Design and Synthesis of the Diazirine-based Clickable Photo-affinity Probe Targeting Sphingomyelin Synthase 2

Author(s): Penghui Wang , Zhining Li , Lulu Jiang , Lu Zhou* , Deyong Ye* .

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 6 , 2019

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Abstract:

Background: SMS family plays a very important role in sphingolipids metabolism and is involved in the membrane mobility and signaling transduction.

Methods: SMS2 subtype was related to a variety of diseases and could be regarded as a promising potential drug target. However, the uncertainty of the binding sites and the molecular mechanism of action limited the development of SMS2 inhibitors. Herein, we discovered a photo-affinity probe PAL-1 targeting SMS2.

Results: The enzyme inhibitory activity and the photo-affinity labeling experiments showed that PAL-1 could be mono-labeled on SMS2.

Conclusion: In summary, starting from the N-arylbenzamides core structure and the minimalist terminal alkyne-containing diazirine photo-crosslinker, we designed and synthesized a photoaffinity probe PAL-1 targeting SMS2. The enzymatic inhibitory activity study showed that PAL-1 exhibited superior selectivities for SMS2 with an IC50 of 0.37 µM over SMS1.

Keywords: Sphingomyelin synthase 2, sphingomyelin, photo-affinity labeling, diazirine, phosphatidylcholine, phosphoethanolamine.

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Article Details

VOLUME: 16
ISSUE: 6
Year: 2019
Page: [678 - 684]
Pages: 7
DOI: 10.2174/1570180816666181106154601
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