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Structure-based design of cathepsin K inhibitors containing a benzyloxy- substituted benzoyl peptidomimetic
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid- based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
Thompson, Scott K.,Smith, Ward W.,Zhao, Baoguang,Halbert, Stacie M.,Tomaszek, Thaddeus A.,Tew, David G.,Levy, Mark A.,Janson, Cheryl A.,D'Alessio, Karla J.,McQueney, Michael S.,Kurdyla, Jeff,Jones, Christopher S.,Desjarlais, Renee L.,Abdel-Meguid, Sherin S.,Veber, Daniel F.
p. 3923 - 3927
(1998)
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Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
Aylott, Helen E.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Hayhow, Thomas G.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alexander,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Seal, Jonathan T.,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
p. 3249 - 3281
(2021/04/06)

Synthesis and evaluation of new sesamol-based phenolic acid derivatives with hypolipidemic, antioxidant, and hepatoprotective effects
The objective of this study is to synthesize a series of sesamol-based phenolic acid derivatives, which were designed by combination principle. The hypolipidemic activity of all these compounds was preliminarily screened by acute hyperlipidemic mice model induced by Triton WR 1339, in which compound T6 exhibited more significant reducing plasma TG and TC than fenofibrate. Compound T6 was also found to obviously decrease TG and TC both in the plasma and hepatic tissue of high-fat-diet-induced hyperlipidemic mice. Moreover, T6 showed hepatoprotective effects, which remarkable amelioration in characteristic liver enzymes was examined and the histopathological observation displayed that compound T6 inhibited lipids accumulation in the hepatic. The levels of PPAR-α receptor related to lipids metabolism in hepatic tissue were upregulated after T6 treatment. Other potent effects of T6 such as antioxidant and anti-inflammatory activity were also observed. On the bases of these findings, compound T6 may serve as an effective hypolipidemic and hepatoprotective agent. [Figure not available: see fulltext.]
Xie, Yundong,Liu, Jiping,Shi, Yongheng,Bin Wang,Wang, Xiaoping,Wang, Wei,Sun, Meng,Xu, Xinya,He, Shipeng
p. 1688 - 1702
(2021/07/26)

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease
A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.
Bai, Renren,Gu, Jinping,Guo, Jianan,Jiang, Xiaoying,Xie, Yuanyuan,Zhang, Changjun,Zhou, Tao
p. 2045 - 2054
(2021/10/08)

Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels
Reported herein is a series of pore-containing polymeric nanotubes based on a hydrogen-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of about a 6.5 ? diameter, mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membranes. The reported polymer channel, having an average molecular weight of 18.2 kDa and 3.6 nm in helical height, exhibits the highest anion-transport activities for iodide (EC50=0.042 μm or 0.028 mol % relative to lipid), whcih is transported 10 times more efficiently than chlorides (EC50=0.47 μm). Notably, even in cholesterol-rich environment, iodide transport activity remains high with an EC50 of 0.37 μm. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.
Aksimentiev, Aleksei,Chen, Feng,Joshi, Himanshu,Roy, Arundhati,Shen, Jie,Ye, Ruijuan,Zeng, Huaqiang
p. 4806 - 4813
(2020/02/11)

Formamide pyridone iron chelating agent derivative with potential multi-target anti-AD activity as well as preparation method and application thereof
The invention provides a formamide pyridone iron chelating agent derivative shown as a formula (I) or a formula (II) which is described in the specification and a preparation method and application thereof. The formamide pyridone iron chelating agent derivative shown in the formula (I) or the formula (II) and the pharmaceutically acceptable salt thereof have the effects of inhibiting monoamine oxidase, chelating metal iron ions, resisting A beta and resisting oxidation activity. The derivative can be used for preparing medicines for resisting Alzheimer's disease, Parkinson's disease or other diseases treated by inhibiting monoamine oxidase, chelating metal iron ions, resisting A beta and resisting oxidation.
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Paragraph 0096-0097; 0100; 0240-0241; 0244

(2020/12/10)

Studies towards hypoxia-activated prodrugs of PARP inhibitors
Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.
Dickson, Benjamin D.,Wong, Way Wua,Wilson, William R.,Hay, Michael P.
(2019/05/02)

Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
Li, Yali,Huang, Taomin,Lou, Bin,Ye, Deyong,Qi, Xiangyu,Li, Xiaoxia,Hu, Shuang,Ding, Tingbo,Chen, Yan,Cao, Yang,Mo, Mingguang,Dong, Jibin,Wei, Min,Chu, Yong,Li, Huiti,Jiang, Xian-Cheng,Cheng, Nengneng,Zhou, Lu
p. 864 - 882
(2019/01/04)

Metal-free Synthesis of Spiro-2,2′-benzo[b]furan-3,3′-ones via PhI(OAc)2-Mediated Cascade Spirocyclization
Treating the benzyl protected 3-hydroxy-1,3-bis(2-hydroxyphenyl)prop-2-en-1-ones solely with PhI(OAc)2 (PIDA) in DCE at room temperature readily furnished the seldom studied spiro-2,2′-benzo[b]furan-3,3′-ones in satisfactory to excellent yields. The hypervalent iodine reagent enables the metal-free cascade spirocyclization resulting in the dual oxidative C?O bond formation. (Figure presented.).
Xing, Qingyu,Liang, Huiyuan,Bao, Mingmai,Li, Xuemin,Zhang, Jingran,Bi, Tianhao,Zhang, Yilin,Xu, Jun,Du, Yunfei,Zhao, Kang
p. 4669 - 4673
(2019/09/17)

How Many O-Donor Groups in Enterobactin Does It Take to Bind a Metal Cation?
The E. coli siderophore enterobactin, the strongest FeIII chelator known to date, forms hexacoordinate complexes with SiIV, GeIV, and TiIV. Synthetic protocols have been developed to prepare non-symmetric entero
Baramov, Todor,Schmid, Bianca,Ryu, Ho,Jeong, Jinhoon,Keijzer, Karlijn,von Eckardstein, Leonard,Baik, Mu-Hyun,Süssmuth, Roderich D.
supporting information
p. 6955 - 6962
(2019/04/17)

GLUCOSAMINE DERIVATIVES AND PHARMACEUTICAL USES THEREOF
There are provided compounds of Formula (A) and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, used for the prevention or treatment in a mammal of joint and bone disorders such as arthritis and osteoporosis.
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Paragraph 0189

(2019/07/03)

Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition
Mycobacterium tuberculosis produces dideoxymycobactin-838 (DDM-838), a lipopeptide that potently activates T cells upon binding to the MHC-like antigen-presenting molecule CD1a. M. tuberculosis produces DDM-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. We describe a high-yielding solution-phase synthesis of DDM-838 that features a Mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation conditions that prevent double-bond isomerization of the Z-C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM-838. Isomers of DDM-838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a-restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM-838 isomers, highlighting the exquisite sensitivity of lipopeptide-reactive T cells for the natural DDM stereochemistry.
Cheng, Janice M. H.,Liu, Ligong,Pellicci, Daniel G.,Reddiex, Scott J. J.,Cotton, Rachel N.,Cheng, Tan-Yun,Young, David C.,Van Rhijn, Ildiko,Moody, D. Branch,Rossjohn, Jamie,Fairlie, David P.,Godfrey, Dale I.,Williams, Spencer J.
p. 1694 - 1701
(2017/02/10)

2-ALKYLOXY BENZENE FORMYL ARYLAMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
The present invention relates to 2-alkoxy benzene formyl arylamine compounds as scheme I , in which the R, G, X, Y, Z are consistent with the detailed description in the patent claim. The compounds can act as sphingomyelin synthase (SMS) inhibitors to treat diseases caused by abnormal increasing of sphingomyelin(SM). This invention also includes compounds as scheme I , their pharmaceutically acceptable salts, pharmaceutical compositions as the active ingredients, and their application in drugs which can prevent and cure diseases caused by SM level abnormal increase. These diseases include atherosclerosis, fatty liver, obesity, type II diabetes, and other metabolic syndromes.
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(2017/08/29)

LANTHANIDE CLUSTERS AND METHODS OF USE THEREOF
The present invention is directed to multinuclear lanthanides chiral clusters, based on phenyl-oxazoline-amide (POxA) ligands, and to methods of use thereof. The chiral clusters of this invention are highly fluorescent with high stability.
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(2016/01/30)

Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments
A series of monomeric and dimeric FeIII complexes bearing benzoic hydroxamates as O,O-chelates has been prepared and characterized by elemental analysis, IR spectroscopy, UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry, EPR spectroscopy and for some examples by X-ray diffraction analysis. The stability of the synthesized complexes in pure water and seawater was monitored over 24 h by means of UV-Vis spectrometry. The ability to release iron from the synthesized model complexes has been investigated with algae growth experiments.
Orlowska, Ewelina,Roller, Alexander,Wiesinger, Hubert,Pignitter, Marc,Jirsa, Franz,Krachler, Regina,Kandioller, Wolfgang,Keppler, Bernhard K.
p. 40238 - 40249
(2016/05/24)

