Synthesis and structure-activity relationship study of novel 3-diethoxyphosphorylfuroquinoline-4,9-diones with potent antitumor efficacy
- Eur J Med Chem. 2021 Jul 5:219:113429. doi: 10.1016/j.ejmech.2021.113429.
- 1. Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Łódź, Poland.
- 2. Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215, Łódź, Poland.
- 3. Institute of General and Ecological Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Łódź, Poland.
- 4. Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215, Łódź, Poland. Electronic address: [email protected].
- 5. Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Łódź, Poland. Electronic address: [email protected].
Herein we report an efficient synthesis of a series of regioisomeric N,O-syn and N,O-anti 3-diethoxyphosphorylfuroquinoline-4,9-diones combining furoquinoline-5,8-dione skeleton, present in several highly cytotoxic compounds, with diethoxyphosphoryl moiety. The cytotoxic activity of the obtained analogs was tested against two human Cancer cell lines: promyelocytic leukemia HL-60 and breast Cancer adenocarcinoma MCF-7 and for comparison on human umbilical vein endothelial cells HUVEC and mammary gland/breast MCF-10 A cells. Several diethoxyphosphorylfuroquinoline-4,9-diones proved to be highly cytotoxic for Cancer cells with IC50 values even below 0.1 μM. Interestingly, N,O-syn 3-diethoxyphosphorylfuroquinoline-4,9-diones were 3- to 7-fold more active against HL-60 cells than the respective N,O-anti regioisomers. The most promising analogs 9c and 9i, with the highest Cancer/healthy cells cytotoxicity ratio, were further evaluated to establish their mode of action. In HL-60 cells these analogs enhanced intracellular ROS generation and NAD(P)H:quinone oxidoreductase 1 (NQO1) depletion which led to the cell cycle arrest in the S-phase, reduced cell proliferation, DNA damage and Apoptosis.