69954-66-1Relevant articles and documents
The discovery of highly potent thp derivatives as octn2 inhibitors: From structure‐based virtual screening to in vivo biological activity
Di Cristo, Francesca,Calarco, Anna,Digilio, Filomena Anna,Sinicropi, Maria Stefania,Rosano, Camillo,Galderisi, Umberto,Melone, Mariarosa Anna Beatrice,Saturnino, Carmela,Peluso, Gianfranco
, p. 1 - 19 (2020/10/22)
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.
Design, Synthesis, and Biological Evaluation of a Novel Water-soluble Prodrug of Docetaxel with Amino Acid as a Linker
Ma, Huan,Chen, Gang,Wang, Tao,Li, Qingeng,Liu, Yan
, p. 363 - 369 (2016/10/19)
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.
Targeting carnitine biosynthesis: Discovery of new inhibitors against γ-butyrobetaine hydroxylase
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
, p. 2213 - 2236 (2014/04/17)
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 (
