- A strategic approach to [6,6]-bicyclic lactones: Application towards the CD fragment of DHβE
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We report an effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of t
- Jepsen, Tue Heesgaard,Glibstrup, Emil,Crestey, Fran?ois,Jensen, Anders A.,Kristensen, Jesper Langgaard
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Read Online
- Synthesis and structure-bactericidal activity relationships of non-ketolides: 9-Oxime clarithromycin 11,12-cyclic carbonate featured with three-to eight-atom-length spacers at 3-OH
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In general, potent non-ketolide versions of erythromycin possessed conformationally constricted two- or three-atom-length sidechains at 3-OH. Novel 14-membered non-ketolides possessing long spacers beyond three-atom length were evaluated for antibacterial
- Li, Xue-Meng,Lv, Wei,Guo, Si-Yang,Li, Ya-Xin,Fan, Bing-Zhi,Cushman, Mark,Kong, Fan-Sheng,Zhang, Jun,Liang, Jian-Hua
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Read Online
- An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase
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NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Analysis of existing inhibitor scaffolds and early structure-activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogues in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.
- Al-Khawaldeh, Islam,Al Yasiri, Mohammed J.,Aldred, Gregory G.,Basmadjian, Christine,Bordoni, Cinzia,Harnor, Suzannah J.,Heptinstall, Amy B.,Hobson, Stephen J.,Jennings, Claire E.,Khalifa, Shaimaa,Lebraud, Honorine,Martin, Mathew P.,Miller, Duncan C.,Shrives, Harry J.,de Souza, Jo?o V.,Stewart, Hannah L.,Temple, Max,Thomas, Huw D.,Totobenazara, Jane,Tucker, Julie A.,Tudhope, Susan J.,Wang, Lan Z.,Bronowska, Agnieszka K.,Cano, Céline,Endicott, Jane A.,Golding, Bernard T.,Hardcastle, Ian R.,Hickson, Ian,Wedge, Stephen R.,Willmore, Elaine,Noble, Martin E. M.,Waring, Michael J.
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Read Online
- Design and synthesis of a peptide derivative of ametantrone targeting the major groove of the d(GGCGCC)2 palindromic sequence
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In oncology, some DNA intercalating agents have been used in chemotherapy for years to eradicate cancer cells, but these drugs generally suffer from a lack of selectivity for malignant tissues and consequently induce major side-effects. We report herein the design and synthesis of an antitumor intercalating agent ametantrone complemented with two identical peptide arms including a central Lys residue in order to selectively target palindromic sequences of DNA of malignant cells. The peptide arms are linked to the ametantrone core through 1,2,3-triazole. According to our docking prediction, this compound should be double-stranded β-sheet structured, and it has been designed to interact with two guanine residues upstream from a central d(CpG)2 intercalation site on each DNA strand, owing to the H-bonds involving the Lys terminal side chain ammonium group of the peptide arms. This new ametantrone derivative has been obtained thanks to a convergent synthetic pathway, whose key steps were double nucleophilic substitution performed on the ametantrone core, followed by "double-site" 1,3-dipolar cycloaddition affording the 1,4-disubstituted triazole linker almost quantitatively. Preliminary binding assays performed by mass spectrometry proved its accuracy for DNA palindromic sequences. The cytotoxicity of this compound was evaluated on three cancer cell lines and one healthy cell line, and compared to that of mitoxantone, a dihydroxylated analog of ametantrone. Such a peptide derivative was about ten-fold less cytotoxic than mitoxantrone on these cancer cell lines, but about fifty times less cytotoxic on healthy cells. This study could open new avenues towards the design of targeted intercalating agents.
- Braud, Emmanuelle,De Franco, Michele,Demange, Luc,Ethève-Quelquejeu, Mélanie,Garbay, Christiane,Gresh, Nohad,Ongaro, Alberto,Ribaudo, Giovanni,Zagotto, Giuseppe
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p. 3624 - 3631
(2020/03/17)
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- Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and beyond
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The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from b
- Wu, Chien-Huang,Song, Jen-Shin,Kuan, Hsuan-Hao,Wu, Szu-Huei,Chou, Ming-Chen,Jan, Jiing-Jyh,Tsou, Lun K.,Ke, Yi-Yu,Chen, Chiung-Tong,Yeh, Kai-Chia,Wang, Sing-Yi,Yeh, Teng-Kuang,Tseng, Chen-Tso,Huang, Chen-Lung,Wu, Mine-Hsine,Kuo, Po-Chu,Lee, Chia-Jui,Shia, Kak-Shan
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supporting information
p. 818 - 833
(2018/02/17)
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- Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy
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The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure–activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.
