Synthesis and Binding Profile Using Molecular Dynamics of New Building Blocks for PSMA Theranostics and the PSMA617-Cystine-Doxorubicin Therapeutic Bioconjugate Against Prostate Cancer

GCPII also known as Prostate Specific Membrane Antigen (PSMA), is overexpressed in prostate cancer (PCa) cells and provide a biomarker for tumor targeting PSMA receptor. The development of lysine-urea-glutamate pharmacophore based inhibitors targeting PSMA for theranostics applications led to PSMA11 and PSMA617. In PSMA11, this pharmacophore is attached via aminohexanoic acid (Ahx) spacer to a chelator while in PSMA617 the pharmacophore is connecting with the linker 2-naphthyl-L-Ala, trans-4-(aminomethyl)cyclohexanecarboxylic acid and then to chelator. Here, we synthesized: (a) a squaramide analog of lysine-urea-glutamic acid; (b) two new building blocks for PSMA theranostics in which lysine-urea-glutamic acid was attached with two (i) phenyl alanine residues to target arene binding site of PSMA receptor and (ii) amino hexanoic acid residues. (d) Inspired from the promising structure of PSMA617 we synthesized a new bioconjugate prodrug in which we replaced the chelator in PSMA617 with a cleavable cystine linker attached to the anticancer drug Doxorubicin. Induced fit docking and MD simulations explored the binding profile of the new molecules.