Seela Frank, Xu Kuiying
Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstrasse 11, 48149 Münster, Germany.
Org Biomol Chem. 2007 Sep 21;5(18):3034-45. doi: 10.1039/b708736e. Epub 2007 Aug 14.
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.
描述了与2-氨基腺苷和异鸟苷相关的8-氮杂-7-脱氮嘌呤（吡唑并[3,4-d]嘧啶）核糖核苷的合成及性质。在三氟化硼乙醚（BF₃·Et₂O）作为催化剂的存在下，8-氮杂-7-脱氮嘌呤-2,6-二胺5与1-O-乙酰基-2,3,5-三-O-苯甲酰基-β-D-呋喃核糖（12）进行糖基化反应，得到N(8)异构体14（73%）以及痕量的N(9)异构体13a（4.8%）。在相同反应条件下，7-卤代的8-氮杂-7-脱氮嘌呤-2,6-二胺6 - 8仅得到热力学上更稳定的N(9)核苷13b - d作为唯一产物（53 - 70%）。因此，7位上的卤素使糖基化从N(8)转移至N(9)。8-氮杂-7-脱氮嘌呤-4,6-二胺核糖核苷1a - d通过2-氨基的重氮化反应转化为异鸟苷衍生物3a - d。尽管化合物1a、b在7位（酶结合位点）不含氮，但它们会被腺苷脱氨酶脱氨；然而，它们的脱氨速度比相关嘌呤的脱氨速度慢得多。pKₐ值表明，7-未官能化的核苷1a（pKₐ5.8）和15（pKₐ6.4）在掺入RNA时，在中性条件下可能会被质子化。核苷3a - d主要以酮（内酰胺）形式存在，K(TAUT)（酮/烯醇）值为400 - 1200，而吡咯并[2,3-d]嘧啶异鸟苷衍生物4a - c的该值为10³ - 10⁴，异鸟苷本身的该值为10，这将减少RNA与U的错配。
