Synthesis, DNA Interaction, and Cytotoxic Activity of a Novel Proflavine−Dithiazolidinone Pharmacophore

• Published in: Bioconjugate chemistry 2007-01, Vol.18 (1), p.93-100
• Main Authors: Janovec, Ladislav, Sabolová, Danica, Kožurková, Mária, Paulíková, Helena, Kristian, Pavol, Ungvarský, Ján, Moravčíková, Erika, Bajdichová, Mária, Podhradský, Dušan, Imrich, Ján
• Format: Article
• Language: English
• Subjects: Acridines - chemistry; Animals; Biochemistry; Cattle; Cell Line, Tumor; Cell Shape; Cell Survival - drug effects; Cells; Deoxyribonucleic acid; DNA; DNA - chemistry; Electrons; Humans; Mice; Molecular Structure; Nucleic Acid Denaturation; Organic chemistry; Photochemistry; Proflavine - chemical synthesis; Proflavine - chemistry; Proflavine - toxicity; Spectrum Analysis; Thiazoles - chemistry; Titrimetry; Toxins; Transition Temperature
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc060168v

Five novel proflavine−dithiazolidinone derivatives 4a−4e have been designed and synthesized by the reaction of dialkyl acridin-3,6-diyl dithioureas 3a−3e with methyl bromoacetate. The binding affinity of dithiazolidinone hydrochlorides 5a−5e with calf thymus DNA and plasmid (pUC19) DNA was investigated by a variety of spectroscopic techniques including UV−vis, fluorescence, and CD spectroscopy. The effects of 5a−5e on the thermal denaturation profiles of calf thymus DNA were also studied. From spectrophotometric and spectrofluorimetric titrations, the binding constants for the pUC19 DNA−drug complexes were determined (K = 6.2−2.2 × 104 M-1). In vitro cytotoxic activities of compounds 5a−5e toward murine leukemia cell line L1210 and human uterus carcinoma HeLa cells were also examined. 2‘,2‘ ‘-[(Acridin-3,6-diyl)diimino]-3‘,3‘ ‘-dipropyl-1,3-dithiazolidin-4-one hydrochloride (5b) showed the highest activity against these cells with IC50 values of 6.3 μM and 12.9 μM over the course of 72 h.