Gonzalez Cesar, de Cabrera Maria, Wnuk Stanislaw F
a Department of Chemistry and Biochemistry , Florida International University , Miami , Florida , United States.
Nucleosides Nucleotides Nucleic Acids. 2018;37(4):248-260. doi: 10.1080/15257770.2018.1465186. Epub 2018 May 11.
Gemcitabine analogues with a lipophilic 4-N-alkyl chain bearing a terminal β-keto sulfonate moiety suitable for fluorination compatible with F-radiolabeling have been explored. Displacement of p-toluenesulfonylamino in protected 4-N-tosylgemcitabine with 1-amino-10-undecene gave 4-N-(10-undecenyl)-3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluorocytidine. Oxidation of the terminal double bond in the latter with OsO/NMO afforded 4-N-(10,11-dihydroxyundecanyl) derivative. Regioselective sulfonation of primary hydroxyl followed by oxidation of secondary hydroxyl with Collin's reagent yielded desired β-keto sulfonate analogues 8 or 9. Subsequent displacement of the mesylate or tosylate group with KF in the presence of Kryptofix 2.2.2. or 18-crown-6 ether followed by deprotection with NH/MeOH gave 4-N-(11-fluoro-10-oxoundecanyl)-2'-deoxy-2',2'-difluorocytidine 11.
人们已经探索了具有亲脂性4-N-烷基链且带有适合氟化的末端β-酮磺酸盐部分、与F-放射性标记兼容的吉西他滨类似物。用1-氨基-10-十一碳烯取代受保护的4-N-甲苯磺酰基吉西他滨中的对甲苯磺酰氨基，得到4-N-(10-十一碳烯基)-3',5'-二-O-苯甲酰基-2'-脱氧-2',2'-二氟胞苷。用OsO/NMO氧化后者中的末端双键，得到4-N-(10,11-二羟基十一烷基)衍生物。对伯羟基进行区域选择性磺化，然后用科林试剂氧化仲羟基，得到所需的β-酮磺酸盐类似物8或9。随后在穴状配体2.2.2.或18-冠-6醚存在下，用KF取代甲磺酸酯或甲苯磺酸酯基团，然后用NH/MeOH脱保护，得到4-N-(11-氟-10-氧代十一烷基)-2'-脱氧-2',2'-二氟胞苷11。
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