title: Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides.
abstract: A series of C-4 substituted pyrazolo[3,4-b]pyridine nucleosides have been synthesized and evaluated for their biological activity. Successful synthesis of various C-4 substituted pyrazolo[3,4-b]pyridine nucleosides involves nucleophilic displacement by a suitable nucleophile at the C-4 position of 4-chloro-1H-pyrazolo[3,4-b]pyridine (5), followed by glycosylation of the sodium salt of the C-4 substituted pyrazolo[3,4-b]pyridines with a protected alpha-halopentofuranose. Use of this methodology furnished a simple and direct route to the beta-D-ribofuranosyl, beta-D-arabinofuranosyl, and 2-deoxy-beta-D-erythro-pentofuranosyl nucleosides of C-4 substituted pyrazolo[3,4-b]pyridines, wherein the C-4 substituent was azido, amino, methoxy, chloro, or oxo. The regiospecificity of these glycosylations was determined on the basis of UV data and the anomeric configuration was established by 1H NMR analysis. Conclusive structural assignment was made by a single-crystal X-ray diffraction study of three compounds, 15, 31, and 42, as representatives of ribo-2'-deoxy-, and aranucleosides, respectively. The stereospecific attachment of all three alpha-halogenoses appears to occur by a Walden inversion (SN2 mechanism) at the C-1 carbon of the halogenose by the anionic N-1 of pyrazolo[3,4-b]pyridine. All deprotected nucleosides were tested against various viruses and tumor cells in culture. The effects of these compounds on de novo purine and pyrimidine nucleotide biosynthesis was also evaluated. Among the compounds tested, 4-chloro-1-beta-D-ribofuranosylpyrazolo[3,4-b]pyridine (16) and 1-beta-D-ribofuranosyl-4,7-dihydro-4-oxopyrazolo[3,4-b]pyridine (19) were found to be moderately cytotoxic to L1210 and WI-L2 in culture.
authors.affiliation: Nucleic Acid Research Institute, Costa Mesa, California 92626.
authors.forename: Y S
authors.initials: YS
authors.lastname: Sanghvi
authors.forename: S B
authors.initials: SB
authors.lastname: Larson
authors.forename: R C
authors.initials: RC
authors.lastname: Willis
authors.forename: R K
authors.initials: RK
authors.lastname: Robins
authors.forename: G R
authors.initials: GR
authors.lastname: Revankar
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003460:Crystallization; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011685:Purine Nucleotides / Q000096:biosynthesis; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009705:Nucleosides; D011684:Purine Nucleosides; D011685:Purine Nucleotides; D011741:Pyrimidine Nucleosides; D011742:Pyrimidine Nucleotides