- Qin, Li-Huai,Wang, Zhi-Long,Xie, Xin,Long, Ya-Qiu
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p. 3559 - 3572
(2018/05/28)
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- HETEROCYCLIC COMPOUNDS AND USE THEREOF
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Heterocyclic compounds of Formula (I) shown herein. Also disclosed are pharmaceutical compositions containing the heterocyclic compounds and methods of using the heterocyclic compounds to mobilize hematopoietic stem cells and endothelial progenitor cells into the peripheral circulation. Further provided are methods for treating tissue injury, cancer, inflammatory disease, and autoimmune disease with the heterocyclic compounds.
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Paragraph 0047; 0048
(2016/04/19)
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- AMIDS SUBSTITUTED INDAZOLE DERIVATIVEES AS PLOY (ADP-RIBOSE) POLYMERASE INHIBITORS
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The present invention relates to amide substituted indazoles and benzotriazoles which are inhibitors of the enzyme poly (ADP-ribose) polymerase (PARP), previously known as poly (ADP-ribose) synthase and poly (ADP-ribosyl) transferase. The compounds of the present invention are useful as mono-therapies in tumors with specific defects in DNA-repair pathways, as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy, for reducing cell necrosis (in stroke and myocardial infarction), regulating inflammation and tissue injury, treating retroviral infections, and protecting against the toxicity of chemotherapy.
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Page/Page column 41; 42
(2015/04/28)
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- Pathways to Functionalized Heterocycles: Propargyl Rearrangement using B(C6F5)3
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The reactions of propargyl amides, ureas, carbamates, and carbonates with B(C6F5)3 proceed via an intramolecular 5-exo-dig cyclization across the alkyne unit to yield the corresponding vinyl borate species. The generated sp2 carbocation is stabilized by the flanking heteroatoms, allowing for isolation of oxazoline intermediates. The fate of these intermediates is strongly dependent upon the propargyl-functionalized starting material, with the carbamates and carbonates undergoing a ring-opening mechanism (propargyl rearrangement) to give cyclic allylboron compounds, while prolonged heating of the urea derivatives shows evidence of oxazole formation. In a deviation away from the reactivity of carbamates stated previously, the benzyl carbamate substrate undergoes dealkylation at the benzylic position, liberating 5-methyloxazol-2-(3H)-one.
- Wilkins, Lewis C.,Wieneke, Philipp,Newman, Paul D.,Kariuki, Benson M.,Rominger, Frank,Hashmi, A. Stephen K.,Hansmann, Max M.,Melen, Rebecca L.
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p. 5298 - 5309
(2015/11/18)
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- Stem cell mobilizers targeting chemokine receptor CXCR4: Renoprotective application in acute kidney injury
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We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4+ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.
- Wu, Chien-Huang,Song, Jen-Shin,Chang, Kuei-Hua,Jan, Jiing-Jyh,Chen, Chiung-Tong,Chou, Ming-Chen,Yeh, Kai-Chia,Wong, Ying-Chieh,Tseng, Chen-Tso,Wu, Szu-Huei,Yeh, Ching-Fang,Huang, Chung-Yu,Wang, Min-Hsien,Sadani, Amit A.,Chang, Chun-Ping,Cheng, Chia-Yi,Tsou, Lun K.,Shia, Kak-Shan
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supporting information
p. 2315 - 2325
(2015/03/30)
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- Iron-catalyzed reductive cyclization of 1,6-enynes
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A precatalyst of FeCl2 and iminopyridine was activated in situ by a combination of diethylzinc and magnesium bromide etherate; it catalyzed the reductive cyclization of 1,6-enynes to give pyrrolidine and tetrahydrofuran derivatives from N-and O
- Lin, Aijun,Zhang, Zhi-Wei,Yang, Jiong
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p. 386 - 389
(2014/04/03)
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- One-point binding ligands for asymmetric gold catalysis: Phosphoramidites with a TADDOL-related but acyclic backbone
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Readily available phosphoramidites incorporating TADDOL-related diols with an acyclic backbone turned out to be excellent ligands for asymmetric gold catalysis, allowing a number of mechanistically different transformations to be performed with good to outstanding enantioselectivities. This includes [2 + 2] and [4 + 2] cycloadditions of ene-allenes, cycloisomerizations of enynes, hydroarylation reactions with formation of indolines, as well as intramolecular hydroaminations and hydroalkoxylations of allenes. Their preparative relevance is underscored by an application to an efficient synthesis of the antidepressive drug candidate (-)-GSK 1360707. The distinctive design element of the new ligands is their acyclic dimethyl ether backbone in lieu of the (isopropylidene) acetal moiety characteristic for traditional TADDOLs. Crystallographic data in combination with computational studies allow the efficiency of the gold complexes endowed with such one-point binding ligands to be rationalized.
