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

Yahui Huang; Shuqiang Chen; Shanchao Wu; Guoqiang Dong; Chunquan Sheng

doi:10.1016/j.apsb.2019.11.011

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

Acta Pharm Sin B. 2020 Jul;10(7):1294-1308. doi: 10.1016/j.apsb.2019.11.011. Epub 2019 Nov 21.

Authors

Yahui Huang¹, Shuqiang Chen¹, Shanchao Wu¹, Guoqiang Dong¹, Chunquan Sheng^{1

2}

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
² School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.

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.

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.