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.
Dalton, Neal,Gordon, Christopher P.,Boyle, Timothy P.,Vandegraaf, Nicholas,Deadman, John,Rhodes, David I.,Coates, Jonathan A.,Pyne, Stephen G.,Keller, Paul A.,Bremner, John B.
p. 6010 - 6023
(2016/07/06)

High diastereoselectivity in the yang photocyclization via remote hydrogen abstraction reaction
1-Benzoyl-1-(o-alkoxyphenyl)cyclopropanes undergo Yang photocyclization to form dihydrobenzopyranols in a stereospecific manner. The cyclopropyl group at alpha position to carbonyls gives not only a bias in the most stable geometries of the starting ketones but also conformational restriction on geometries of biradical intermediates. More importantly, intramolecular hydrogen bonds seem to give an additional effect on conformational control of the biradical reactivity.
Jang, Mi,Park, Bong Ser
p. 1509 - 1514
(2016/10/09)

TETRAZOLINONE COMPOUND AND USE THEREOF
A tetrazolinone compound represented by formula (1): wherein R1 represents a C1-C6 alkyl group; R2, R3, and R4 are the same or different and represent a hydrogen atom; R5 represents a C1-C3 alkyl grou
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Paragraph 0414

(2016/09/26)

Design, synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents
A series of novel salicylic acid derivatives containing metronidazole as Staphylococcus aureus Tyrosyl-tRNA synthetase (TyrRS) inhibitors have been synthesized and evaluated their biology activities as potential antibacterial agents. Among these compounds
Guo, Zhi-Hua,Yin, Yong,Wang, Cong,Wang, Peng-Fei,Zhang, Xing-Tao,Wang, Zhong-Chang,Zhu, Hai-Liang
p. 6148 - 6156
(2015/09/15)

Oxidative cyclization of alkenoic acids promoted by AgOAc
Alkenoic acids derived from salicylic acid and analogues undergo an unexpected oxidative cyclization process triggered by AgOAc leading to 4H-benzo[d][1,3]dioxin-4-ones. The process is affected by the substitution on the aryl and the allyl units.
Carrillo-Arcos, Ulises A.,Rojas-Ocampo, Jonathan,Porcel, Susana
supporting information
p. 479 - 483
(2016/01/09)

Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors
A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.
Deberardinis, Albert M.,Madden, Daniel J.,Banerjee, Upasana,Sail, Vibhavari,Raccuia, Daniel S.,De Carlo, Daniel,Lemieux, Steven M.,Meares, Adam,Hadden, M. Kyle
p. 3724 - 3736
(2014/05/20)

COMPOUNDS AND METHODS FOR USE IN TREATING NEOPLASIA AND CANCER
The present invention relates to a novel method for the treatment of neoplasia, including cancer and other diseases and conditions in humans and mammals. More particularly, in preferred aspects, the present invention provides a method for the use of novel compounds for the treatment of neoplasia, hyperproliferative cell growth including psoriasis, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others.
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Page/Page column 63

(2013/03/26)

Highly selective binding of nitric oxide by CoIII and Fe III complexes
In order to construct compounds with highly selective binding activity for NO, two CoIII and two FeIII complexes with square-planar N2O2-type donor sets, N-[2-(2-hydroxybenzylamino)ethyl]-2- hydroxybenzamide (H3L1) and 1,2-bis(2-hydroxybenzoylamino)ethane (H4L2), [CoIII(L1)] (1), Na[CoIII(L2)] (2), [FeIII(L1)] (3), and (PPh4)[FeIII(L2)] (4), were designed and synthesized. These compounds were characterized by electronic absorption, FT-IR, 1H-NMR spectroscopies, ESI-mass spectrometry, and elemental analyses. The redox potentials of the CoIII and Fe III complexes with L1, 1 and 3, have quasi-reversible waves at -0.51 and -0.49 V, respectively, and those with L2, 2 and 4, afforded reversible and irreversible waves at -0.96 and -1.04 V, respectively. Interestingly, all complexes quickly react with NO under an Ar atmosphere to form nitrosyl complexes, as monitored by UV-vis spectroscopy. The formation of nitrosyl complexes was confirmed by the appearance of the N-O stretching vibration at about 1650 cm-1; 1649 for 1, 1651 for 2, 1648 for 3, and 1650 cm -1 for 4. The reactivity of each of these complexes with other small molecules such as NO2-, NO3-, CO, and O2 was also studied. None of the complexes react with CO and O2. CoIII complexes 1 and 2 react with NO2 -, while FeIII complexes, 3 and 4, do not react with small amounts of NO2-. Complex 3 reacts with NO 2- at concentrations above 100 equiv. of NO 2-. We succeeded in preparing complexes with highly selective reactivity for NO. The Royal Society of Chemistry 2013.
Zhang, Zizheng,Suwabe, Tatsuya,Ishikawa, Mai,Funahashi, Yasuhiro,Inomata, Tomohiko,Ozawa, Tomohiro,Masuda, Hideki
p. 4470 - 4478
(2013/04/24)

