Design, synthesis, and biological evaluation of novel thiourea derivatives as small molecule inhibitors for prostate specific membrane antigen

Abstract

Prostate cancer (PCa) has emerged to be the second leading cause of cancer-related deaths in men. Molecular imaging of PCa using targeted radiopharmaceuticals specifically to PCa cells promises accurate staging of primary disease, detection of localized and metastasized tumours, and helps predict the progression of the disease. Glutamate urea heterodimers have been popularly used as high-affinity small molecules in the binding pockets of popular and well-characterized PCa biomarker, prostate specific membrane antigen (PSMA). However, extensive studies in molecular docking and the QSAR model have predicted that bioisotere substitution of an oxygen atom with sulfur in the glutamate urea heterodimer molecules would yield a new library of high-affinity ligands in the nanomolar range to target PSMA. Based on these predictions, a new class of glutamate thiourea derivatives has been designed and developed for binding with PSMA. The in silico guided selection and chemical synthesis of glutamate thiourea small molecule PSMA inhibitors by a new methodology is described in this report. One of the high-affinity glutamate thiourea ligands was further chelated to radioisotopes such as 99mTechnetium using a chelating moiety via a peptide spacer and targeted to PSMA+ LNCaP and 22Rv1 cells. The newly synthesized 99mTc-bioconjugate has shown nanomolar affinity to selectively target PSMA+ cancers during in vitro studies. Collectively, these PSMA-specific small molecule radio-imaging agents show significant promise in monitoring disease prognosis and treatment selection of PCa patients. © 2025 Elsevier Inc.