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Stereoselective synthesis of sugar-modified enyne analogues of adenosine and uridine. Interaction with S-adenosyl-L-homocysteine hydrolase and antiviral and cytotoxic effects.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Wnuk, Stanislaw F. Lewandowska, Elzbieta Crain, Leigh N. Zhang, Jinsong Clercq, Erik De |
| Copyright Year | 2004 |
| Abstract | Sonogashira coupling of (E)-6'-iodohomovinyl nucleosides 1 with (trimethylsilyl)acetylene gave the conjugated 8'-(trimethylsilyl)enyne derivatives of the adenosine 2a and uridine 2b with expected E-stereochemistry. Desilylation of 2a,b with tetrabutylammonium fluoride followed by treatment with N-iodosuccinimide/AgNO(3) afforded 8'-iodoenynes 4a,b. Analogous coupling of (Z)-6'-iodohomovinyl nucleosides 7a,b produced (Z)-8'-(trimethylsilyl)enynes 8a,b, which were deprotected with aqueous trifluoroacetic acid to give the Z-enynes 9a,b. Stereoselective coupling of the adenosine 4'-acetylenic 11 and ethyl (Z)-3-bromoacrylate followed by deprotection gave the conjugated enyne system attached in the reverse orientation at C4' 13. Because of their diverse stereochemical attributes, deprotected enyne analogues 5a, 6a, 9a, and 13 derived from adenosine require a different vicinity for binding with S-adenosyl-l-homocysteine (AdoHcy) hydrolase and/or addition of enzyme-bound water across the conjugated enyne system. Enyne 5a and 8'-iodoenyne 6a produced time-dependent and concentration-dependent inhibition of AdoHcy hydrolase (K(i), 0.55 and 118.5 microM, respectively). No reduction in NAD(+) content of the enzyme and no iodide ion released were observed upon incubation of 6a with the enzyme, while incubation of 5a produced 30% reduction in the NAD(+) content of the enzyme. No specific antiviral activity was noted for 5a,b, 6a,b, 9a,b, and 13 against any of the viruses tested; the E-iodoenynes 6a and 6b inhibited HIV-1 virus (IC(50), 1.1 and 1.8 microM; selectivity index, 7 and 3, respectively). The E-enyne 5a showed activity against cytomegalovirus at a concentration (EC(50), 30 microM) that was 3- to 10-fold lower than the cytotoxic concentration. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://faculty.fiu.edu/~wnuk/Publications-pdf%20files/82.pdf |
| PubMed reference number | 15456269v1 |
| Volume Number | 47 |
| Issue Number | 21 |
| Journal | Journal of medicinal chemistry |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Adenosine Antiviral Agents HIV Homocysteine S-Methyltransferase Hydrolase Immunostimulating conjugate (antigen) Iodides Ions Maxillary left central incisor abutment Maxillary right canine abutment Maxillary right central incisor abutment Maxillary right first premolar abutment Maxillary right lateral incisor abutment Maxillary right second premolar abutment Purine Nucleosides Pyrimidine Nucleosides S-Adenosylhomocysteine Stereochemistry (discipline) Sugars Trifluoroacetic Acid Uridine Virus betaine-homocysteine methyltransferase tetrabutylammonium fluoride |
| Content Type | Text |
| Resource Type | Article |
