Prospects for Prostate Cancer Chemotherapy: Cytotoxic Evaluation and Mechanistic Insights of Quinolinequinones with ADME/PK Profile.

The evaluation of in vitro biological activity of several previously reported quinolinequinones () against 60 human cancer cell lines (NCI-60) used by the National Cancer Institute's Developmental Therapeutics Program (DTP) contributed to our earlier research on possible anticancer and/or antibacterial agents. Of interest, NCI-60 screening revealed that two quinolinequinones ( and ) significantly reduced the proliferation of several cancer genotypes. Following the administration of a single dose and five additional doses, all quinolinequinones demonstrated a significant inhibitory effect on the growth of leukemia and other cancer cell lines. Hence, a series of subsequent in vitro biological assessments were performed to further understand the mechanistic impact of the compounds. In MTT assays, it was found that and exhibited higher efficacy against DU-145 cells (IC 4.18 µM and 4.17 µM, respectively) compared to MDA-MB-231 (IC 8.27 and 13.33 µM, respectively) and HCT-116 cells (IC 5.83 and 9.18 µM, respectively). Additionally, demonstrated greater activity in this context. Further investigations revealed that inhibited DU-145 cell growth and migration dose-dependently. Remarkably, arrest of the DU-145 cell cycle at G0/G1 phase and ROS elevation were observed. Pharmacokinetic (PK) studies revealed that has better PK parameters than with %F of 9.83 in rat. Considering the data obtained with human liver microsomal stability studies, should have a better PK profile in human subjects. In silico studies (molecular dynamics) with three kinases (CDK2, CDK4, and MAPK) leading to cell cycle arrest at G/G identified MAPK as a probable target for . Taken together, our results showed that could be a potential chemotherapeutic lead molecule for prostate cancer.