Design, Synthesis and Anti-Proliferative Activities of 2,6-Substituted Thieno[3,2-d]pyrimidine Derivatives Containing Electrophilic Warheads.

Qiumeng Zhang,Zonglong Hu,Yi Chen,Wei Lu,Qianqian Shen

doi:10.3390/molecules22050788

Abstract

Thieno[3,2-d]pyrimidine as an effective pharmacophore has been extensively studied. However, its 2,6-substituted derivatives are rarely reported. In the present study, eighteen 2,6-substituted thieno[3,2-d]pyrimidine derivatives containing electrophilic warheads were designed based on the first known Fibroblast growth factor receptor-4 (FGFR4) inhibitor Blu9931. Unexpectedly, all of the derivatives exhibited negligible activity against FGFR4. However, most of the target compounds exhibited antiproliferative activities against four human cancer cell lines, including A431, NCI-H1975, Ramos and SNU-16. Compound 12 showed the most potent antiproliferative activities on the above four cell lines with IC50 values of 1.4 μM, 1.2 μM, 0.6 μM, and 2.6 μM, respectively. Additionally, the antiproliferative activity of 12 against MDA-MB-221 proved that 12 had the selectivity towards certain tumor cell lines. Furthermore, preliminary structure-activity relationship analysis was discussed based on the experimental data.

Highlights

Cancer is one of the most formidable enemies to the public health worldwide [1]
Over the past few decades, more and more drugs with fused bicyclic pyrimidine scaffolds have been approved by the Food and Drug Administration (FDA) with significant biological activities, especially antitumor activities
Compound 4 was synthesized according to published procedures [29] and treated with urea at 170 ◦ C to produce compound 5

Summary

Introduction

Cancer is one of the most formidable enemies to the public health worldwide [1]. Over the past few decades, more and more drugs with fused bicyclic pyrimidine scaffolds have been approved by the Food and Drug Administration (FDA) with significant biological activities, especially antitumor activities. These fused bicyclic pyrimidines exhibit anticancer function by targeting different kinases, such as Epidermal growth factor receptor (EGFR), Brutons tyrosine kinase (BTK), Janus Kinase (JAK), and Phosphatidylinositol 3 kinase (PI3 K) (Figure 1) [2,3,4,5,6]. Various thieno[3,2-d]pyrimidine derivatives have attracted attention due to their broad spectrum activities, such as GDC-0941 and Olmutinib (Figure 2) [7,8,9,10,11,12,13,14,15,16,17,18]

Methods

Results

Conclusion