- The discovery of highly potent thp derivatives as octn2 inhibitors: From structure‐based virtual screening to in vivo biological activity
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A mismatch between β‐oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3‐(2,2,2‐ trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP‐derived carnitine‐lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.
- Di Cristo, Francesca,Calarco, Anna,Digilio, Filomena Anna,Sinicropi, Maria Stefania,Rosano, Camillo,Galderisi, Umberto,Melone, Mariarosa Anna Beatrice,Saturnino, Carmela,Peluso, Gianfranco
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- Formulation optimization of an ephrin A2 targeted immunoliposome encapsulating reversibly modified taxane prodrugs
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Ephrin A2 targeted immunoliposomes incorporating pH-sensitive taxane prodrugs were developed for sustained delivery of active drug to solid tumors. Here we describe the systematic formulation development and characterization of these immunoliposomes. We s
- Huang, Zhaohua Richard,Tipparaju, Suresh Kumar,Kirpotin, Dmitri B.,Pien, Christine,Kornaga, Tad,Noble, Charles O.,Koshkaryev, Alexander,Tran, Jimmy,Kamoun, Walid S.,Drummond, Daryl C.
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- Design, Synthesis, and Biological Evaluation of a Novel Water-soluble Prodrug of Docetaxel with Amino Acid as a Linker
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The synthesis and preliminary evaluation of derivatives of docetaxel with novel amino acid as a linker named as LK-193?LK-196 was described. The C2′-modified compound LK-196 behaves as a prodrug; that is, docetaxel is generated upon exposure to human plasma. The compound was also found to have greatly improved water solubility. The pharmacodynamic results showed LK-196 had the self-evident inhibitory effect on tumor growth in vivo, which is a promising candidate for further biological evaluation.
- Ma, Huan,Chen, Gang,Wang, Tao,Li, Qingeng,Liu, Yan
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p. 363 - 369
(2016/10/19)
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- SANTACRUZAMATE A COMPOSITIONS AND ANALOGS AND METHODS OF USE
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The compositions and methods described herein relate generally to Santacruzamate A compositions and analogs, which, among other features, are useful as histone deacetylase (HDAC) inhibitors.
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Page/Page column 48
(2014/02/16)
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- Targeting carnitine biosynthesis: Discovery of new inhibitors against γ-butyrobetaine hydroxylase
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γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (
- Tars, Kaspars,Leitans, Janis,Kazaks, Andris,Zelencova, Diana,Liepinsh, Edgars,Kuka, Janis,Makrecka, Marina,Lola, Daina,Andrianovs, Viktors,Gustina, Daina,Grinberga, Solveiga,Liepinsh, Edvards,Kalvinsh, Ivars,Dambrova, Maija,Loza, Einars,Pugovics, Osvalds
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p. 2213 - 2236
(2014/04/17)
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- Synthesis of benzoic acids and polybenzamides containing tertiary alkylamino functionality
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The high-yielding and easily scalable synthesis of a number of benzoic acids bearing a tertiary alkylamino functionality has been achieved. The flexible synthesis began from readily available aminobenzoic acids or terephthaloyl chloride and requires almost no chromatography. Coupling of the synthesised amino acids to a range of substituted anilines was achieved when utilizing a specific combination of DIC, HOBt and DMAP.
- Khan, Gul Shahzada,Dickson, Benjamin D.,Barker, David
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scheme or table
p. 1790 - 1801
(2012/03/11)
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- N,N-dimethyl-β-alanine as an inexpensive and efficient ligand for palladium-catalyzed Heck reaction
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N,N-Dimethyl-β-alanine was found to be a more powerful phosphine-free ligand than the previously reported ligand, N,N-dimethylglycine, in the Pd-catalyzed Heck reaction for a variety of aryl bromides, aryl iodides, and activated aryl chlorides with a practical turnover number of 103. Both kinetic and theoretical studies suggested that N,N-dimethyl-β-alanine led to faster oxidative addition of an aryl halide to Pd than N,N-dimethylglycine.
- Cui, Xin,Li, Zhe,Tao, Chuan-Zhou,Xu, Yu,Li, Juan,Liu, Lei,Guo, Qing-Xiang
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p. 2467 - 2470
(2007/10/03)
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- Selected soluble esters of hydroxyl-containing indolocarbazoles
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Esters of hydroxyl-containing indolocarbazoles and acids containing selected solubilizing groups are provided. Compositions including the indolocarbazole esters and methods for the use of the indolocarbazole esters are also provided.
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