Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 121, Issue -, Pages 272-282Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.05.033
Keywords
Design and synthesis; Hsp90 inhibitors; CETSA; Molecular dynamics simulation
Categories
Funding
- 973 Program [2010CB833802]
- NSFC [81273384, 91313303, U1405223]
- Natural Science Foundation of Shandong Province, China [ZR2013HQ048]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13028]
- Distinguished Young Scholars Grant [30325044]
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Heat shock protein 90 (Hsp90) is an attractive chemotherapeutic target for antitumor drug development. Herein, we reported the design and synthesis of two series of novel N-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamides as Hsp90 inhibitors using (S)-Tic (1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid) (A1-13) and (R)-Tic (B1-13) as scaffold, respectively. Cellular thermal shift assay (CETSA) screening showed that compounds B1-13 with (R)-Tic scaffold exhibited potent ability to stabilize Hsp90 alpha. Compound B7 showed not only the most potent ability to induce thermal stabilization of Hsp90 alpha but also the strongest cytotoxicity. The IC50 values of B7 were 0.98 mu M and 1.74 mu M against the proliferation of human breast cancer MDA-MB-231 and human cervical cancer HeLa cell lines, respectively. Moreover, CETSA melt and ITDRFCETSA (isothermal dose-response fingerprint) curves confirmed that B7 bound to Hsp90 alpha in 293T cells. Western blotting results indicated that B7 induced the degradation of Hsp90 clients CDK4, Her2, Cdc-2 and C-raf. In addition, docking and Molecular dynamics (MD) refinement of the B7-Hsp90 complex showed that the binding model of B7 to Hsp90 was similar with that of 8-benzyladenines. The overall properties warrant compound B7 a promising lead for the development of Hsp90 inhibitor antitumor drugs. (C) 2016 Elsevier Masson SAS. All rights reserved.
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