- Dinaphthoporphycenes
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Figure Presented. Naphthobipyrrole is a potentially useful building block for porphyrin and porphyrin analogue synthesis. Reported here is a simple, generalizable synthetic route to α-formylated, β-substituted naphthobipyrroles and their use in the preparation of binaphthoporphycenes. The resulting binaphthoporphycenes possess a planar geometry as determined via a single-crystal X-ray diffraction analysis; they also display absorption maxima that are bathochromically shifted compared to simple porphycenes.
- Roznyatovskiy, Vladimir,Lynch, Vincent,Sessler, Jonathan L.
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Read Online
- Discovery and mechanistic study of thiazole-4-acylsulfonamide derivatives as potent and orally active ChemR23 inhibitors with a long-acting effect in cynomolgus monkeys
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Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that can secrete large amounts of type I interferon. ChemR23, a G protein-coupled receptor (GPCR) expressed on the surface of pDCs, contributes to the recruitment of pDCs to inflamed tissues through chemotaxis signaling, and is therefore considered an attractive target for the treatment of autoimmune diseases. We previously reported benzoxazole-based compounds that can inhibit ChemR23 signaling through receptor internalization. Although these compounds showed ChemR23 internalization on pDCs in cynomolgus monkeys after oral administration, further improvement of the pharmacokinetics profile was needed for a clinical candidate and we therefore attempted scaffold-hopping from the benzoxazole core structure leading to novel thiazole derivatives. In this report, the design, synthesis, and biological evaluation of new thiazole-based ChemR23 inhibitors were described. Through sequential structure–activity relationship studies regarding (i) the side chain of the N-acylsulfonamide moiety, (ii) the 5-position of the thiazole ring, and (iii) the 1,2,4-oxadiazol-5-one moiety, we have succeeded in finding a potent thiazole-based ChemR23 inhibitor, 14f (IC80 = 12 nM). In addition, the oral administration of 14f at 30 mg/kg to cynomolgus monkeys demonstrated a sustained pharmacological effect of ChemR23 internalization on pDCs until 8 h after dosing, which was considered a longer effect in comparison to previously reported 2-aminobenzoxazole-based ChemR23 inhibitors. This report also shows the synthesis and evaluation of fluorescein-labeled compound 45c for a mechanistic study, and we could confirm the direct binding of our thiazole derivative to ChemR23. We believe that our research on small molecule ChemR23 inhibitors and chemical probe will contribute to the elucidation and analysis of the functions of ChemR23 as well as identifying novel therapeutics for autoimmune diseases.
- Imaizumi, Takamichi,Otsubo, Shigeki,Maemoto, Michihiro,Kobayashi, Atsuko,Komai, Masato,Takada, Hidenori,Sakaida, Yumi,Otsubo, Nobumasa
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- Design, synthesis and antimalarial evaluation of novel thiazole derivatives
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As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.
- Bueno, José María,Carda, Miguel,Crespo, Benigno,Cu?at, Ana Carmen,de Cozar, Cristina,León, María Luisa,Marco, J. Alberto,Roda, Nuria,Sanz-Cervera, Juan F.
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supporting information
p. 3938 - 3944
(2016/08/01)
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- Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step
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Piperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r-3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised.
- Anderson, James C.,Kalogirou, Andreas S.,Porter, Michael J.,Tizzard, Graham J.
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p. 1737 - 1744
(2013/10/22)
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- 3-substituted indole antiproliferative angiogenesis inhibitors
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3-Substituted indole carbohydrazides having the formula are useful for inhibiting angiogenesis and cell proliferation. Also disclosed are compositions which inhibit angiogenesis and cell proliferation and methods of inhibiting angiogenesis and cancer in a mammal.
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- Amino acid derivatives inhibiting extracellular matrix metalloproteinase and TNF alpha release
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The invention concerns compounds of general formula (X) in which Y represents in particular —CONHOH, R1represents in particular a C1-C5alkyl group, AA represents an amino acid, or an amino acid sequence, and R3represents in particular a group of formula —NH—(CH2)2—SCH3. The invention also concerns the pharmaceutical compositions containing them, and the methods for obtaining them.
