Synthesis and cytotoxicity evaluation of polyfluorinated 1,4-naphthoquinones containing amino acid substituents

Abstract

New conjugates of polyfluorinated 1,4-naphthoquinone core with amino acid fragments were synthesized by the reactions of hexafluoro-1,4-naphthoquinone (1) with ethyl aminoacetate, glycine, 3-aminopropanoic, 4-aminobutanoic, and 6-aminohexanoic acids. In all the cases, the quinone 1 aminodefluorination on the 2-position occurred to give ethyl (3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)aminoacetate (2), (3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]acetic (3), 3-[(3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]propanoic (4), 4-[(3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]butanoic (5), and 6-[(3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]hexanoic acid (6), respectively. A possibility to further modify a carboxylic function of ω-[5,6,7,8-tetrafluoro-1,4-naphthoquinon-2-yl]aminocarboxylic acids was demonstrated by transformation of acids 3 and 5 into the corresponding acyl chlorides 10 and 12 followed by their in situ conversion into N,N-diethylamides 13 and 14 or ethyl esters 15 and 16. Upon the analogous treatment of acid 4 the primary generated acyl chloride 11 underwent an intramolecular N-acylation to yield 2,5,6,7,8-pentafluoro-3-(2-oxopyrrolidin-1-yl)naphthalene-1,4-dione (17) which was smoothly diethylaminodefluorinated at the 3-position to afford 2-(2-oxopyrrolidin-1-yl)-3-diethylamino-5,6,7,8-tetrafluoronaphthalene-1,4-dione (18). The cytotoxicity evaluation of twelve new quinones in human myeloma, human mammary adenocarcinoma, human hepatocellular carcinoma HepG2 epithelial tumor cells, normal mouse fibroblasts and Chinese hamster Ag 17 cells as well as their mutagenic and antioxidant properties in a Salmonella tester strain was performed. All the compounds effectively suppressed the growth of three lines of tumor cells. These data together with the better cytotoxic effect against cancer cells compared to normal mammalian cells, the bacterial cells protection against spontaneous and H2O2-dependent mutagenesis, and lower general toxicity toward different cells, reveal quinones 2, 13, 15, 16, and 18 as best inhibitors of tumor cells growth among the tested substances.