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6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases
- Source :
- Bioorganic Chemistry. 65:9-16
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- 6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli PNP. The prototype MeP releasing prodrug, 9-(β-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction with E. coli PNP. In this work, we report on the synthesis of 9-(6-deoxy-β-d-allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-β-d-ribo-hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl-α-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C-methyl-β-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O-isopropylidine-α-d-glucofuranose in 9 and 11 steps, respectively. Coupling of 10 and 15 with silylated 6-methylpurine under Vorbrüggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5'-C-methylated-6-methylpurine nucleosides 3 and 4, respectively. Unlike 9-(6-deoxy-α-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity with E. coli PNP mutant (M64V), the β-d-allo-furanosyl derivative 3 and the 5'-di-C-methyl derivative 4 were poor substrates for all tested glycosidic bond cleavage enzymes.
- Subjects :
- 0301 basic medicine
Glycosylation
Stereochemistry
Carbohydrates
Molecular Conformation
Purine nucleoside phosphorylase
medicine.disease_cause
01 natural sciences
Biochemistry
Substrate Specificity
03 medical and health sciences
chemistry.chemical_compound
Drug Discovery
medicine
Humans
Glycosyl
Molecular Biology
Escherichia coli
chemistry.chemical_classification
010405 organic chemistry
Organic Chemistry
Nucleosides
Glycosidic bond
Prodrug
0104 chemical sciences
030104 developmental biology
Enzyme
Purine-Nucleoside Phosphorylase
Adenine analog
chemistry
Purines
Subjects
Details
- ISSN :
- 00452068
- Volume :
- 65
- Database :
- OpenAIRE
- Journal :
- Bioorganic Chemistry
- Accession number :
- edsair.doi.dedup.....0a5f1b1f0795cb27c3e6660ae64956e4