Design, synthesis and evaluation of new indolylpyrimidylpiperazines for gastrointestinal cancer therapy
| Autor: | Maria V. Babak, Giampiero Spalluto, Wei-Yi Ong, Aaron Tan, Siew Lee Cheong, Giorgia Pastorin, Clarissa Lim, Yu Zong Chen, Karl-Norbert Klotz, Deron R. Herr, Jason S. E. Loo, Stephanie Federico, Gopalakrishnan Venkatesan |
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| Přispěvatelé: | 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., Pastori, G. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Indoles Tertiary amine HA Pharmaceutical Science Pharmacology Analytical Chemistry 0302 clinical medicine Cricetinae Drug Discovery Receptor Cytotoxicity Gastrointestinal Neoplasms Indolylpyrimidylpiperazine 0303 health sciences Chemistry Communication Ligand (biochemistry) Adenosine A2 Receptor Antagonists Chemistry (miscellaneous) 030220 oncology & carcinogenesis Molecular Medicine ha3ar Receptor Adenosine A2A hA3AR Indolylpyrimidylpiperazines CHO Cells Pyrimidinones Partial agonists Partial agonist lcsh:QD241-441 03 medical and health sciences Structure-Activity Relationship Gastrointestinal cancer Cricetulus lcsh:Organic chemistry Structure–activity relationship Animals Humans ddc:610 Physical and Theoretical Chemistry Piperazine Binding selectivity 030304 developmental biology Cell Proliferation Organic Chemistry Receptor Adenosine A3 Adenosine receptor 3 AR |
| Zdroj: | Molecules Molecules, Vol 24, Iss 20, p 3661 (2019) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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