Design, synthesis and anti-tumor activities of carbamate derivatives of cinobufagin

Yang Zhou; Jinjun Hou; Huali Long; Zijia Zhang; Min Lei; Wanying Wu

doi:10.1016/j.steroids.2020.108749

Design, synthesis and anti-tumor activities of carbamate derivatives of cinobufagin

Steroids. 2020 Dec:164:108749. doi: 10.1016/j.steroids.2020.108749. Epub 2020 Oct 13.

Authors

Yang Zhou¹, Jinjun Hou¹, Huali Long¹, Zijia Zhang¹, Min Lei², Wanying Wu³

Affiliations

¹ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
² Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: mlei@simm.ac.cn.
³ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: wanyingwu@simm.ac.cn.

PMID: 33065151
DOI: 10.1016/j.steroids.2020.108749

Abstract

A series of cinobufagin-3-yl nitrogen-containing-carbamate derivatives were designed, synthesized, and evaluated for their proliferation inhibition activities. The structure-activity relationships suggested that the substituents at C-16 was a crucial factor for the potency and that follows this trends: acetic ester ≫ benzoic ester ≈ hydroxy > carbamate. Compounds 3f, 3g, 3h, and 3i exhibited significant in vitro antiproliferative activities against the eight tested tumor cell lines, with IC₅₀ values ranging from 8.1 to 237.4 nM. Furthermore, 3g tartrate (3g-TA) significantly inhibited tumor growth by 64.5%, 83.9%, and 93.0% at a doses of 4, 6, 8 mg/kg/qod by ip, respectively.

Keywords: Antiproliferative activities; Cardiac glycosides; Cinobufagin; Cytotoxicity; Natural product.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Bufanolides / chemistry
Bufanolides / pharmacology*
Carbamates / chemistry*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Design*
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Solubility
Spectrum Analysis / methods

Substances

Antineoplastic Agents
Bufanolides
Carbamates
cinobufagin