Nucleic acid related compounds. 57. Synthesis, x-ray crystal structure, lipophilic partition properties, and antiretroviral activities of anomeric 3'-azido-2',3'-dideoxy-2,6-diaminopurine ribosides.
Trimethylsilyl triflate-catalyzed transfer glycosylation of 2,6-diamino-9-(3-azido-2,3-dideoxy-alpha- and -beta-D-erythro-pentofuranosyl)purines (3 and 4) in low yields. Selective 2'-O-tosylation of 2,6-diamino-9-(beta-D-ribofuranosyl)purine (2,6-diaminopurine riboside, DAPR, 5) followed by our lithium triethylborohydride promoted 1,2-hydride rearrangement gave 2,6-diamino-9-(2-deoxy-beta-D-threo-pentofuranosyl)purine (7). Tritylation of 7 followed by mesylation at O3', deprotection, and displacement of the 3'-mesylate with azide provided a stereodefined synthesis of 2,6-diamino-9-(3-azido-2, 3-dideoxy-beta-D-erythro-pentofuranosyl)purine (AzddDAPR, 4). X-ray crystallographic analysis of 4 showed two orientations of the azido group, but consistent conformational features in the remainder of the molecule. In contrast, two independent conformations have been found for AZT. The azido function confers enhanced lipophilicity, which could be expected to contribute significantly to nonselective transport across membranes. A large difference in the octanol/water partition coefficients of the alpha (3) and beta (4) anomers wes found. The beta anomer (4) exerts potent inhibition of HIV-induced cytopathogenicity in human MT-4 cells (ED50: 0.3 microM). This concentration is an order of magnitude lower than that required for ddDAPR, AzddAdo, and AzddGuo. Potent inhibition of Moloney sarcoma virus induced transformation of murine C3H cells by AzddDAPR (4) was also observed. The alpha anomer (3) had no observed antiviral activity.
Department of Chemistry, Brigham Young University, Provo, Utah 84602.
M J
MJ
Robins
S G
SG
Wood
N K
NK
Dalley
P
P
Herdewijn
J
J
Balzarini
E
E
De Clercq
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002472:Cell Transformation, Viral / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D016048:Dideoxyadenosine / Q000031:analogs & derivatives*; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D012190:Retroviridae / Q000187:drug effects*; D012995:Solubility; D014961:X-Ray Diffraction
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C052692:2,6-diaminopurine 2',3'-dideoxyriboside; D016048:Dideoxyadenosine