Synthesis and biological activity of 5-fluorotubercidin.
The electrophilic fluorination of 4-chloropyrrolo[2,3-d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4-chloro-5-fluoropyrrolo[2,3-d]pyrimidine (2) using Selectfluor. This transformation proceeded via the 4-chloro-5,6-dihydro-5-fluoro-6-hydroxypyrrolo[2,3-d]pyrimidine (3) in a 9:1 trans:cis ratio. The trans isomer of compound 3 was studied by 1H NMR and 19F NMR, and the 5-H tautomer (4) was observed as another intermediate. A modified Vorbruggen procedure of compound 2 and tetra-O-acetylribose gave 4-chloro-5-fluoro-7-(2,3,5,-tri-O-benzoyl-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (6) in a 65% yield. Treatment of compound 6 with ammonia (l) in dioxane gave 5-fluorotubercidin (7). No antibacterial activity was observed. An MTT assay (Promega) against Huh-7 liver cells, normal mouse spleen cells stimulated with Con A (a T-cell mitogen), and normal mouse spleen stimulated with LPS (a B-cell mitogen) showed no significant toxicity. Increased activity of 7 over tubercidin was observed against L-1210 cells and toxicity in fibroblast cells was reduced.
Wang
Xiaojing
X
Ibis Therapeutics, A Division of Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
Seth
Punit P
PP
Ranken
Ray
R
Swayze
Eric E
EE
Migawa
Michael T
MT
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D002850:Chromatography, Gel; D004926:Escherichia coli / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry*; D017930:Genes, Reporter; D009682:Magnetic Resonance Spectroscopy; D014176:Protein Biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D000903:Antibiotics, Antineoplastic; D005461:Fluorine; D014372:Tubercidin