Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity.
10.1016/j.apsb.2019.11.011
- Author:
Yahui HUANG
1
;
Shuqiang CHEN
1
;
Shanchao WU
1
;
Guoqiang DONG
1
;
Chunquan SHENG
1
Author Information
1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Publication Type:Journal Article
- Keywords:
Antitumor activity;
BSA, bovine serum albumin;
CCK-8, cell counting kit-8;
CPT, camptothecin;
DIPEA, N,N-diisopropylethylamine;
DMF, dimethylformamide;
Dual inhibitors;
Eto, etoposide;
Evodiamine;
HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;
HDAC, histone deacetylase;
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;
Topoisomerase;
ZBG, zinc-binding group
- From:
Acta Pharmaceutica Sinica B
2020;10(7):1294-1308
- CountryChina
- Language:English
-
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 and antitumor potency. Particularly, compound was orally active and possessed excellent antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, .) 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.
