Kevin W. Morin

Radiolabelled Pyrimidine Nucleosides to Monitor the Expression of HSV-1 Thymidine Kinase in Gene Therapy

Selective radiolabelling and imaging of transduced HSV tk expressing cells was studied using [123I]IVFRU, [125I]FIRU and [125I]FIAU. Although all three radionucleosides accumulated in the KBALB-STK transduced murine tumour line in vitro and in vivo, [125I]FIRU provided optimal performance in terms of selectivity for HSV tk expressing cells and % of injected dose accumulating in the tumor.

Synthesis of brain-targeted 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-(E)-5-(2-iodovinyl)uracil coupled to a dihydropyridine ↔pyridinium salt redox chemical-delivery system

1-(2-Deoxy-2-fluoro-beta-D-ribofuranosyl-(E)-5-(2-iodovinyl)uracil (IVFRU) was coupled to a dihydropyridine <---> pyridinium salt redox chemical-delivery system (CDS) via a cleavable sugar-ester linkage as a site-directed approach to increase diffusion of the parent nucleoside into the central nervous system. Treatment of 1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)uracil with Bu(t)Me(2)SiCl in the presence of imidazole in DMF yielded the protected 5-O-tert-butyldimethylsilyl derivative. Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded 1-[5-O-tert-butyldimethylsilyl-2-deoxy-2-fluoro-3-O-(3-pyridylcarbony l )-beta-D-ribofuranosyl]uracil. Reaction with iodine monochloride in methanol simultaneously cleaved the silyl ether moiety and iodinated the uracil ring at the 5-position. Coupling with (E)-Bu(3)Sn-CH = CH-SiMe(3) in the presence of (Ph3P)2Pd2(II)Cl2 in THF gave 1-[2-deoxy-2-fluoro-3-O-(3-pyridylcarbonyl)-beta-D-ribofuranosyl]- (E)-5-(2-trimethylsilylvinyl)uracil. Quaternization with iodomethane in acetone yielded the N-methylpyridinium iodide salt. Ionation of the reactive (E)-trimethylsilylvinyl moiety with iodine monochloride in acetonitrile and reduction of the quaternary pyridinium iodide salt with sodium dithionite in the presence of sodium hydrogen carbonate was carried out as a one-pot procedure to afford 1-[2-deoxy-2-fluoro-3-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-b eta-D-ribofuranosyl]-(E)-5-(2-iodovinyl)uracil (IVFRU-CDS). This synthetic strategy is readily amenable to the high specific-activity radioiodination of IVFRU.

5-Halo-6-alkoxy-5,6-dihydro-pyrimidine Nucleosides: Antiviral Nucleosides or Nucleoside Prodrugs?

Abstract 5-Halo-6-alkoxy-5,6-dihydro derivatives of azidothymidine (AZT) and ethyldeoxyuridine (EDU) were developed and evaluated using in vitro and in vivo models. Although most of these 5,6-dihydro derivatives served as prodrugs in improving sitespecific delivery and pharmacokinetic parameters, some unique characteristics were exhibited.

Accumulation of 5‐Ethyl‐2′‐deoxyuridine and its 5,6‐Dihydro Prodrugs in Murine Lung and its Potential Clinical Application

The accumulation of 5‐ethyl‐2′‐deoxyuridine (EDU), (–)‐trans‐(5S, 6S)‐5‐bromo‐5‐ethyl‐6‐methoxy‐5,6‐dihydro‐2′‐deoxyuridine [(5S, 6S)‐BMEDU], (+)‐trans‐(5R, 6R)‐5‐bromo‐5‐ethyl‐6‐methoxy‐5,6‐dihydro‐2′‐deoxyuridine [(5R, 6R)‐BMEDU], (+)‐trans‐(5.R, 6R)‐5‐bromo‐5‐ethyl‐6‐ethoxy‐5, 6‐dihydro‐2′‐deoxyuridine (BEEDU), (+)‐trans‐(5R, 6R)‐5‐bromo‐5‐ethyl‐6‐ethoxy‐5,6‐dihydro‐5′‐O‐valeryl‐2′‐ deoxyuridine (VBEEDU) and (+)‐trans‐(5R, 6R)‐5‐bromo‐5‐ethyl‐6‐ethoxy‐5,6‐dihydro‐3′‐5′‐di‐O‐valeryl‐2′‐deoxyuridine (DVBEEDU) in lung and other tissues was investigated in male Balb‐C mice following intravenous injection of the corresponding 4‐14C‐labelled compounds.