TY  - JOUR
A1  - Shao, Yi-Ming
A1  - Ma, Xiaohua
A1  - Paira, Priyankar
A1  - Tan, Aaron
A1  - Herr, Deron Raymond
A1  - Lim, Kah Leong
A1  - Ng, Chee Hoe
A1  - Venkatesan, Gopalakrishnan
A1  - Klotz, Karl-Norbert
A1  - Federico, Stephanie
A1  - Spalluto, Giampiero
A1  - Cheong, Siew Lee
A1  - Chen, Yu Zong
A1  - Pastorin, Giorgia
T1  - Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment
JF  - PLoS ONE
N2  - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7–11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5–40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237766
VL  - 13
ER  - 
TY  - JOUR
A1  - Tan, Aaron
A1  - Babak, Maria V.
A1  - Venkatesan, Gopalakrishnan
A1  - Lim, Clarissa
A1  - Klotz, Karl-Norbert
A1  - Herr, Deron Raymond
A1  - Cheong, Siew Lee
A1  - Federico, Stephanie
A1  - Spalluto, Giampiero
A1  - Ong, Wei-Yi
A1  - Chen, Yu Zong
A1  - Loo, Jason Siau Ee
A1  - Pastorin, Giorgia
T1  - Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy
JF  - Molecules
N2  - 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.
KW  - gastrointestinal cancer
KW  - hA<sub>3</sub>AR
KW  - partial agonists
KW  - indolylpyrimidylpiperazines
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193271
SN  - 1420-3049
VL  - 24
IS  - 20
ER  -