SYNTHESIS AND ANTICANCER ACTIVITY OF ARYL AND HETEROARYL-QUINOLIN DERIVATIVES
A compound of Formula I is disclosed as follows: or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof, wherein R is hydrogen, P(═O)(OH)2, P(═O)(O(C1-C18)alkylene(C6-C20)aryl)2, P(═O)(OH)(OM), P(═O)(OM)2, P═O(O2M), S(═O)(OH)2, S(═O)(O(C1-C18)alkylene(C6-C20)aryl)2, S(═O)(OH)(OM), S(═O)(OM)2; M is a monovalent or divalent metal ion, or alkylammonium ion; W is (C6-C20)aryl, (C6-C20)heteroaryl, (C1-C18)alkyl(C6-C20)aryl, (C1-C18)alkyl(C6-C20)heteroaryl, hydroxy(C6-C20)aryl, hydroxy(C6-C20)heteroaryl, (C1-C18)alkoxy(C6-C20)aryl, (C1-C18)alkoxy(C6-C20)heteroaryl, (C1-C18)alkylenedioxy(C6-C20)aryl, (C1-C18)alkylenedioxy(C6-C20)heteroaryl, halo(C6-C20)aryl, halo(C6-C20)heteroaryl, (C1-C18)alkylamino(C6-C20)aryl, (C1-C18)alkylamino(C6-C20)heteroaryl, (C1-C18)cycloalkylamino(C6-C20)aryl, or (C1-C18)cycloalkylamino(C6-C20)heteroaryl, and their OR8 substutes; R5 is (C1-C18alkoxy, hydrogen, hydroxyl, O—(C1-C18)alkyl(C6-C20)aryl, halo or OR8, or R5 and R6 are (C1-C18)dioxy provided that R7 is hydrogen; R6 is hydroxyl, O—(C1-C18)alkyl(C6-C20)aryl, halo or ORR, (C1-C18)alkoxy, (C1-C18)alkylamino, or (C1-C18)cycloalkylamino, or R6 and R7 are (C1-C18)dioxy provided that R5 is hydrogen; R7 is hydrogen, halo or OR8, hydroxyl, or O—(C1-C18)alkyl(C6-C20)aryl; and R8 is P(═O)(OH)2, P(═O)(O(C1-C18)alkyl(C6-C20)aryl)2, P(═O)(OH)(OM), or P(═O)(OM)2, P═O(O2M).
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(2012/02/01)

Amide-modified prenylcysteine based Icmt inhibitors: Structure-activity relationships, kinetic analysis and cellular characterization
Human protein isoprenylcysteine carboxyl methyltransferase (hIcmt) is the enzyme responsible for the α-carboxyl methylation of the C-terminal isoprenylated cysteine of CaaX proteins, including Ras proteins. This specific posttranslational methylation event has been shown to be important for cellular transformation by oncogenic Ras isoforms. This finding led to interest in hIcmt inhibitors as potential anti-cancer agents. Previous analog studies based on N-acetyl-S-farnesylcysteine identified two prenylcysteine-based low micromolar inhibitors (1a and 1b) of hIcmt, each bearing a phenoxyphenyl amide modification. In this study, a focused library of analogs of 1a and 1b was synthesized and screened versus hIcmt, delineating structural features important for inhibition. Kinetic characterization of the most potent analogs 1a and 1b established that both inhibitors exhibited mixed-mode inhibition and that the competitive component predominated. Using the Cheng-Prusoff method, the K i values were determined from the IC50 values. Analog 1a has a KIC of 1.4 ± 0.2 μM and a KIU of 4.8 ± 0.5 μM while 1b has a KIC of 0.5 ± 0.07 μM and a KIU of 1.9 ± 0.2 μM. Cellular evaluation of 1b revealed that it alters the subcellular localization of GFP-KRas, and also inhibits both Ras activation and Erk phosphorylation in Jurkat cells.
Majmudar, Jaimeen D.,Hodges-Loaiza, Heather B.,Hahne, Kalub,Donelson, James L.,Song, Jiao,Shrestha, Liza,Harrison, Marietta L.,Hrycyna, Christine A.,Gibbs, Richard A.
p. 283 - 295
(2012/02/17)

Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer
In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.
Yuan, Lei,Li, Yanchun,Zou, Chunyang,Wang, Chao,Gao, Jian,Miao, Caixia,Ma, Enlong,Sun, Tiemin
scheme or table
p. 2216 - 2220
(2012/04/18)

Novel inhibitors of basal glucose transport as potential anticancer agents
Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated.
Zhang, Weihe,Liu, Yi,Chen, Xiaozhuo,Bergmeier, Stephen C.
scheme or table
p. 2191 - 2194
(2010/06/15)

Novel 4- and 7-sulfonylated 2-substituted benzoxazoles
The efficient synthesis of sulfonylated benzoxazoles at positions C 4 or C7 is reported. The condensation reactions involve original anilide acetal reagents which, upon acid catalysis, allow an easy cyclization reaction with the sulfonylated o-aminophenol partners. This method circumvents the classical use of orthoesters which drawback is the limited access to aromatic reagents. Georg Thieme Verlag Stuttgart.
Bruyneel, Frédéric,Marchand-Brynaert, Jacqueline
supporting information; experimental part
p. 1974 - 1978
(2010/10/03)

CYCLIC TRIAZO AND DIAZO SODIUM CHANNEL BLOCKERS
Compounds of general structure in which X and Y are each N or C with at least one of X and Y being N; Z is a single bond or an optionally substituted linking group R1 is hydrogen or a substituent group; R2 is amino or a substituent group; N* is amino when RI is hydrogen or =NH when R1 is a substituent group; or N* is a group NRaRb where Ra and Rb are independently H or an alkyl group; or N* is an optionally substituted piperazinyl ring; and A is an optionally substituted heterocyclic or carbocyclic ring system which may be linked to the triazo/diazo ring through R2 to form a fused multicyclic ring; are indicated as suitable for treatment of disorders in mammals that are susceptible to sodium channel blockers and antifolates, and particularly disorders such epilepsy, multiple sclerosis, glaucoma and uevitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia and trigeminal autonomic cephalalgias; for treatment of mammalian cancers; and for treatment of malaria.
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Page/Page column 34

(2009/08/16)

An efficient chemoselective etherification of phenols in polyfunctional aromatic compounds
A simple and efficient chemoselective alkylation of phenols in polyfunctional aromatic compounds with different alkyl halides in the presence of K2CO3/TBAB is reported. The method is successful with various hydroxy aromatic acids or oximes possessing other functional groups.
Pandey, Jyoti,Mishra, Mridul,Bisht, Surendra Singh,Sharma, Anindra,Tripathi, Rama P.
p. 695 - 698
(2008/09/17)

Discovery of a "true" aspirin prodrug
Aspirin prodrugs formed by derivatization at the benzoic acid group are very difficult to obtain because the promoiety accelerates the rate of hydrolysis by plasma esterases at the neighboring acetyl group, generating salicylic acid derivatives. By tracing the hydrolysis pattern of the aspirin prodrug isosorbide-2,5-diaspirinate (ISDA) in human plasma solution, we were able to identify a metabolite, isosorbide-2-aspirinate-5-salicylate, that undergoes almost complete conversion to aspirin by human plasma butyrylcholinesterase, making it the most successful aspirin prodrug discovered to date.
Moriarty, Louise M.,Lally, Maeve N.,Carolan, Ciaran G.,Jones, Michael,Clancy, John M.,Gilmer, John F.
scheme or table
p. 7991 - 7999
(2009/12/07)

Synthesis of brasilibactin A and confirmation of absolute configuration of β-hydroxy acid fragment
A synthesis of brasilibactin A, a cytotoxic siderophore from the actinomycete of Nocardia brasiliensis, and three unnatural diastereomers of the natural product is described. Four possible diastereomers of the β-hydroxy acid fragment were prepared via asy
Ying, Yongcheng,Hong, Jiyong
p. 8104 - 8107
(2008/03/13)

