Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2′-deoxyuridine and 2′-deoxy-2′-fluoro-β-D-arabinofuranosyluracilt Journal Article
| Authors: | Matulic-Adamic, J.; Takahashi, K.; Chou, T. C.; Gadler, H.; Price, R. W.; Venugopala Reddy, A. R.; Kalman, T. I.; Watanabe, K. A. |
| Article Title: | Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2′-deoxyuridine and 2′-deoxy-2′-fluoro-β-D-arabinofuranosyluracilt |
| Abstract: | A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2′-deoxy-2′-fluoro-β-D-arabmofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3′.5′-Di-O-tert-butyldiphenyl)silylated thymidine or FMAU was photochemicaUy brominated with NBS to the corresponding -monobromide, which was hydrolyzed to the 5-hydroxymethyl derivative. Further oxidation of the latter with MnO2 afforded the 5-formyluracil nucleoside. Treatment of these nucleosides with DAST in CH2Cl2 gave the protected -fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2′,-deoxy-2′,-fluoro-β-D-arabinofuranosyluracil (F3-FMAU) was synthesized by copper-catalyzed trifluoromethylation of 5-iodo-2′-fluoro-ara-U (FIAU). These new nucleosides were studied, in comparison with the corresponding 2′-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TDR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2). F2-TDR and F3-TDR strongly inhibited TS and were also quite cytotoxic and antiherpetic, whereas FTDR was only active in the antiviral assay. In the 2,-fluoroarabino series, fluorine substitution at the -methyl function did not alter significantly the antiherpetic activity. Although FMAU and F-FMAU did not inhibit TS to any significant extent, F2-FMAU and F3-FMAU were weakly inhibitory. The latter nucleosides did not inhibit [3H]TDR incorporation into DNA, while all the other -fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [3H]TDR into DNA to various extents. F2-FMAU and FS-FMAU were about 2 orders of magnitude less cytotoxic against HL-60 cells than were F2-TDR and F3-TDR. The results strongly suggest that in both the 2′-deoxy-2′-fluoroarabino and the 2′-deoxy-erythro-pentofurano series the cytotoxic action of theα,α-difluoro and α,α,α-trifluoro derivatives may involve the inhibition of TS. The synthesis of [2-14C]F2-FMAU, as an experimental imaging agent, is also described. Unfortunately, the highly selective uptake of the labeled compound within infected brain regions previously noted with [2-14C]FMAU was not detected with the derivative [2-14C]F2-FMAU. © 1988, American Chemical Society. All rights reserved. |
| Keywords: | leukemia; unclassified drug; human cell; nonhuman; animal cell; animal; cell division; enzyme inhibition; animal experiment; animal model; herpes simplex; cytotoxicity; structure-activity relationship; chemistry; drug distribution; cell culture; brain; rat; simplexvirus; arabinofuranosyluracil; rats; encephalitis; thymidylate synthase; herpes simplex virus 1; nuclear magnetic resonance; uridine; antiviral agents; herpes simplex virus 2; nucleosides; cell strain hl 60; human; deoxyuridine; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; leukemia l 1210; 2' fluoro 2' deoxyuracil arabinoside derivative; deoxyuridine derivative |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 31 |
| Issue: | 8 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1988-08-01 |
| Start Page: | 1642 |
| End Page: | 1647 |
| Language: | English |
| DOI: | 10.1021/jm00403a026 |
| PUBMED: | 2840503 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 August 2020 -- Source: Scopus |
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