Design, synthesis and SAR studies of NAD analogues as potent inhibitors towards CD38 NADase

  • Molecules. 2014 Sep 29;19(10):15754-67. doi: 10.3390/molecules191015754.
Shengjun Wang  1 ,  Wenjie Zhu  2 ,  Xuan Wang  3 ,  Jianguo Li  4 ,  Kehui Zhang  5 ,  Liangren Zhang  6 ,  Yong-Juan Zhao  7 ,  Hon Cheung Lee  8 ,  Lihe Zhang  9
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 2. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518052, China. [email protected].
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 5. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 6. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 7. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518052, China. [email protected].
  • 8. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518052, China. [email protected].
  • 9. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
PMID: 25268725 DOI: 10.3390/molecules191015754
Abstract

Nicotinamide adenine dinucleotide (NAD), one of the most important coenzymes in the cells, is a substrate of the signaling enzyme CD38, by which NAD is converted to a second messenger, cyclic ADP-ribose, which releases calcium from intracellular calcium stores. Starting with 2'-deoxy-2'-fluoroarabinosyl-β-nicotinamide adenine dinucleotide (ara-F NAD), a series of NAD analogues were synthesized and their activities to inhibit CD38 NAD glycohydrolase (NADase) were evaluated. The adenosine-modified analogues showed potent inhibitory activities, among which 2'-deoxy-2'-fluoroarabinosyl-β-nicotinamide guanine dinucleotide (ara-F NGD) was the most effective one. The structure-activity relationship of NAD analogues was also discussed.

Products