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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

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

Detail(s)

Original languageEnglish
Article number3661
Journal / PublicationMolecules
Volume24
Issue number20
Online published11 Oct 2019
Publication statusPublished - Oct 2019
Externally publishedYes

Link(s)

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.

Research Area(s)

  • Gastrointestinal cancer, HA3AR, Indolylpyrimidylpiperazines, Partial agonists

Citation Format(s)

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy. / Tan, Aaron; Babak, Maria V.; Venkatesan, Gopalakrishnan et al.

In: Molecules, Vol. 24, No. 20, 3661, 10.2019.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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