A Microwave-Enhanced Synthesis and Biological Evaluation of N-Aryl‑5,6,7,8‑tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amines

Qing Han,Qingming Wang,Yaquan Sun,Jingjiao Sui,Zijian Yin

doi:10.21577/0103-5053.20190044

Abstract

A series of N-aryl-5,6,7,8-tetra-hydrobenzo[4,5]thieno[2,3-d ]pyrimidin-4-amines were synthesized in moderate to good yield by using a microwave-enhanced conditions. The selected compounds were evaluated for their cytotoxic effects (IC50 values) on human pulmonary carcinoma (A549), murine BALB/c spontaneous colon adenocarcinoma (CT26) and human hepatocellular liver carcinoma (HepG2) cell lines in vitro. Amongst these compounds, one compound was found to have the better cytotoxic activity with reference to the standard Erlotinib hydrochloride (Tarceva™) against A549 (IC50 = 16.06 ± 0.09 µM) and HepG2 (IC50 = 15.01 ± 0.31 µM) cell lines. Especially, two compounds showed best cytotoxic effects against CT26 (IC50 = 11.38 ± 0.44 µM) and HepG2 (IC50 = 8.51 ± 0.52 µM) cell lines, respectively. The preliminary structure-activity relationships were disclosed and the thieno[2,3-d] pyrimidine skeleton could be exploited to potential antitumor agents in the future.

Highlights

In investigation, we found the presence of several marketed anticancer drugs such as gefitinib I (IressaTM),1 vandetanib II (CaprelsaTM),2 lapatinib III (TykerbTM),3 erlotinib IV (TarcevaTM),4 tandutinib V (MLN518)5 and icotinib VI (ConmanaTM)6 (Figure 1), which have a quinazoline nucleus, the thieno[2,3-d]pyrimidine core can be considered a bioisostere of this quinazoline core.7In literatures,8-10 thieno[2,3-d]pyrimidin-4-amine derivatives exhibit a broad range of biological and pharmacological activities associated with their heterocyclic scaffold and have been widely used in the medical field
The first method involves the synthesis of thieno[2,3-d] pyrimidin-4(3H)-one (XVII) from compounds XIV, XV and XVI, compound XVII is converted to 4-chlorothieno[2,3-d]pyrimidine (XIX), and the target compound XX is obtained from XIX
The synthetic strategy used in this study is outlined in Scheme 1. 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene3-carbonitrile was prepared using a modified Gewald procedure via the reaction of cyclohexanone, malononitrile and sulfur in the presence of potassium carbonate (K2CO3), which serves as a heterogeneous solid basic catalyst, in ethanol

Summary

Introduction

We found the presence of several marketed anticancer drugs such as gefitinib I (IressaTM), vandetanib II (CaprelsaTM), lapatinib III (TykerbTM), erlotinib IV (TarcevaTM), tandutinib V (MLN518) (phase II clinical trials) and icotinib VI (ConmanaTM) (Figure 1), which have a quinazoline nucleus, the thieno[2,3-d]pyrimidine core can be considered a bioisostere of this quinazoline core.. Thieno[2,3-d]pyrimidin-4-amine derivatives exhibit a broad range of biological and pharmacological activities associated with their heterocyclic scaffold and have been widely used in the medical field. Thieno[2,3-d]pyrimidin-4-amine displays a wide range of biological activity including anti-tumor, anti-bacterial,

A Microwave-Enhanced Synthesis and Biological Evaluation

Results and Discussion

Conclusions