2. Academic Validation
  3. Design and synthesis of neolamellarin a derivatives targeting heat shock protein 90

Design and synthesis of neolamellarin a derivatives targeting heat shock protein 90

  • Eur J Med Chem. 2017 Jul 28:135:24-33. doi: 10.1016/j.ejmech.2017.04.019.
Long Jiang 1,  Ruijuan Yin 1,  Xueting Wang 1,  Jiajia Dai 1,  Jing Li 1,  Tao Jiang 2,  Rilei Yu 3
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China. Electronic address: jiangtao@ouc.edu.cn.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China. Electronic address: ryu@ouc.edu.cn.
PMID: 28426997 DOI: 10.1016/j.ejmech.2017.04.019
Abstract

In this study, we designed and synthesized a novel family of neolamellarin A derivatives that showed high inhibitory activity toward heat shock protein 90 (HSP90), a kinase associated with cell proliferation. The 3,4-bis(catechol)pyrrole scaffold and the benzyl group with methoxy modification at N position of pyrrole are essential to the HSP90 inhibitory activity and cytotoxicity of these compounds. Western blot analysis demonstrated that these compounds induced dramatic depletion of the examined client proteins of HSP90, and accelerated Cancer cell Apoptosis. Docking simulations suggested that the binding mode of 9p was similar to that of the VER49009, a potent inhibitor of HSP90. Further molecular dynamics simulation indicated that the hydrophobic interactions as well as the hydrogen bonds contributed to the high affinity of 9p to HSP90.

Keywords

3,4-Bis(catechol)pyrrole scaffold; Docking; Hsp90 inhibition; Molecular dynamics simulation; Neolamellarin A derivatives.

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