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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2014-09, Vol.19 (10), p.15754-15767
• Main Authors: Wang, Shengjun, Zhu, Wenjie, Wang, Xuan, Li, Jianguo, Zhang, Kehui, Zhang, Liangren, Zhao, Yong-Juan, Lee, Hon Cheung, Zhang, Lihe
• Format: Article
• Language: English
• Subjects: Adenosine; ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - chemistry; CD38; Chemistry Techniques, Synthetic; Drug Design; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Guanine Nucleotides - chemical synthesis; Guanine Nucleotides - chemistry; Guanine Nucleotides - pharmacology; inhibitors; Molecular Structure; NAD - analogs & derivatives; NAD - chemical synthesis; NAD - chemistry; NAD - pharmacology; NAD analogues; Phosphates; Physiology; Protein Binding; Reagents; Substrate Specificity; synthesis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules191015754

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.