Design, synthesis and biological characterization of novel inhibitors of CD38

Min Dong; Yuan-Qi Si; Shuang-Yong Sun; Xiao-Ping Pu; Zhen-Jun Yang; Liang-Ren Zhang; Li-He Zhang; Fung Ping Leung; Connie Mo Ching. Lam; Anna Ka Yee Kwong; Jianbo Yue; Yeyun Zhou; Irina A. Kriksunov; Quan Hao; Hon Cheung Lee

doi:10.1039/C0OB00768D

Design, synthesis and biological characterization of novel inhibitors of CD38†

Min Dong,^a Yuan-Qi Si,^a Shuang-Yong Sun,^a Xiao-Ping Pu,^a Zhen-Jun Yang,^a Liang-Ren Zhang,^a Li-He Zhang,*^a Fung Ping Leung,^b Connie Mo Ching. Lam,^b Anna Ka Yee Kwong,^b Jianbo Yue,^b Yeyun Zhou,^c Irina A. Kriksunov,^c Quan Hao^b and Hon Cheung Lee*^b

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* Corresponding authors

^a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
E-mail: zdszlh@bjmu.edu.cn
Fax: +86-10-82802724
Tel: +86-10-82801700

^b Department of Physiology, University of Hong Kong, Hong Kong, China
E-mail: leehc@hku.hk
Fax: +852-2817-1334
Tel: +852-2819-9163

^c MacCHESS, Cornell High Energy Synchrotron Source, Cornell University, Ithaca, USA

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.

Organic & Biomolecular Chemistry

Design, synthesis and biological characterization of novel inhibitors of CD38†

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Design, synthesis and biological characterization of novel inhibitors of CD38

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