Toti Kiran S, Jain Shanu, Ciancetta Antonella, Balasubramanian Ramachandran, Chakraborty Saibal, Surujdin Ryan, Shi Zhen-Dan, Jacobson Kenneth A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD 20850 USA.
Medchemcomm. 2017 Oct 1;8(10):1897-1908. doi: 10.1039/C7MD00397H. Epub 2017 Sep 6.
Both agonists and antagonists of the UDP-activated P2Y receptor (P2YR) 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 P2YR 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 N-methoxy modification on the proximal nucleoside that is assumed to bind at the P2YR similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2YR 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.
UDP 激活的 P2Y 受体（P2YR）的激动剂和拮抗剂都已被提议用于治疗癌症、炎症、神经退行性疾病和糖尿病等病症。合成了含有南 - 双环[3.1.0]己烷（(S)-甲碳环）环系统取代核糖环的尿嘧啶核苷酸，并在钙动员试验中显示为有效的 P2YR 激动剂。(S)-甲碳环修饰与嘧啶上的 5 - 碘或 4 - 甲氧基亚氨基基团兼容，但与α,β - 亚甲基 5´ - 二磷酸不兼容。(S)-甲碳环二核苷酸的效力与近端核苷上的 N - 甲氧基修饰兼容，该修饰被认为在 P2YR 上的结合方式与 UDP 类似；远端核苷部分优选(N)-甲碳环。这表明远端二核苷酸 P2YR 结合位点更喜欢能够获得(N)构象而非(S)构象的类似核糖的基团。通过同源建模、对接和分子动力学模拟对二核苷酸结合进行建模，结果表明从实验中发现了相同的核糖构象偏好。
