Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo[2,1-f][1,2,4]triazine derivatives

Hao-Yue Xiang; Yan-Hong Chen; Yi Wang; Xi Zhang; Jian Ding; Ling-Hua Meng; Chun-Hao Yang

doi:10.1016/j.bmcl.2020.127194

Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo[2,1-f][1,2,4]triazine derivatives

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127194. doi: 10.1016/j.bmcl.2020.127194. Epub 2020 Apr 13.

Authors

Hao-Yue Xiang¹, Yan-Hong Chen², Yi Wang², Xi Zhang², Jian Ding², Ling-Hua Meng³, Chun-Hao Yang⁴

Affiliations

¹ College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address: lhmeng@simm.ac.cn.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address: chyang@simm.ac.cn.

PMID: 32317209
DOI: 10.1016/j.bmcl.2020.127194

Abstract

A series of 6-aminocarbonyl pyrrolo[2,1-f][1,2,4]triazine derivatives were designed by scaffold hopping strategy. The IC₅₀ values of compound 14a against PI3Ks were measured, showing selective activity against p110α and p110δ with IC₅₀s of 122 nM and 119 nM respectively. All the synthesized compounds were evaluated for their antiproliferative activity against human cancer cells by SRB assay. Compounds 14a, 14p and 14q exhibited potent antiproliferative activity against five types of human cancer cells and the PK property of 14q was also investigated here.

Keywords: Antiproliferative; Cancer; Kinase; PI3K inhibitors; Pyrrolo[2,1-f][1,2,4]triazine; Therapy.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Triazines
pyrrolo(2,1-f)(1,2,4)triazine
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human