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Issue 9, 2011
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Design, synthesis and biological characterization of novel inhibitors of CD38

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Abstract

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca2+ messenger molecule, cyclic ADP-ribose, from NAD+. It is well established that this novel Ca2+ signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD+ complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound1–14). A number of these compounds exhibited moderate inhibition of the NAD+ utilizing activity of CD38, with Compound4 showing the highest potency. The crystal structure of CD38/Compound4 complex and computer simulation of Compound7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.

Graphical abstract: Design, synthesis and biological characterization of novel inhibitors of CD38

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Supplementary files

Article information


Submitted
23 Sep 2010
Accepted
17 Feb 2011
First published
17 Feb 2011

Org. Biomol. Chem., 2011,9, 3246-3257
Article type
Paper

Design, synthesis and biological characterization of novel inhibitors of CD38

M. Dong, Y. Si, S. Sun, X. Pu, Z. Yang, L. Zhang, L. Zhang, F. P. Leung, C. M. Ching. Lam, A. K. Y. Kwong, J. Yue, Y. Zhou, I. A. Kriksunov, Q. Hao and H. Cheung Lee, Org. Biomol. Chem., 2011, 9, 3246
DOI: 10.1039/C0OB00768D

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