Synthesis of 3'-amino-3'-deoxyguanosine and 3'-amino-3'-deoxyxyloguanosine monophosphate HepDirect prodrugs from guanosine.
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.
Bookser
Brett C
BC
Metabasis Therapeutics, Inc., La Jolla, California, USA. brett_bookser@mac.com
Raffaele
Nicholas B
NB
Reddy
K Raja
KR
Fan
Kevin
K
Huang
Wenjian
W
Erion
Mark D
MD
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
D011355:Prodrugs; C045544:3'-amino-3'-deoxyguanosine; D003849:Deoxyguanosine