or a divalent straight-chain group having 1-6 atoms which may be substituted; Y is —S—, —O—, or —N(R2— (R2 is H or a substituent group), Z is —N= or —C(R3)= (R3 is H or a hydrocarbon group), ring A is a benzene ring; ring B is a 5- to 7-membered ring which may be substituted, or a salt thereof is useful for eliciting a prostaglandin I2 receptor agonistic effect.
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(2008/06/13)

Dimerization of o-hydroxycyclohexadienones related to calicheamicinone: S(N)2 displacement of the 12α-hydroxyl group
Deprotection of the readily available bicyclo[7,3,1]enediyne alcohol 14 resulted in dimerization to give 18. Replacement of the 12α-hydroxyl group with a p-methoxyanilino group proceeded with overall retention to give 23 which also produced a dimer on attempted deprotection.
Churcher, Ian,Hallett, David,Magnus, Philip
p. 1597 - 1606
(2007/10/03)