Targeting Cancer Cell Proliferation Using Piperazine-Linked Quinolinequinones: Mechanism and Metabolic Profile

A series of aminated quinolinequinones linked to piperazine analogs (QQ1-7) were synthesized and screened against the full panel of National Cancer Institute (NCI) cancer cell lines for their potential as cytotoxic agents. The Developmental Therapeutics Program of the NCI analyzed the NCI-60 screening results and revealed that seven QQs were potent inhibitors of cancer cell growth across several cell lines, advancing them to the five-dose assay. Encouraged by the NCI five-dose assay results, the cytotoxicity of the selected QQs (QQ1 and QQ4) was further studied in three cancer cell lines—HCT-116 (colon cancer), ACHN (renal cancer), MCF7, and T-47D (breast cancer)—as well as in a normal cell line (HUVEC) for a deeper understanding. QQ1 was the hit compound for ACHN cells with an IC₅₀ value of 1.55 μM. QQ1 could inhibit ACHN cell proliferation, induce oxidative stress, and cause cell cycle arrest in ACHN cells. QQ1 did not affect the apoptotic value in ACHN cells. Oral bioavailability was poor for both QQ1 and QQ4 in vivo in rats due to faster intrinsic hepatic clearance in comparison with humans, as evidenced by in vitro metabolic studies with rat and human liver microsomes. Molecular docking simulation with putative target CDC25A revealed the interaction of QQ1 and QQ4 with active site residues responsible for substrate recognition.