- Teller, Henrik,Corbet, Matthieu,Mantilli, Luca,Gopakumar, Gopinadhanpillai,Goddard, Richard,Thiel, Walter,Fuerstner, Alois
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supporting information
p. 15331 - 15342
(2012/11/07)
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- Concise synthesis of the antidepressive drug candidate GSK1360707 by a highly enantioselective gold-catalyzed enyne cycloisomerization reaction
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Out of depression: Indeed, no depressing results are obtained from a gold-catalyzed enyne cycloisomerization controlled by phosphoramidite ligands with TADDOL-related but acyclic backbones (see scheme; Cbz=benzyloxycarbonyl). The "triple-reuptake inhibito
- Teller, Henrik,Fuerstner, Alois
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supporting information; experimental part
p. 7764 - 7767
(2011/08/06)
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- Synthesis of orthogonally protected angular nitrogen polyheterocycles via CpCo-catalyzed pyridine formation
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Unprecedented nitrogen polyheterocycles have been prepared by means of intramolecular Co-catalyzed [2+2+2] cycloaddition of two alkynes to one nitrile. They exhibit two nitrogen-containing rings fused in an angular fashion to one pyridine unit. Several relative positions of the nitrogen atoms have been studied, giving rise to eight different new scaffolds. In order to allow selective functionalization of the two amino groups, orthogonal protecting groups (PG1 and PG2) were introduced prior to cyclization. Eleven combinations of seven different protecting groups (Bn, COCF3, Cbz, Boc, Ts, SO2-2-py, Ns) were tested, most of them being perfectly tolerated under the cyclization conditions. Georg Thieme Verlag Stuttgart - New York.
- Miclo, Yves,Garcia, Pierre,Evanno, Yannick,George, Pascal,Sevrin, Mireille,Malacria, Max,Gandon, Vincent,Aubert, Corinne
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scheme or table
p. 2314 - 2318
(2010/11/03)
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- Development of chemical probes: Toward the mode of action of a methylene-linked di(aryl acetate) E1
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Analogues of the novel inhibitor of the PI3-K/PKB pathway, 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate (E1), have been prepared and preliminary SAR performed. This established that at least one of the chloroethyl para-substituents could be removed or modified and the ability to inhibit PKB/Akt activation retained. Synthetic methodologies were then developed to methylene-linked aryl acetates for use as molecular probes to identify the target of compound E1.
- Smith, Mark E.B.,Gunn, Richard M.,Rosivatz, Evelyn,Mak, Lok H.,Woscholski, Ruediger,Hailes, Helen C.
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experimental part
p. 4917 - 4927
(2010/09/10)
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- Synthesis of trisubstituted pyrroles from rhodium-catalyzed alkyne head-to-tail dimerization and subsequent goldcatalyzed cyclization
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Dimerization of N-protected propargylic amines in a rather rare head-to-tail mode has been achieved under mild conditions with high selectivity using rhodium catalysts. The JV-protecting group could be a sulfonyl, carbamate, or carbonyl functionality and
- Peng, Hong Mei,Zhao, Jing,Li, Xingwei
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supporting information; experimental part
p. 1371 - 1377
(2009/12/07)
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- TRICYCLIC DERIVATIVES AS INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
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The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of poly(ADP-ribose)polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusion
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Page/Page column 68
(2009/10/22)
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- Chemical aminoacylation of RNA by an intermolecular adenosine transfer reaction
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RNA aminoacylation, based on an adenosine transfer mechanism, was achieved by the intermolecular transfer of phenylalaninyl adenosine from a donor probe to an acceptor RNA. This method can be applied to a wide variety of unnatural amino acids for tRNA ami
- Liu, Mingzhe,Jinmei, Hiroshi,Abe, Hiroshi,Ito, Yoshihiro
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p. 102 - 103
(2008/09/20)
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- Natural products in parallel synthesis: Triazole libraries of nonactic acid
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The synthesis of a library of nonactic acid-derived triazoloamide derivatives and their evaluation as antimicrobial agents is described.
