Anti-cancer and dual inhibitory potential of PI3K/AKT and Ras/MAPK/ERK signalling of a novel zinc (II) trinuclear complex with tetradentate schiff base ligand and azido ion in prostate adenocarcinoma: synthesis, in silico and in vitro evaluation

Background: Prostate adenocarcinoma (PAC), especially metastatic, castration-resistant (mCRPC) ranks second most common cause of cancer-related deaths in men worldwide. Despite development of several improved treatments including PSMA-targeted radioligand therapy, mCRPC remains largely unmanageable due to chemoresistance and high relapse rate. Hence, identification of novel druggable targets and development of novel therapeutic interventions are highly warranted to improve patient outcomes. Novelty: A novel azido trinuclear zinc (II) Schiff base complex [{ZnL(N3)}2 Zn]. H2O (1) (Compound AR1, abbreviated ComAR1) was synthesized using NaN3, methanolic solution of Zn (CH3COO)2.2H2O and Schiff base ligand H2L derived from condensation of 1,4-butadiamine and 3-methoxy salicylaldehyde (O-valine) at 1:2 ratio. Results: ComAR1 suppressed PAC cell proliferation, EMT, migration and induced G0/G1 cell cycle arrest following apoptosis. Molecular docking, simulation and ADMET analyses revealed that ComAR1 interacted with key components of signalling circuits associated with tumorigenesis including H-Ras, AKT, ERK1/2, exhibited excellent pharmacokinetic and drug-like features. Mechanistically, ComAR1 dampened PI3K/AKT and Ras/MAPK/ERK signalling activation, stabilized pro-apoptotic BAD by suppressing its AKT- and ERK-mediated phosphorylation in PAC cells.

Journal Article