2. Academic Validation
  3. Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents

Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents

  • Eur J Med Chem. 2018 Feb 10:145:11-22. doi: 10.1016/j.ejmech.2017.12.094.
Yun-Kai Shi 1,  Bo Wang 1,  Xiao-Li Shi 1,  Yuan-Di Zhao 1,  Bin Yu 2,  Hong-Min Liu 3
Affiliations

Affiliations

  • 1 Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China.
  • 2 Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China. Electronic address: zzuyubin@hotmail.com.
  • 3 Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China. Electronic address: liuhm@zzu.edu.cn.
PMID: 29310026 DOI: 10.1016/j.ejmech.2017.12.094
Abstract

A series of new steroidal pyridines have been synthesized through the based-promoted three-component reaction and preliminarily evaluated for their antiproliferative activity against different types of Cancer cell lines. SARs studies showed that the heterocyclic rings attached to the 4-position of the pyridine ring were preferred over the phenyl rings for the activity. Among these compounds, the most potent compound exhibited good growth inhibition against all the tested Cancer cells, especially for PC-3 cells with an IC50 value of 1.55 μM. Further mechanistic studies revealed that the most potent compound inhibited colony formation, migration and evasion of PC-3 cells in a concentration-dependent manner as well as induced Apoptosis of PC-3 cells possibly through the mitochondria-related apoptotic pathways. Caspase-3/-9 and PARP were activated, finally leading to the Apoptosis of PC-3 cells. For the androgen-sensitive (AR+) prostate Cancer cell line LNCaP, the most potent compound was less potent than abiraterone with the IC50 value of 8.48 and 3.29 μM, respectively. The most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved Anticancer potency and selectivity. The synthesized steroidal pyridines contain the functional -OEt and CN groups, which could be used for further modifications for the construction of the steroid library.

Keywords

Antiproliferative activity; Biaryl compounds; Prostate cancer; Pyridines; Steroids.

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