RESUMEN
The coupling of gemcitabine with functionalized carboxylic acids using peptide coupling conditions afforded 4-N-alkanoyl analogues with a terminal alkyne or azido moiety. Reaction of 4-N-tosylgemcitabine with azidoalkyl amine provided 4-N-alkyl gemcitabine with a terminal azido group. Click reaction with silane building blocks afforded 4-N-alkanoyl or 4-N-alkyl gemcitabine analogues suitable for fluorination. RP-HPLC analysis indicated better chemical stability of 4-N-alkyl gemcitabine analogues versus 4-N-alkanoyl analogues in acidic aqueous conditions. The 4-N-alkanoyl gemcitabine analogues showed potent cytostatic activity against L1210â¯cell line, but cytotoxicity of the 4-N-alkylgemcitabine analogues was low. However, 4-N-alkanoyl and 4-N-alkyl analogues had comparable antiproliferative activities in the HEK293â¯cells. The 4-N-alkyl analogue with a terminal azide group was shown to be localized inside HEK293â¯cells by fluorescence microscopy after labelling with Fluor 488-alkyne. The [18F]4-N-alkyl or alkanoyl silane gemcitabine analogues were successfully synthesized using microscale and conventional silane-labeling radiochemical protocols. Preliminary positron-emission tomography (PET) imaging in mice showed the biodistribution of [18F]4-N-alkyl to have initial concentration in the liver, kidneys and GI tract followed by increasing signal in the bone.
Asunto(s)
Desoxicitidina/análogos & derivados , Fluoruros/química , Radioisótopos de Flúor , Compuestos de Silicona/química , Animales , Línea Celular Tumoral , Desoxicitidina/química , Desoxicitidina/farmacocinética , Tracto Gastrointestinal/diagnóstico por imagen , Tracto Gastrointestinal/metabolismo , Células HEK293 , Humanos , Riñón/diagnóstico por imagen , Riñón/metabolismo , Hígado/diagnóstico por imagen , Hígado/metabolismo , Ratones , Tomografía de Emisión de Positrones , Distribución Tisular , GemcitabinaRESUMEN
Reduction of ribono-1,4-lactones and gulono-1,4-lactone as well as ribono-1,5-lactone and glucono-1,5-lactones with LTBH (1.2 equiv.) in CH2Cl2 at 0 °C for 30 min provided the corresponding pentose or hexose hemiacetals in high yields. Commonly used in carbohydrate chemistry protecting groups such as trityl, benzyl, silyl, acetals and to some extent acyls are compatible with this reduction.