Interaction of O-(undec-10-en)-yl-d-glucose derivatives with the Plasmodium falciparum hexose transporter (PfHT)

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 17, 2007, Pages 4934-4937

  Ionita, Marina ^a   Krishna, Sanjeev ^b   Léo, Pierre Marc ^a   Morin, Christophe ^a   Patel, Asha Parbhu ^b  

^a Centre National de la Recherche Scientifique   (France)

^b ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

Carbohydrate transporters; Glucose; Inhibitors; Malaria; PfHT

Indexed keywords

GLUCOSE DERIVATIVE; GLUCOSE TRANSPORTER; GLUCOSE TRANSPORTER 1; O (UNDEC 10 EN) YL DEXTRO GLUCOSE; PLASMODIUM FALCIPARUM HEXOSE TRANSPORTER; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; IC 50; NONHUMAN; PLASMODIUM FALCIPARUM;

ANIMALS; ANTIGENS, PROTOZOAN; ANTIMALARIALS; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; GLUCOSE; INHIBITORY CONCENTRATION 50; KINETICS; MODELS, CHEMICAL; MONOSACCHARIDE TRANSPORT PROTEINS; OOCYTES; PLASMODIUM FALCIPARUM; PROTEIN BINDING; PROTOZOAN PROTEINS; XENOPUS LAEVIS;

MAMMALIA; PLASMODIUM FALCIPARUM;

EID: 34547525652     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.06.021     Document Type: Article

References (21)

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12. 13 was obtained from the readily available corresponding bromide (. Hodosi G., Podanyi B., and Kuszmann J. Carbohydr. Res. 230 (1992) 327 ) by reaction with potassium nitrite (Raduchel. B., Synthesis 1980, 292)
13. Alkylation procedure: To a stirred solution of alcohols 10-13 in dry DMF (1-2 mL/mmol) at 4 °C was added sodium hydride (1.1 equiv-60% suspension in mineral oil) and the resulting mixture stirred for 30-60 min at the same temperature; then undec-10-enyl bromide (1.1 equiv). was added and the cooling bath was removed. After overnight stirring, quenching with water was followed by extraction with 1:1 n-pentane/diethyl ether and 14-17 were obtained (20-50% yield) after column chromatography on silica gel.
14. Acetal cleavage procedure: To a solution of 14-17 in dioxane (4 mL/mmol) stirred at 60 °C was added dropwise 2 N hydrochloric acid (4 mL/mmol) and the mixture was stirred overnight. After cooling, water was added and the pH set to 7.0 (1 M NaOH). The resulting solution was concentrated to half volume, the pH was checked and if necessary set to 7.0 (0.1 N NaOH) and the solution concentrated to half volume, before being extracted with diethyl ether. Column chromatography on silica gel using dichloromethane with increasing amounts of ethanol afforded 6-9 (20-60% yield).
15. Obtained in three steps from d-glucose; see. Tsuda Y., Hanajima M., Matsuhira N., Okuno Y., and Kanemitsu K. Chem. Pharm. Bull. 37 (1989) 2344
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18. d-Glucose and l-idose can be easily differentiated by the chemical shifts of their anomeric carbons.
19. The low reactivity of the alkoxide derived from 20 stems presumably from steric congestion and/or low nucleophilicity, possibly due to its interactions with neighbouring oxygens.
20. The affinity for PfHT is retained with 2-deoxy-d-glucose, which shows that the 2-OH group is not critical (See Ref. 2).
21. Only the β-pyranose anomer of 6 was detected by NMR spectroscopy.