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

NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Centre for Life Sciences, #05-01, 28 Medical Drive, Singapore 117456, Singapore
Department of Pharmacy, National University of Singapore, Singapore 119260, Singapore
Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany
Department of Pharmacology, National University of Singapore, Singapore 117600, Singapore
Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126 Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, 34127 Trieste, Italy
Department of Anatomy, National University of Singapore, Singapore 119260, Singapore
School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, 1, Jalan Taylors, Subang Jaya, Selangor 47500, Malaysia
Authors to whom correspondence should be addressed.
Academic Editor: Loredana Cappellacci
Molecules 2019, 24(20), 3661; (registering DOI)
Received: 20 September 2019 / Revised: 4 October 2019 / Accepted: 8 October 2019 / Published: 11 October 2019
(This article belongs to the Section Organic Chemistry)
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 (36), 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. View Full-Text
Keywords: gastrointestinal cancer; hA3AR; partial agonists; indolylpyrimidylpiperazines gastrointestinal cancer; hA3AR; partial agonists; indolylpyrimidylpiperazines
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Tan, A.; Babak, M.V.; Venkatesan, G.; Lim, C.; Klotz, K.-N.; Herr, D.R.; Cheong, S.L.; Federico, S.; Spalluto, G.; Ong, W.-Y.; Chen, Y.Z.; Loo, J.S.E.; Pastorin, G. Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy. Molecules 2019, 24, 3661.

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