Synthesis and biological evaluation of 6-phenylpurine linked hydroxamates as novel histone deacetylase inhibitors.

Autor: Chen D; Drug Development Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore., Soh CK; Drug Development Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore., Goh WH; Drug Development Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore., Wang Z; H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA 30318, United States., Wang H; Drug Development Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore; Probit Pharmaceuticals Pte. Ltd., 10 Anson Road #27-15, Singapore 079903, Republic of Singapore. Electronic address: mcbwhs@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 May; Vol. 98, pp. 103724. Date of Electronic Publication: 2020 Mar 04.
DOI: 10.1016/j.bioorg.2020.103724
Abstrakt: A series of 6-phenylpurine based hydroxamates have been designed, synthesized and evaluated. Compound 3b and its analogs are potent histone deacetylase (HDAC) but weak PI3K/mTOR inhibitors. These compounds demonstrated broad anti-cancer activities against 38 cancer cell lines with leukemia, lymphoma, and the majority of liver cancer cell lines exhibiting the most sensitivity towards these compounds. Compound 3b demonstrated modulation of HDAC targets in vitro in a dose-dependent manner. It has good in vitro ADME profile that translated into a greatly improved pharmacokinetic profile. 3b also demonstrated modulation of HDACs in tumors in a PC-3 xenograft model. It was further evaluated in combination therapies in vitro. It exhibited additive or synergistic growth inhibition effect in HepG2 cells when combined with a number of approved drugs such as sorafenib, sunitinib, and erlotinib. Hence, 3b has the potential to be combined with the above to treat advanced liver cancer. As such, current data warrant further evaluation, optimization, and subsequent in vivo validation of the potential combination therapies.
Competing Interests: Declaration of Competing Interest HW, DC, and CKS are inventors of patent applications associated with this publication. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: