Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy.

Aaron Tan,Giorgia Pastorin,Gopalakrishnan Venkatesan,Stephanie Federico,Siew Lee Cheong,Karl-Norbert Klotz,Giampiero Spalluto,Jason Siau Ee Loo,Maria V Babak,Clarissa Lim,Deron Raymond Herr,Yu Zong Chen,Wei-Yi Ong

doi:10.3390/molecules24203661

Abstract

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.

Highlights

Gastrointestinal (GI)-related cancers are pathological conditions that account for at least 30% of cancer-related deaths worldwide [1]
In continuation to the previous studies, we aimed to investigate the effect of switching the position of the carbonyl group on indolylpyrimidylpiperazine (IPP) towards the activity at both A2A and A3 receptors in our present work
Derivatives, compound 4 was shown as a human A3 adenosine receptor (hA3 AR)-selective partial agonist with an EC50 of 2.89 ± 0.55 μM

Summary

Introduction

Gastrointestinal (GI)-related cancers are pathological conditions that account for at least 30% of cancer-related deaths worldwide [1]. Colorectal cancer is becoming a predominant cancer worldwide, with 746,300 and 614,300 new cases reported in 2012 among men and women, respectively [3]; its incidence and death rates are projected to rise by 60% by 2030 [4]. CF101 exhibited a myeloprotective effect in the murine model [7], suggesting improved tolerability and decreased side effects From these studies, it emerges that the activation of the hA3 AR clearly plays a crucial role in tumour progression: this receptor is overexpressed in several pathological conditions [8] such as colorectal cancer [9,10], breast cancer [10,11], brain cancer [12] and leukaemia [13]. The level of upregulation of hA3 AR was found to be directly correlated to the disease severity [9], making it a representative biomarker for colorectal cancer

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