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

[ Vol. 16 , Issue. 6 ]

Author(s):

Penghui Wang, Zhining Li, Lulu Jiang, Lu Zhou* and Deyong Ye*   Pages 678 - 684 ( 7 )

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.

Affiliation:

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai



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