Design and synthesis of phosphoryl-substituted diphenylpyrimidines (Pho-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors: Targeted treatment of B lymphoblastic leukemia cell lines

Yang Ge; Haijun Yang; Changyuan Wang; Qiang Meng; Lei Li; Huijun Sun; Yuhong Zhen; Kexin Liu; Yanxia Li; Xiaodong Ma

doi:10.1016/j.bmc.2016.11.054

Design and synthesis of phosphoryl-substituted diphenylpyrimidines (Pho-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors: Targeted treatment of B lymphoblastic leukemia cell lines

Bioorg Med Chem. 2017 Jan 15;25(2):765-772. doi: 10.1016/j.bmc.2016.11.054. Epub 2016 Nov 29.

Authors

Yang Ge¹, Haijun Yang¹, Changyuan Wang¹, Qiang Meng¹, Lei Li¹, Huijun Sun¹, Yuhong Zhen¹, Kexin Liu¹, Yanxia Li², Xiaodong Ma³

Affiliations

¹ College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
² Department of Respiratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
³ College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.

PMID: 27956037
DOI: 10.1016/j.bmc.2016.11.054

Abstract

A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17μM and 6.69μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.

Keywords: BTK; DPPY; Inhibitor; Leukemia; Phosphoryl.

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Flow Cytometry
Humans
Molecular Dynamics Simulation
Molecular Structure
Organophosphorus Compounds / chemical synthesis*
Organophosphorus Compounds / chemistry
Organophosphorus Compounds / pharmacology*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Organophosphorus Compounds
Protein Kinase Inhibitors
Pyrimidines
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human