Aminated Quinolinequinones With EDG(s) as a Prostate Cancer Inhibitor: Mechanistic Insights and Pharmacokinetic Limitations

In this study, we investigated the effects of aminated quinolinequinones (AQQ6-16) on cancer cell lines previously selected by the National Cancer Institute (NCI). Analysis of the NCI-60 screening data from the Developmental Therapeutics Program (DTP) of the NCI revealed that 11 AQQs exhibited significant growth inhibitory activity across multiple cancer cell lines and were subsequently advanced to the five-dose assay. Most AQQs effectively suppressed the proliferation of all leukemia cell lines in the single-dose and five-dose assays. Encouraged by these findings, we further examined the cytotoxic effects of selected AQQs (AQQ6 and AQQ9) in three human cancer cell lines, including HCT-116 (colon cancer), DU-145 (prostate cancer), and MDA-MB-231 (breast cancer), as well as in a normal cell line (HUVEC). Among the tested compounds, AQQ6 demonstrated the highest potency against DU-145 cells, with an IC₅₀ value of 3.13 ± 0.15 µM. To gain mechanistic insights, the effects of AQQ6 on apoptosis, cell cycle distribution, and oxidative stress were evaluated. AQQ6 inhibited DU-145 cell proliferation by inducing apoptosis/necrosis, accompanied by G₀/G₁ phase cell cycle arrest. In metabolic stability assays using human liver microsomes, AQQ6 exhibited relatively low intrinsic clearance (Cl_int) and an improved half-life (T_1/2) compared to verapamil. However, pharmacokinetic studies in rats indicated poor oral bioavailability (%F = 4.2), likely due to extensive hepatic metabolism in rat liver microsomes. Molecular dynamics simulations targeting MAPK8, the protein likely involved in AQQ6 activity, were conducted to elucidate molecular-level binding interactions.