METHOD OF PREPARING DENDRITIC DRUGS
Synthetic design of drug-incorporated novel dendrimer structures for quantitatively controlled drug delivery. The dendritic drugs have better control and thus a quantitative drug release can be obtained. There are no prior art dendritic drugs that control release both sequentially and quantitatively like the dendritic drugs disclosed herein. The dendritic drugs are formed by incorporating multiple same type drug units or more than two different drug types into a dendritic cascade structure to form a dendrimer drug.
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(2010/11/28)

Clean and selective oxidation of aromatic alcohols using silica-supported Jones' reagent in a pressure-driven flow reactor
By exploiting the high surface to volume ratio obtained within continuous flow reactors, we are able to oxidise selectively an array of primary alcohols to either the aldehyde or carboxylic acid, depending on the flow rates employed, demonstrating a degree of reaction control unattainable in traditional stirred reactors.
Wiles, Charlotte,Watts, Paul,Haswell, Stephen J.
p. 5261 - 5264
(2007/10/03)

Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles
Four classes of UK-1 analogues were synthesized and their cytotoxicity testing against human A-549, BFTC-905, RD, MES-SA, and HeLa carcinoma cell lines was determined. The results revealed that UK-1 and four of these analogues (15-18) are potent against the cancer cell lines. In particular, compound 16 is more potent than UK-1 against A-549 and HeLa cell lines, and compounds 15, 17, and 18 selectively exhibit potent cytotoxic activity against the BFTV-905 cells (IC50 9.6 μM), A-549 cells (IC50 6.6 μM), and MES-SA cells (IC50 9.2 μM), respectively.
Huang, Shu-Ting,Hsei, I-Jen,Chen, Chinpiao
p. 6106 - 6119
(2007/10/03)

COMPOUNDS AND COMPOSITIONS FOR DELIVERING ACTIVE AGENTS
Compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provided as well.
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Page/Page column 89

(2010/02/14)

N-acylation of 5-substituted indoles with carboxylic acids via DCC coupling
A method for the N-acylation of 5-substituted indoles with carboxylic acids using DCC and DMAP is presented. High yields were obtained when an electron-withdrawing group was present at C-5, however the method was less effective with a C-5 electron-donating group.
Bremner, John B.,Samosorn, Siritron,Ambrus, Joseph I.
p. 2653 - 2658
(2007/10/03)

Modulators of protein tyrosine phosphatases (PTPases)
The present invention provides novel thienopyridines, novel compositions, methods of their use, and methods of their manufacture, where such compounds of Formula 1 are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPase's) including PTP1B, T cell PTP (TC-PTP), wherein X, R1, R2, R3, and R4 are defined more fully in the description. The compounds are useful in the treatment of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance, obesity, and other diseases.
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(2008/06/13)

Antimycobacterial agents
Compounds represented by the formula [1] R1is H or a substituent; R2and R3are C1-C3alkyl; R4is siderophore group e.g. CH3—(CH2)n—C(O)—N(OH)—(CH2)m— with n=10-22, m=2-6; X is O, S, or NH; X1is O or NH; Y is H or alkyl; Z is H or substituted amino, e.g., t-BocNH or CbzNH, and r is 2-4; are useful in the method provided for treating tuberculosis. [1] is prepared by coupling [7], wherein HX1is HO— or H2N—, ?with [4] obtained as the free acid after saponification of the methyl ester.
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(2008/06/13)

Total synthesis of a mycobactin S, a siderophore and growth promoter of Mycobacterium Smegmatis, and determination of its growth inhibitory activity against Mycobacterium tuberculosis
A general total synthesis of mycobactins, represented by a mycobactin S, was achieved by a convergent approach. Two hydroxamic acid residues, 28 and 40b, were prepared from commercially available N(α)-Cbz-L-lysine via dimethyldioxirane oxidations. Cycliza
Hu, Jingdan,Miller, Marvin J.
p. 3462 - 3468
(2007/10/03)

