Pyrazolo[3,4-d]pyrimidine ribonucleosides related to 2-aminoadenosine and isoguanosine: synthesis, deamination and tautomerism.
The syntheses and properties of 8-aza-7-deazapurine (pyrazolo[3,4-d]pyrimidine) ribonucleosides related to 2-aminoadenosine and isoguanosine are described. Glycosylation of 8-aza-7-deazapurine-2,6-diamine 5 with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (12) in the presence of BF(3) x Et(2)O as a catalyst gave the N(8) isomer 14 (73%) with a trace amount of the N(9) isomer 13a (4.8%). Under the same reaction conditions, the 7-halogenated 8-aza-7-deazapurine-2,6-diamines 6-8 afforded the thermodynamically more stable N(9) nucleosides 13b-d as the only products (53-70%). Thus, a halogen in position 7 shifts the glycosylation from N(8) to N(9). The 8-aza-7-deazapurine-4,6-diamine ribonucleosides 1a-d were converted to the isoguanosine derivatives 3a-d by diazotization of the 2-amino group. Although compounds 1a,b do not contain a nitrogen at position 7 (the enzyme binding site), they were deaminated by adenosine deaminase; however, their deamination occurred with a much slower velocity than that of the related purines. The pK(a) values indicate that the 7-non-functionalized nucleosides 1a (pK(a) 5.8) and 15 (pK(a) 6.4) are possibly protonated in neutral conditions when incorporated into RNA. The nucleosides 3a-d exist predominantly in the keto (lactam) form with K(TAUT) (keto/enol) values of 400-1200 compared to 10(3)-10(4) for pyrrolo[2,3-d]pyrimidine isoguanosine derivatives 4a-c and 10 for isoguanosine itself, which will reduce RNA mispairing with U.
Seela
Frank
F
Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstrasse 11, 48149 Münster, Germany. Frank.Seela@uni-osnabrueck.de
Xu
Kuiying
K
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D000243:Adenosine Deaminase / Q000378:metabolism; D003641:Deamination; D006151:Guanosine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000737:chemistry*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D011720:Pyrazoles; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D006151:Guanosine; C008184:isoguanosine; C033854:2-aminoadenosine; C014175:pyrazolo(3,4-d)pyrimidine; D000243:Adenosine Deaminase; D000241:Adenosine