1935-18-8Relevant academic research and scientific papers
NOVEL CRYSTALLINE FORMS
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Page/Page column 13, (2017/12/01)
Preparation and characterization of novel forms of (1-hydroxy-2-imidazol-1-yl-1-phosphono-ethyl) phosphonic acid, suitable for pharmaceutical compositions in drug delivery systems for humans.
Combination of l-Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2-Targeting Oral Prodrugs
Wang, Gang,Chen, Hongxiang,Zhao, Dongyang,Ding, Dawei,Sun, Mengchi,Kou, Longfa,Luo, Cong,Zhang, Dong,Yi, Xiulin,Dong, Jinhua,Wang, Jian,Liu, Xiaohong,He, Zhonggui,Sun, Jin
, p. 2552 - 2561 (2017/04/03)
Novel organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, might be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of l-carnitine to its N4-amino group via different lipophilic linkages. Because of the high OCTN2 affinity, the hexane diacid-linked prodrug demonstrated significantly improved stability (3-fold), cellular permeability (15-fold), and oral bioavailability (5-fold), while causing no toxicity as compared to gemcitabine. In addition, OCTN2-targeting prodrugs can simultaneously improve the permeability, solubility, and metabolic stability of gemcitabine. In summary, we present the first evidence that OCTN2 can act as a new molecular target for oral prodrug delivery and, importantly, the linkage carbon chain length is a key factor in modifying the affinity of the substrate for OCTN2.
Stereoselective synthesis of a conformationally defined cyclohexyl carnitine analogue that binds CPT-1 with high affinity
Hutchison, Tracy L.,Saeed, Ashraf,Wolkowicz, Paul E.,McMillin, Jeanie B.,Brouillette, Wayne J.
, p. 1505 - 1511 (2007/10/03)
Carnitine (1, 3-hydroxy-4-trimethylammoniobutyrate) is important in mammalian tissue as a carrier of acyl groups. In order to explore the binding requirements of the carnitine acyltransferases for carnitine, we designed conformationally defined cy- clohexyl carnitine analogues. These diastereomers contain the required gauche conformation between the trimethylammonium and hydroxy groups but vary the conformation between the hydroxy and carboxylic acid groups. Here we describe the synthesis and biological activity of the all-trans diastereomer (2), which was prepared by the ring opening of trans-methyl 2,3-epoxycylohex- anecarboxylate with NaN3 . Racemic 2 was a competitive inhibitor of neonatal rat cardiac myocyte CPT-1 (K(i) 0.5 mMfor racemic 2; K(m) 0.2 mM for L-carnitine) and a noncompetitive inhibitor of neonatal rat cardiac myocyte CPT-2 (K(i) 0.67 mM). These results suggest that 2 represents the bound conformation of carnitine for CPT-1. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.
Synthesis and preliminary evaluation of perfluoroalkylacyl carnitines as surfactants for biomedical use
Nivet, JB,Blanc, M Le,Riess, JG
, p. 953 - 960 (2007/10/02)
A series of acyl carnitines, 4 of which bearing a terminal perfluoroalkyl fragment, was obtained from carnitine in one step in a high grade of purity in yields ranging from 44-81percent.The F-alkyl derivatives display high solubilities in water, strong surface activity and a significant emulsifying power towards fluorocarbons in water.In spite of their strong surface activity, all of the biocompatibility tests performed (in vitro toxicity on Namalva cells cultures, hemolysis on human red blood cells, and iv injections in mice) indicate a significantly better biologicaltolerance than their hydrocarbon analogs, provided the F-alkyl moiety is larger than the alkyl moiety in the hydrophobic tail. fluorinated acyl carnitines / surfactants / emulsifiers / synthesis / biological acceptance / hemolysis / fluorocarbon emulsions
