Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists,RSC Medicinal Chemistry

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Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-09-06 00:00:00 , DOI: 10.1039/c7md00397h
Kiran S. Toti _{1,

2,

3,

4,

5} , Shanu Jain _{1,

2,

3,

4,

5} , Antonella Ciancetta _{1,

2,

3,

4,

5} , Ramachandran Balasubramanian _{1,

2,

3,

4,

5} , Saibal Chakraborty _{1,

2,

3,

4,

5} , Ryan Surujdin _{1,

2,

3,

4,

5} , Zhen-Dan Shi _{4,

6,

7,

8,

9} , Kenneth A. Jacobson _{1,

2,

3,

4,

5}

Affiliation

Both agonists and antagonists of the UDP-activated P2Y₆ receptor (P2Y₆R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a south-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y₆R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5′-diphosphate. (S)-Methanocarba dinucleotide potency was compatible with a N⁴-methoxy modification on the proximal nucleoside that is assumed to bind at the P2Y₆R similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2Y₆R binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested the same ribose conformational preferences found empirically.

中文翻译：

含有（S）-甲氨基甲环作为P2Y ₆受体激动剂的嘧啶核苷酸

UDP激活的P2Y ₆受体（P2Y ₆ R）的激动剂和拮抗剂已被建议用于治疗，例如癌症，炎症，神经退行性疾病和糖尿病。合成了含有南双环[3.1.0]己烷（（S）-甲氨基甲酸）环系统代替核糖环的尿嘧啶核苷酸，并在钙动员测定中显示为有效的P2Y ₆ R激动剂。（S）-甲氨基甲酸酯修饰与嘧啶上的5-碘或4-甲氧基亚氨基相容，但与α，β-亚甲基5'-二磷酸不相容。（S）-Methanocarba二核苷酸效力与假定在P2Y ₆结合的近端核苷上的N ^4-甲氧基修饰兼容R与UDP类似；在远端核苷部分上优选（N）-甲氨基甲酸酯。这表明远端二核苷酸P2Y ₆ R结合位点更喜欢可以达到（N）构象的核糖样基团，而不是（S）。通过同源性建模，对接和分子动力学模拟对二核苷酸结合进行建模，这表明凭经验发现了相同的核糖构象偏好。

更新日期：2017-10-18

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