title: Synthesis of 3'-amino-3'-deoxyguanosine and 3'-amino-3'-deoxyxyloguanosine monophosphate HepDirect prodrugs from guanosine.
abstract: The synthesis of 3'-amino-3'-deoxyguanosine and 3'-amino-3'-deoxyxyloguanosine monophosphate HepDirect prodrugs from guanosine is reported. Initial incorporation of N,N-dibenzylformamidino protection of the C2-amino of guanosine masked the reactivity of that group and simplified purification of subsequent analogues. The first key intermediate, 9-(2,5-bis-O-tert-butyldimethylsilyl-beta-D-ribofuranosyl)-2-N-(N,N-dibenzylformamidino)guanine (3a), was prepared in 60% yield after recycling of the undesired 3',5'-bis-O-protected byproduct (4a) by simple equilibration in methanol to a mixture of the two bis-O-protected compounds. Thus, protected, the 3'-position was manipulated to form the 3'-deoxyribo- or 3'-deoxyxylo-3'-azido derivatives (9 or 16, respectively). Further selective manipulations provided the cis-5'-monophosphate (3-chlorophenyl)-1,3-propanyl diester prodrugs (HepDirect prodrugs), 15 and 21. These HepDirect prodrugs were demonstrated to activate to their respective NTPs in rat hepatocytes.
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California, USA. brett_bookser@mac.com
authors.forename: Brett C
authors.initials: BC
authors.lastname: Bookser
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Raffaele
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Kevin
authors.initials: K
authors.lastname: Fan
authors.forename: Wenjian
authors.initials: W
authors.lastname: Huang
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000818:Animals; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008968:Molecular Conformation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats
chemical_list: D011355:Prodrugs; C045544:3'-amino-3'-deoxyguanosine; D003849:Deoxyguanosine