Synthesis, Structure, and Antitumor and Antiviral Activities of a Series of 5-Halouridine Cyclic 3’,5’-Monophosphates

Jözsef Béres, Wesley G. Bentrude, Alajos Kalman, Laszlo Parkanyi, Jan Balzarini, Erik De Clercq

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A series of potential prodrug 5-halouridine 3’,5’-cyclic monophosphates (5-X-cUMPs, X = F, Cl, Br, I, 1–4) has been prepared and tested for antitumor activity against murine leukemia L1210/0 and human lymphoblast Raji/0 cells and their deoxythymidine kinase deficient (TK-) counterparts, as well as for antiviral activity in primary rabbit kidney cells infected with herpes simplex virus type 1 or 2, vaccinia virus, or vesicular stomatitis virus. The 5-halopyrimidine bases, nucleosides (5-X-U), and 5’-monophosphates (5-X-UMP) were tested for comparison. 5-F-cUMP (1) showed reasonably potent inhibition of tumor cell proliferation (ID50 = 0.33–1.6 µg/mL), while the remaining diesters displayed ID50’s ranging from 210 to >1000 µg/mL. 5-F-cUMP was 70- to 300-fold less active than 5-F-dU in the same systems. With TK- L1210 cells, 5-F-cUMP was as potent as with the normal (LI210/0) line but was about fourfold less active with TK- Raji cells compared to Raji/0 cells. The 5-X-cUMPs showed little potency as antivirals. A single-crystal X-ray analysis of the ammonium salt of 5-I-cUMP confirmed its structure and showed the conformation of the phosphate ring to be the expected chair. The ribose pucker is near 34T, and the torsion angle about the ß-glycosidic N(1)-C(1’) bond is in the syn range (–84.8°).

Original languageEnglish
Pages (from-to)488-493
Number of pages6
JournalJournal of Medicinal Chemistry
Volume29
Issue number4
DOIs
Publication statusPublished - Jan 1 1986

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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