Synthesis, biological evaluation and molecular modeling studies of psammaplin A and its analogs as potent histone deacetylases inhibitors and cytotoxic agents

[Display omitted] In this study, a concise synthetic method of psammaplin A was achieved from 3-bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs f...

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Published in:Bioorganic & medicinal chemistry letters 2016-09, Vol.26 (17), p.4372-4376
Main Authors: Wen, Jiachen, Bao, Yu, Niu, Qun, Liu, Jiang, Yang, Jinyu, Wang, Wanqiao, Jiang, Tao, Fan, Yinbo, Li, Kun, Wang, Jian, Zhao, Linxiang, Liu, Dan
Format: Article
Language:English
Subjects:
Antiproliferation
Cytotoxins - chemical synthesis
Cytotoxins - chemistry
Cytotoxins - pharmacology
Disulfides - chemical synthesis
Disulfides - chemistry
Disulfides - pharmacology
Enzyme Activation - drug effects
Histone Deacetylase Inhibitors - chemical synthesis
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Histone deacetylases inhibitors
Humans
Molecular Docking Simulation
Molecular modeling
Psammaplin A
Structure activity relationship
Tyrosine - analogs & derivatives
Tyrosine - chemical synthesis
Tyrosine - chemistry
Tyrosine - pharmacology
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Summary:[Display omitted] In this study, a concise synthetic method of psammaplin A was achieved from 3-bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs focused on the variations of substituents at the benzene ring and modifications at the oxime moiety were synthesized. Among all the synthesized compounds, 5d and 5e showed better HDAC inhibition than psammaplin A and comparable cytotoxicity against four cancer cell lines (PC-3, MCF-7, A549 and HL-60). Molecular docking and dynamics simulation revealed that (i) hydrogen atom of the oxime group interacts with Asp99 of HDAC1 through a water bridged hydrogen bond and (ii) a hydroxyl group is optimal attached on the para-position of benzene, interacting with Glu203 at the entrance to the active site tunnel.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.12.094