- Luesse, Sarah B.,Wells, Gregg,Nayek, Abhijit,Smith, Adrienne E.,Kusche, Brian R.,Bergmeier, Stephen C.,McMills, Mark C.,Priestley, Nigel D.,Wright, Dennis L.
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body text
p. 3946 - 3949
(2009/04/07)
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- 5-HT2C RECEPTOR AGONISTS AS ANORECTIC AGENTS
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This invention relates to compounds which modulate receptors of the 5-HT2 family of receptors, and particularly to compounds which modulate 5-HT2C receptors. Compounds of the invention include agonists and selective agonists for the 5-HT2C receptor. Compounds of the invention include selective agonists for the 5-HT2C receptor which exhibit significantly less or no agonist activity on the 5-HT2A receptor and/or the 5-HT2B receptor. Compounds of this invention are those of Formula I and pharmaceutically acceptable salts, esters and solvates (including hydrates) wherein variables are defined in the specification hereof.
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Page/Page column 138
(2008/06/13)
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- Cyclization reactions of N-acryloyl-2-aminobenzaldehyde derivatives: formal total synthesis of martinellic acid
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N-Alkyl acryloylamides derived from o-aminobenzaldehyde derivatives react with N-alkyl glycine derivatives to provide cis-fused pyrrole[3,2-c]quinolones in moderate yield and high diastereoselectivity. These same substrates engage in a tandem Michael-Mann
- He, Yong,Mahmud, Hossen,Moningka, Remond,Lovely, Carl J.,Dias, H.V. Rasika
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p. 8755 - 8769
(2007/10/03)
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- Methods of treatment using an EP2 selective receptor agonist
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The present invention relates to methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by metastatic bone disease using an EP2 selective receptor agonist.
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(2010/02/13)
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- Method for treating glaucoma
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Methods of using prostaglandin agonists for the reduction of intraocular pressure, and accordingly glaucoma.
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- Prostaglandin agonists and their use to treat bone disorders
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This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.
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- Prevention of loss and restoration of bone mass by certain prostaglandin agonists
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Prostaglandin agonists of formula (I), in which, for example, A is a sulphonyl or acyl group, B is N or CH, M contains a ring and K and Q are linking groups, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits useful for the treatment of bone disorders including osteoporosis. STR1
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- Osteoporosis compounds
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This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.
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- Pd/C(en)-catalyzed chemoselective hydrogenation with retention of the N-Cbz protective group and its scope and limitations
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A chemoselective method for the hydrogenation of acetylene, olefin, azide, nitro and benzyl ester functionalities with retention of the aliphatic N-Cbz group was established. The chemoselectivity was accomplished by using a combination of 5% Pd/C-ethylenediamine [5% Pd/C(en)] and THF (or 1,4-dioxane) as a solvent, and the scope and limitations of this methodology were investigated. These results reinforce the utility of N-Cbz protective groups in synthetic chemistry, especially in peptide synthesis. (C) 2000 Elsevier Science Ltd.
- Hattori, Kazuyuki,Sajiki, Hironao,Hirota, Kosaku
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p. 8433 - 8441
(2007/10/03)
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- A new approach to the synthesis of N-protected 2- and 5-substituted 3-halopyrroles
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A new and efficient method for the preparation of N-protected 5- and 2-substituted 3-bromopyrroles 15 and 16 via acid-catalyzed cyclization of the corresponding acetylenic ketones 6 and acetylenic acetals 14 has been found (Scheme 3). Using this methodolo
- Masquelin,Obrecht
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p. 276 - 284
(2007/10/02)
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