ORIGINAL ARTICLE
Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

https://doi.org/10.1016/j.apsb.2019.11.011Get rights and content
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Abstract

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

Graphical abstract

Evodiamine derivative 30a is a dual-selective inhibitor against histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2), which possesses excellent in vivo antitumor activity in the HCT116 xenograft model without significant toxicity.

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Key words

Evodiamine
Histone deacetylase
Topoisomerase
Dual inhibitors
Antitumor activity

Abbreviations

BSA
bovine serum albumin
CCK-8
cell counting kit-8
CPT
camptothecin
DIPEA
N,N-diisopropylethylamine
DMF
dimethylformamide
Eto
etoposide
HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
HDAC
histone deacetylase
IP
intraperitoneal injection
OD
optical density
PI
propidium iodide
SD
Sprague–Dawley
SDS
sodium dodecyl sulfate
TAE
Tris-acetate-EDTA
TGI
tumor growth inhibition
TOP
topoisomerase
ZBG
zinc-binding group

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Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.