Synthesis of 3'-amino-3'-deoxyguanosine and 3'-amino-3'-deoxyxyloguanosine monophosphate HepDirect prodrugs from guanosine.
Nucleosides Nucleotides Nucleic Acids
; 28(10): 969-86, 2009 Oct.
Article
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| MEDLINE
| ID: mdl-20183565
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.
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MEDLINE
Asunto principal:
Profármacos
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Desoxiguanosina
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Animals
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En
Año:
2009
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Article