- 1-Benzyl-4-phenyl-1H-1,2,3-triazoles improve the transcriptional functions of estrogen-related receptor γ and promote the browning of white adipose
-
The estrogen-related receptor γ (ERRγ) is a potential molecular target for the development of small molecules to stimulate the adipose browning process, which may represent a novel attractive strategy to treat obesity related disorders. The receptor possesses a very small ligand binding cavity and therefore identification of small molecule ERRγ modulators is a considerable challenge. We have successfully designed and synthesized a series of 1-benzyl-4-phenyl-1H-1,2,3-triazoles and demonstrated that they improve the transcriptional functions of ERRγ, potently elevating both the mRNA levels and the protein levels of ERRγ downstream targets. One of the most promising compounds, 4-(1-(4-iso-propylbenzyl)-1H-1,2,3-triazol-4-yl)benzene-1,2-diol (2e) was further shown to directly bind with the ERRγ ligand binding domain (ERRγ-LBD) in an isothermal calorimetric (ITC) assay and to thermally stabilize ERRγ-LBD protein by increasing its melting temperature (Tm) as demonstrated by circular dichroism (CD) spectroscopy. Furthermore, 2e potently stimulates the adipocyte browning process and induces mitochondrial biogenesis both in vitro and in vivo, suggesting the considerable therapeutic potential of this compound for the treatment of obesity and related disorders.
- Xu, Shilin,Mao, Liufeng,Ding, Ping,Zhuang, Xiaoxi,Zhou, Yang,Yu, Lei,Liu, Yingxue,Nie, Tao,Xu, Tingting,Xu, Yong,Liu, Jinsong,Smaill, Jeff,Ren, Xiaomei,Wu, Donghai,Ding, Ke
-
p. 3751 - 3760
(2015/07/27)
-
- Synthesis, structure, and SAR of tetrahydropyran-based LpxC inhibitors
-
In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization.
- Murphy-Benenato, Kerry E.,Olivier, Nelson,Choy, Allison,Ross, Philip L.,Miller, Matthew D.,Thresher, Jason,Gao, Ning,Hale, Michael R.
-
p. A1213 - A1218
(2015/04/27)
-
- ASCORBATE, VITAMIN K3 AND HYDROXYTOLANS IN THE TREATMENT OF CANCER
-
The combination of compounds of the hydroxytolan family with ascorbate plus naphthoquinone (Vitamin K3; VK3), or a quinone or semiquinone analogue of VK3, kill tumor cells, inhibit tumor growth and development, and treat cancer in subjects in need thereof.
- -
-
-
- Liquid crystal dimers derived from naturally occurring chiral moieties: synthesis and characterization
-
Naturally occurring cholesterol and α-chloroalkanoyl units derived from natural α-amino acids (l-valine, l-leucine, and l-isoleucine) have been utilized to prepare three different series of nonsymmetric liquid crystal dimers. Tolane (diphenylacetylene), w
- Yelamaggad, Channabasaveshwar V.,Shanker, Govindaswamy
-
p. 3760 - 3771
(2008/09/20)
-
- Hydroxycruciforms: Amine-responsive fluorophores
-
The synthesis of three hydroxy-substituted cruciforms (XF, 1,4-bis(4′-hydroxystyryl)-2,5-bis(4″-methoxyphenylethynyl)benzene, 1,4-bis(4′-methoxystyryl)-2,5-bis(4″-hydroxyphenylethynyl)benzene, and 1,4-bis(4′-hydroxystyryl)-2,5-bis(4″-hydroxyphenylethynyl)
- McGrier, Psaras L.,Solntsev, Kyril M.,Miao, Shaobin,Tolbert, Laren M.,Miranda, Oscar R.,Rotello, Vincent M.,Bunz, Uwe H. F.
-
supporting information; experimental part
p. 4503 - 4510
(2009/05/08)
-
- Convenient syntheses of m- and p-ethynylphenols
-
m-lodophenol (4a) was found to couple with 2-methylbut-3-yn-2-ol (5) in the presence of PdCl2-CuI-Ph3P-in triethylamine to afford 3-(3-hydroxy-3-methylbut-1-ynyl)phenol(6a), which was conveniently converted into m-ethynylphenol (7a). Under the same conditions, p-iodophenol did not couple with 5. However, p-iodo-1-[(tetrahydro-2H-pyran-2-yl)oxy]benzene (4b) did react with 5 to afford 1-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[2-hydroxy-2-methyl- 4-but-3-ynyl]benzene (6b), which was similarly converted into 1-[(tetrahydro-2H-pyran-2-yl)oxy]-4-ethynylbenzene (7b) with loss of acetone. Removal of the tetrahydropyranyl protecting group from 7b furnished p-ethynylphenol (8).
