Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities

Jia-Li Song; Juan Zhang; Chang-Liang Liu; Chao Liu; Kong-Kai Zhu; Fei-Fei Yang; Xi-Gong Liu; João Paulo Figueiró Longo; Luis Alexandre Muehlmann; Ricardo Bentes Azevedo; Yu-Ying Zhang; Yue-Wei Guo; Cheng-Shi Jiang; Hua Zhang

doi:10.1016/j.bmcl.2017.09.013

Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4682-4686. doi: 10.1016/j.bmcl.2017.09.013. Epub 2017 Sep 8.

Authors

Affiliations

¹ School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
² Faculty of Ceilandia, University of Brasilia, Brasilia 72220275, Brazil; Institute of Biological Sciences, University of Brasília, Brasília 70910900, Brazil.
³ Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan 250100, China.
⁵ Institute of Biological Sciences, University of Brasília, Brasília 70910900, Brazil.
⁶ School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
⁷ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
⁹ School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].

PMID: 28919340
DOI: 10.1016/j.bmcl.2017.09.013

Abstract

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC₅₀=2.5μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC₅₀=6.5-36.2μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.

Keywords: 2-Cyanoacryloyl; Anti-proliferative activity; Michael acceptor; NF-κB; Pregnenolone.

Publication types

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

MeSH terms

A549 Cells
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyanoacrylates / chemistry*
Drug Design*
Drug Screening Assays, Antitumor
HL-60 Cells
Humans
MCF-7 Cells
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism*
Pregnenolone / chemistry*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Cyanoacrylates
NF-kappa B
Pregnenolone