Antiproliferative actions of 7-substituted 1,3-dihydroxyacridones; possible involvement of DNA topoisomerase II and protein kinase C as biochemical targets

• Published in: Bioorganic & medicinal chemistry 1994-12, Vol.2 (12), p.1403-1411
• Main Authors: Bastow, Kenneth F., Itoigawa, Masataka, Furukawa, Hiroshi, Kashiwada, Yoshiki, Bori, Ibrahim D., Ballas, Lawrence M., Lee, Kuo-Hsiung
• Format: Article
• Language: English
• Subjects: Acridines - chemical synthesis; Acridines - pharmacology; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Division - drug effects; Cell Survival - drug effects; Cercopithecus aethiops; DNA - biosynthesis; DNA - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Isoenzymes - antagonists & inhibitors; KB Cells; Molecular Structure; Protein Kinase C - antagonists & inhibitors; Simplexvirus - drug effects; Topoisomerase II Inhibitors; Vero Cells
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)82092-1

7-Chloro-1,3-dihydroxyacridone ( 1) reversibly inhibited growth of KB and vero cell lines with IC 50's of 35 and 40 μM, respectively, and a topoisomerase II-mediated multidrug resistant KB sub-clone was found to be about three-fold more susceptible to 1. In contrast, two cell lines of lymphoid origin were killed following treatments with 60 μM and at higher concentrations of 1. KB cell growth inhibition correlated with a rapid, reversible suppression of thymidine incorporation. Uridine but not leucine incorporation was also rapidly suppressed. The in vitro activities of DNA topoisomerase II and novel protein kinase C-subtype delta were inhibited at effective concentrations in tissue-culture, but 1 did not stimulate intracellular protein-associated DNA breaks nor interfere initially with topoisomerase II-mediated DNA cleavage in KB cells. In addition to antiproliferative effects against cells, the compound was weakly virustatic for herpes simplex virus type I with an IC 50 of 8 μM. Limited studies comparing three 1-congeners and citpressine- I, an acridone alkaloid with reported antiherpes activity, demonstrated that 7-substituted 1,3-dihydroxyacridones are novel antiproliferative agents which share similar biological and biochemical properties. 7-Chloro-1,3,-dibydroxyacridone ( 1) as an in vitro inhibitor of DNA topoisomerase II and Protein Kinase C subtype delta and as a cytostatic/cytotoxic, antiviral agent is reported.