Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogs of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC) Journal Article
| Authors: | Watanabe, K. A.; Harada, K.; Zeidler, J.; Matulic-Adamic, J.; Takahashi, K.; Ren, W. Y.; Cheng, L. C.; Fox, J. J.; Chou, T. C.; Zhu, Q. Y.; Polsky, B.; Gold, J. W.; Armstrong, D. |
| Article Title: | Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogs of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC) |
| Abstract: | 1- (3-Azido-2,3-dideoxy-2-fluoro-β-D-arabinofuranosyl)thymine (6, F-AZT) and l-(2,3-dideoxy-2-fluoro-β-D-t/ireopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides l-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymine (1, FMAU) and l-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2'-“up”-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3-anhydro-l-(2-fluoro-2-deoxy-5-O-trityl-β-D-lyxo-furanosyl)thymine (4), which when treated with NaN3followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldiimidazole afforded the 5‘-0-trity1-3’-0-(imidazolypthiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5’-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12’ was obtained in crystalline form. Alternatively, FAC (14) was converted into N4, O6‘-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT. © 1990, American Chemical Society. All rights reserved. |
| Keywords: | unclassified drug; human cell; nonhuman; cell survival; cell line; cytotoxicity; drug screening; drug synthesis; fluorescent antibody technique; chemistry; cell culture; molecular structure; human immunodeficiency virus; enzyme-linked immunosorbent assay; hiv-1; zidovudine; antiviral agents; cell strain hl 60; rna directed dna polymerase; human; priority journal; article; hiv antigens; zalcitabine; support, u.s. gov't, p.h.s.; rna-directed dna polymerase; 1 (2,3 dideoxy 2 fluoro beta d threopentofuranosyl)cytosine; 1 (3 azido 2,3 dideoxy 2 fluoro beta d arabinofuranosyl)thymine; tetrahydrouridine |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 33 |
| Issue: | 8 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1990-08-01 |
| Start Page: | 2145 |
| End Page: | 2150 |
| Language: | English |
| DOI: | 10.1021/jm00170a016 |
| PUBMED: | 1695683 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 27 January 2020 -- Source: Scopus |
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