- Lai, Guo-Qiao,Liu, Shi-Ling,Xu, Jin-Feng,Shen, Yong-Jia
-
p. 203 - 204
(2007/10/03)
-
- Methods for treating subjects infected with a herpes virus or neisseria gonorrheae
-
The present invention provides a method of inhibiting the formation of infectious herpes virus particles, particularly infectious herpes simplex virus (HSV) particles, in a host cell. The method involves administering an effective amount of a hydroxylated
- -
-
-
- High birefringence phenylacetylene liquid crystals with low viscosity
-
We have synthesized new high Δ n 3-ring phenylacetylene(3PA) liquid crystals which have substituent groups with core center phenyl ring and investigated the effects of substitution on physical properties. Nematic range and viscosity were improved remarkab
- Sekine, Chizu,Fujisawa, Koichi,Iwakura, Kazunori,Minai, Masayoshi
-
p. 711 - 718
(2007/10/03)
-
- A novel calamitic liquid crystalline oligomer composed of three non- identical mesogenic entities: Synthesis and characterization
-
The synthesis and evaluation of the mesomorphic properties of the first trimesogen consisting of three non-identical calamitic mesogenic entities have been described.
- Yelamaggad,Hiremath,Shankar Rao,Krishna Prasad
-
-
- Molecular design of nonchiral bent-core liquid crystals with antiferroelectric properties
-
Novel bent-core (banana-shaped) liquid crystals without Schiff-base units have been synthesized and investigated by polarized light optical microscopy, differential scanning calorimetry, X-ray scattering, and electrooptical investigations. These molecules are 4-(4- alkylbenzoyloxy)benzoates and 4-(4-alkoxybenzoyloxy)benzoates of resorcinol, 3,4'-dihydroxybiphenyl, and 4,4'-dihydroxy- 1,1':3', 1'-terphenyl. Three different mesophases were found depending on the molecular structure and the length of the terminal alkyl chains: a rectangular columnar phase, a highly ordered low-temperature mesophase, and an antiferroelectric switchable fluid smectic mesophase designated as SmCP(A). The influence of the molecular structure on the occurrence of the SmCP(A) phase was investigated. The spontaneous polarization of these molecules is quite high (P(s) = 500700 nC cm-2) and specially those molecules with long alkyl chains and short bent- core structures have low melting points and broad regions of this switchable mesophase. Furthermore, first examples of antiferroelectric switchable bent- core molecules with semifluorinated terminal chains will be described.
- Shen, Dong,Pegenau, Annegret,Diele, Siegmar,Wirth, Ina,Tschierske, Carsten
-
p. 1593 - 1601
(2007/10/03)
-
- Designing banana-shaped liquid crystals without Schiff's base units: m- Terphenyls, 2,6-diphenylpyridines and V-shaped tolane derivatives
-
This paper reports attempts to obtain (anti)ferroelectric switchable achiral banana-shaped molecules without Schiff's base units. For this purpose we have synthesized novel V-shaped molecules consisting of rigid angular central units [1,3-disubstituted be
- Shen, Dong,Diele, Siegmar,Pelzl, Gerhard,Wirth, Ina,Tschierske, Carsten
-
p. 661 - 672
(2007/10/03)
-
- New chiral tolane series with antiferroelectric properties
-
A new series of chiral tolane with aliphatic end chains ranging from heptyloxy to dodecyloxy has been synthesized and characterized. The mesomorphic properties have been analyzed by optical microscopy on pure compounds and mixtures, D.S.C, electro-optical
- Cluzeau,Nguyen,Destrade,Isaert,Barois,Babeau
-
-
- Development of a highly cardioselective ultra short-acting β-blocker, ONO-1101
-
A novel, highly cardioselective ultra short-acting β-blocker, ONO-1101, has been developed for application in the emergency treatment of tachycardia and better control of heart rate in surgery. This agent is approximately nine times more potent in β-blocking activity in vivo and eight times more cardioselective in vitro than esmolol. This β-blocking drug has a short duration of activity, enabling rapid recovery after cessation of administration if side effects occur. It can be used safely in patients suffering from acute heart disease and represents a major therapeutic advance in the treatment of heart disease.
- Iguchi,Iwamura,Nishizaki,Hayashi,Senokuchi,Kobayashi,Sakaki,Hachiya,Ichioka,Kawamura
-
p. 1462 - 1469
(2007/10/02)
-
- Synthesis of Some Substituted Dimethyl and Diethyl 4-(Phenylethynyl)-2,6-pyridinedicarboxylates
-
Substituted dimethyl and diethyl 4-(phenylethynyl)-2,6-pyridinedicarboxylates were prepared by coupling reactions between dialkyl 4-halo-2,6-pyridinedicarboxylates and terminal arylacetylenes in the presence of an organopalladium catalyst and copper(I) iodide in a suitable solvent system.The terminal acetylenes needed in this work were synthesized from the corresponding aryl halides using either (trimethylsilyl)acetylene or 2-methyl-3-butyn-2-ol followed by deprotection of the triple bond, depending on the nature of the compound in question.
- Takalo, Harri,Kankare, Jouko,Haenninen, Elina
-
p. 448 - 454
(2007/10/02)
-