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Page column 36
(2010/11/29)
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- 3-substituted indole angiogenesis inhibitors
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3-Substituted indole carbohydrazides having the formula are useful for inhibiting angiogenesis. Also disclosed are angiogenesis-inhibiting compositions and methods of inhibiting angiogenesis in a mammal.
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- Synthesis and reactivity of β-phenylselanyl α-oxoesters
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β-Phenylsetanyl α-oxoesters 2 were prepared by N-phenylselanyl morpholine treatment of α-oxoesters 1, oxidized into β-unsaturated α- oxoesters 5 and subjected to the Wittig-Horner olefination. The diethyl (l- phenylselanylalkyl)maleates 6 have led, after [2,3]sigmatropic rearrangement of the corrsponding selenoxides to the diethyl 3-alkylidene-2- hydroxysuccinates 7. The 2-(1-butoxycarbonylamino)-3-alkylidenesuccinates 8 were prepared in a similar way. The decomposition of halo-adducts derived from components 6 has the synthesis of the siethyl 3-alkylidene-2- halosuccinates 9 and 10.
- Boivin, Stephane,Outurquin, Francis,Paulmier, Claude
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p. 16767 - 16782
(2007/10/03)
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- Methods for the synthesis of L-leucine selectively labelled with carbon-13 or deuterium in either diastereotopic methyl group
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A versatile approach is described for the enantioselective synthesis of isotopically labelled L-leucine involving the preparation of 4-methylpentanoic acid labelled selectively with carbon-13 or deuterium in either the pro-R or pro-S methyl group followed by a reductive amination of the ketone catalysed by leucine dehydrogenase. This strategy is applied to the total synthesis of (2S,4R)-[5,5,5-D3]-leucine using CD3I as the source of deuterium.
- Kelly,Kelly, Nicholas M.,Reid,Gordon Reid,Willis,Willis, Christine L.,Winton,Winton, Peter L.
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p. 8315 - 8318
(2007/10/02)
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- PHOSPHORUS-CONTAINING HMG-COA REDUCTASE INHIBITORS, NEW INTERMEDIATES AND METHOD
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Compounds which are useful as inhibitors of cholesterol biosynthesis and thus as hypocholesteroleumic agents are provided which have the structure STR1 wherein R is OH, or salts thereof or lower alkoxy; R. sup.x is H or alkyl;X is--CH 2--,--
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- Tungsten complex induced dehydration of 2,3-dihydroxycarboxylic acids to α-keto acids
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In the absence of added base, WOCl4 induces rapid dehydration of the title compounds to give α-keto acids. A mechanism is suggested based on a neighboring group effect.
- Yu,Schwartz
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p. 6791 - 6794
(2007/10/02)
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- Base-Promoted Rearrangement of Carbonate Esters Derived from Aldehyde Cyanohydrins: Application to the Synthesis of α-Keto Esters
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Acylation of the cyanohydrin derivative (2) of representative aldehydes with ethyl chloroformate, followed by treatment of the corresponding mixed carbonate esters (3) with lithium hexamethyldisilazide, afforded the cyanohydrin derivative (4) of α-keto esters.Cleavage of the latter (4) with 2,6-lutidine in the presence of silver nitrate led to the procurement of α-keto esters in >50percent overall yield.
- Babler, James H.,Marcuccilli, Charles J.,Oblong, John E.
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p. 1831 - 1836
(2007/10/02)
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- REACTION OF ORGANOCADMIUM REAGENTS WITH ETHYL CYANOFORMATE: PREPARATION OF α-KETO ESTERS
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Organocadmium reagents reacted with the cyano-function of ethyl cyanoformate in the presence of ZnCl2 to afford the corresponding α-keto esters.
- Akiyama, Yasunobu,Kawasaki, Tomomi,Sakamoto, Masanori
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p. 1231 - 1232
(2007/10/02)
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- REACTION OF ORGANOMETALLIC REAGENTS WITH TRIETHOXYACETONITRILE. A NEW AND SHORT SYNTHESIS OF α-KETOESTERS.
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Grignard reagents react with triethoxyacetonitrile to give esters, while organolithium reagents provide α-ketoesters in excellent yields.
- Axiotis, Georges P.
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p. 1509 - 1510
(2007/10/02)
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