Synthesis and molecular structure of new O/N/O ligands: bis-phenol-pyridine and bis-phenol-pyrazole
Two new heterocyclic ligands, 2,6-bis-(2'-hydroxphenyl)pyridine 2 and 3,5-bis-(2'-hydroxyphenyl)pyrazole 4 have been prepared. The molecular structures of 2,6-bis-(2'-methoxyphenyl)pyridine 1, the tetrafluoroborate salt of 2,6-bis-(2'-hydroxyphenyl)pyridine 3 (a monohydrate) and that of compound 4 have been determined by X-Ray analysis. In 1, the phenyl rings are oriented so that the oxygen atoms of the methoxy groups are placed away from the nitrogen of the pyridine to overcome electronic repulsion. In salt 3, intramolecular hydrogen bonds are found between tile pyridinium proton and the hydroxyl atoms which are involved in strong O-H···O and O-H···F interactions. In addition, the water molecule participates in a bridging hydrogen bond network with the BF4-. The molecules in 4, are also held together by hydrogen bonds where the hydroxyl groups act as both a donor and an acceptor and are responsible for the formation of chains.
Silva, Artur M. S.,Almeida, Lucia M. P. M.,Cavaleiro, Jose A. S.,Foces-Foces, Concepcion,Llamas-Saiz, Antonio L.,Fontenas, Christophe,Jagerovic, Nadine,Elguero, Jose
p. 11645 - 11658
(2007/10/03)

Selective endothelin A receptor ligands. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives
This paper describes the discovery of a new non-peptide endothelin A (ET(A)) selective ligand, 2,4-dibenzyloxybenzoic acid 3, which inhibits the binding of [125I]ET-1 to ET(A) receptors with an IC50 of 9 μM (ET-1 = endothelin-1). Optimisation of 3 resulted in compound 52 which had an IC50 of 1 μM. One of the analogues of 3, compound 15, was examined in a functional assay and shown to antagonise ET-1-induced contraction of rat aorta. The identification of 3 was made through the application of ChemDBS-3D searching of our corporate database. The 3D query, using an aromatic ring to a carboxylic acid group separated by 10.2 ± 1.1 A, was derived from an examination of common pharmacophoric distances found in the low energy conformations of two known ET(A) antagonists, the cyclic pentapeptide BQ 123 1 and myriceron caffeoyl ester 2.
Astles,Brown,Handscombe,Harper,Harris,Lewis,Lockey,McCarthy,McLay,Porter,Roach,Smith,Walsh
p. 409 - 423
(2007/10/03)

Chemoselectivity and stereoselectivity of cyclisation of α-diazocarbonyls leading to oxygen and sulfur heterocycles catalysed by chiral rhodium copper catalysts
Good levels of enantioselectivity have been achieved in intramiolecular C-H insertion reactions of α-diazocarbonyl compounds leading to six-membered oxygen heterocycles (chromanones) through the use of chiral rhodium(II) carboxylates as catalysts.Competition between C-H insertion and sigmatropic rearrangement, the latter leading to five-membered oxygen heterocycles (furanones), was observed with precursors containing a proximal O-allyl side chain.Whereas rhodium carboxylates produced C-H insertion products predominantly, a copper catalyst produced sigmatropic rearrangement products exclusively.A precursor with S-allyl side chain exhibited cyclisation via sigmatropic rearrangement with both copper and rhodium catalyst.
Ye, Tao,Garcia, Concepcion Fernandez,McKervey, M. Anthony
p. 1373 - 1380
(2007/10/02)

Quantitative structure-activity analysis of larvicidal 1-(substituted benzoyl)-2-benzoyl-1-tert-butylhydrazines against Chilo suppressalis
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Oikawa,Nakagawa,Nishimura,Ueno,Fujita
p. 139 - 148
(2007/10/03)

Asymmetric Synthesis of Substituted Chromanones via C-H Insertion Reactions of α-Diazoketones Catalysed by Homochiral Rhodium(II) Carboxylates
High levels of regio-, stereo- and enantio-selectivity are achieved in the asymmetric synthesis of six-membered oxygen heterocycles via intramolecular C-H insertion reactions of α-diazoketones catalysed by chiral rhodium(II) carboxylates.
McKervey, M. Anthony,Ye, Tao
p. 823 - 824
(2007/10/02)

Total Synthesis of Parabactin, a Spermidine Siderophore
The stereoselective total synthesis of parabactin (1) has been efficiently carried out using substituted 1,3-thiazolidine-2-thione as a leaving group.
Nagao, Yoshimitsu,Miyasaka, Tadayo,Hagiwara, Yuichi,Fujita, Eiichi
p. 183 - 187
(2007/10/02)