Synthesis and preclinical validation of novel P2Y1 receptor ligands as a potent anti-prostate cancer agent

Abstract

Purinergic receptor is a potential drug target for neuropathic pain, Alzheimer disease, and prostate cancer. Focusing on the structure-based ligand discovery, docking analysis on the crystal structure of P2Y1 receptor (P2Y1R) with 923 derivatives of 1-indolinoalkyl 2-phenolic compound is performed to understand the molecular insights of the receptor. The structural model identified the top novel ligands, 426 (compound 1) and 636 (compound 2) having highest binding affinity with the docking score of −7.38 and −6.92. We have reported the interaction efficacy and the dynamics of P2Y1R protein with the ligands. The best hits synthesized were experimentally optimized as a potent P2Y1 agonists. These ligands exhibits anti-proliferative effect against the PC-3 and DU-145 cells (IC50 = 15 µM – 33 µM) with significant increase in the calcium level in dose- and time-dependent manner. Moreover, the activation of P2Y1R induced the apoptosis via Capase3/7 and ROS signaling pathway. Thus it is evidenced that the newly synthesized ligands, as a P2Y1R agonists could potentially act as a therapeutic drug for treating prostate cancer.

P2Y1 agonist HIC in combination with androgen receptor inhibitor abiraterone acetate impairs cell growth of prostate cancer

“…PC3 and DU145 cells were incubated with DMSO, HIC (1,5,10,15, and 20 μM), AA (3,15,30,45, and 60 μM), or combination of HIC and AA for 48 h. HEK293 and MEF cells were treated with HIC (1, 5, 10, and 15 μM) and AA (3, 15, 30, and 45 μM) together. After 48 h treatment, cell death was determined using MTT cell proliferation and cytotoxicity assay kit (Bosterbio, CA, USA) as described previously [28]. Briefly, the cells were labelled with MTT labelling reagent (0.5 mg/mL MTT reagent final concentration in phosphatebuffered saline, PBS) and incubated for 4 h in a humidified chamber.…”

“…For example, MRS 2365, a selective agonist of P2Y1R, decrease cell proliferation and increase apoptotic cells' and Caspase 3's activities in PC3 cells [26]. Recently, we designed and synthesized a P2Y 1 R agonist, 1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile (HIC) to activate the P2Y 1 R signaling [28][29][30]. HIC is a time-and dose-dependent selective inhibitor of PC3 and DU145 cell growth [28].…”

“…Recently, we designed and synthesized a P2Y 1 R agonist, 1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile (HIC) to activate the P2Y 1 R signaling [28][29][30]. HIC is a time-and dose-dependent selective inhibitor of PC3 and DU145 cell growth [28]. In addition, the activation of P2Y1R induces apoptosis, Caspase 3/7 activity, and ROS production in these cell lines [28].…”

“…HIC is a time- and dose-dependent selective inhibitor of PC3 and DU145 cell growth [ 28 ]. In addition, the activation of P2Y1R induces apoptosis, Caspase 3/7 activity, and ROS production in these cell lines [ 28 ]. Although the activity of HIC was identified as a potential drug-like compound again the growth of PC3 and DU145, the combinatorial effect of HIC along with any known clinical drug is yet to be investigated.…”

Increased antibacterial properties of indoline-derived phenolic Mannich bases

“…Moreover, the capacity of these pathogens to form biofilms on inert surfaces that are highly resistant to antibiotic treatments and host immune response 18,19 20 contributes even more for their persistence and dissemination in the health care setting. The ability of phenolic Mannich bases to interact with living organisms 21 has been documented in several reports, biological properties such as antibacterial 22 and antitumoral, [23][24][25][26][27][28] to name a few, have been described. We have previously reported the antibacterial properties of a family of aminoalkylphenols in which the indoline amine counterpart and a para-nitrophenol group were deemed important in conferring antimicrobial properties (Figure 1).…”