Novel 2, 5-diketopiperazine derivatives as potent selective histone deacetylase 6 inhibitors: Rational design, synthesis and antiproliferative activity

Xin Chen; Xinyang Chen; Raphael R Steimbach; Tong Wu; Hongmei Li; Wenjia Dan; Peidong Shi; Chenyu Cao; Ding Li; Aubry K Miller; Zhixia Qiu; Jinming Gao; Yong Zhu

doi:10.1016/j.ejmech.2019.111950

Novel 2, 5-diketopiperazine derivatives as potent selective histone deacetylase 6 inhibitors: Rational design, synthesis and antiproliferative activity

Eur J Med Chem. 2020 Feb 1:187:111950. doi: 10.1016/j.ejmech.2019.111950. Epub 2019 Dec 6.

Authors

Xin Chen¹, Xinyang Chen¹, Raphael R Steimbach², Tong Wu¹, Hongmei Li³, Wenjia Dan¹, Peidong Shi¹, Chenyu Cao¹, Ding Li¹, Aubry K Miller⁴, Zhixia Qiu⁵, Jinming Gao⁶, Yong Zhu⁷

Affiliations

¹ Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
² Cancer Drug Development Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; Biosciences Faculty, University of Heidelberg, 69120, Heidelberg, Germany.
³ School of Science, China Pharmaceutical University, Nanjing, 210009, PR China.
⁴ Cancer Drug Development Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
⁵ School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
⁶ Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China. Electronic address: [email protected].
⁷ School of Science, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].

PMID: 31865013
DOI: 10.1016/j.ejmech.2019.111950

Abstract

Histone deacetylase 6 (HDAC6) has gained popular attention for its wide participation in various pathological process recently. In this paper, a series of novel derivatives containing 2, 5-diketopiperazine (DKP) skeleton were developed as potent selective HDAC6 inhibitors (sHDAC6is). Most of these compounds exhibited low nanomolar IC₅₀ values toward HDAC6, and the best compound was 21b (IC₅₀ = 0.73 nM) which had 144-10941-fold selectivity over other HDAC isoforms. Western blot assay further validated these compounds to be sHDAC6is. Molecular simulation of 21b was conducted to rationalize the high binding affinity for HDAC6. In the cytotoxicity experiment, 18a, 18b and 18d gave superior or comparable influence on the growth of two multiple myeloma cells U266 and RPMI-8226 compared to ACY-1215. Moreover, the combination of 18a and adriamycin showed synergistic effect against non-small cell lung cancer cell A549. 18a and 18b also demonstrated appropriate drug metabolism in human liver microsome (HLM).

Keywords: Combination therapy; DKP; HDAC6 inhibitor; Selectivity; Synthesis.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Histone Deacetylase 6 / antagonists & inhibitors*
Histone Deacetylase 6 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
HDAC6 protein, human
Histone Deacetylase 6