Synthesis and antiproliferative effects of novel 5'-fluorinated analogues of 5'-deoxy-5'-(methylthio)adenosine.

Abstract

5'-Deoxy-5'-[(monofluoromethyl)thio]adenosine (9) and 5'-deoxy-5'-fluoro-5'-(methylthio)adenosine (10), two novel analogues of 5'-deoxy-5'-(methylthio)adenosine (MTA), have been synthesized and evaluated for their substrate and inhibitory activities toward MTA phosphorylase and for their biological effects in L1210 (MTA phosphorylase deficient) and L5178Y (MTA phosphorylase containing) murine leukemia cell lines. Compound 9 was a potent competitive inhibitor of MTA phosphorylase with a Ki value of 3.3 microM and was also a substrate, with activity approximately 53% that of MTA. Compound 10 was significantly less inhibitory toward the phosphorylase with a Ki value of 141 microM; its lack of substrate activity was attributed to rapid nonenzymatic degradation. The 50% growth inhibitory concentrations (48 h) of 9 were 300 and 200 microM in L1210 and L5178Y cells, respectively; for 10, these respective values were 2 and 0.7 microM. The initial characterization of 9 in these systems reveals that it differs from MTA by not acting as a product regulator of the polyamine biosynthetic pathway.

• Authors: J R Sufrin, A J Spiess, D L Kramer, P R Libby, C W Porter
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 32 Issue 5 Pg. 997-1001 (May 1989) ISSN: 0022-2623 [Print] United States
• PMID: 2496231 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biogenic Polyamines
• Deoxyadenosines
• Thionucleosides
• 5'-deoxy-5'-((monofluoromethyl)thio)adenosine
• 5'-deoxy-5'-fluoro-5'-(methylthio)adenosine
• 5'-methylthioadenosine
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase
• Adenosine

Topics

• Adenosine (analogs & derivatives, chemical synthesis, pharmacology)
• Animals
• Biogenic Polyamines (biosynthesis)
• Cell Division (drug effects)
• Deoxyadenosines
• Leukemia, Experimental (pathology)
• Mice
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
• Thionucleosides (chemical synthesis, pharmacology)
• Tumor Cells, Cultured (drug effects)