Abstract: Fluorinated derivatives of 1,4-naphthoquinones are highly potent inhibitors of Cdc25A and Cdc25B phosphatases; they suppress the growth of tumor cells. Four derivatives of phosphonium betaines derived from hexafluoro-1,4-naphthoquinone: (triphenyl[5,6,7,8-tetrafluoro-1-oxido-4-oxo-3-(phenylirnino)-3,4-dihydronaphthalen-2-yl]phosphonium) (4), ((3,5-difluorophenyl)(methyl)phenyl(5,6,7,8-tetrafluoro-3-oxido-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phosphonium) (5), ((2,5-difluorophenyl) (methyl)pheny1(5,6,7,8-tetrafluoro-3-oxido-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phosphonium) (6) and ((3,5-difluorophenyl)diphenyl(5,6,7,8-tetrafluoro-3-oxido-1,4-dioxo-1,4-dihydronaphthalen-2-yl) phosphonium) (7) were synthesized for the first time. Their cytotoxicity toward human mammary adenocarcinoma, human myeloma, hamster and murine and fibroblasts as well as their antioxidant and mutagenic effects on a Salmonella tester strain were analyzed. All four substances showed comparable IC50 values in terms of suppression of tumor cell growth, which were from two- to ninefold lower comparing with those of fibroblasts. To identify the features of spatial orientation and noncovalent interactions of the new phosphonium betaines in the binding site of Cdc25B, a molecular docking analysis was carried out. It showed that the interactions of the analyzed compounds with a Cdc25B model binding site are characterized by the presence of a large number of acceptors (fluorine and oxygen atoms, forming halogen and hydrogen bonds) and by participation of pi-systems and phosphorus in specific electrostatic interactions that may result in inhibition of enzymes of the Cdc25 family. In addition, compounds 5 and 6 (especially the latter) were found to be effective antioxidants protecting bacterial cells from H2O2-induced and spontaneous and mutagenesis at significantly lower concentrations (IC50=0.09 to 1.8 mu M) than those of derivatives 4 and 7 (86-92 mu M). Taking into account these data (together with the good cytotoxic effect on cancer cells comparing with normal mammalian cells) we can propose compounds 5 and 6 as possible useful inhibitors of tumor cell growth and antioxidants. (C) 2016 Elsevier B.V. All rights reserved.

Cite: Zhivetyeva S.I. , Zakharova O.D. , Ovchinnikova L.P. , Baev D.S. , Bagryanskaya I.Y. , Shteingarts V.D. , Tolstikova T.G. , Nevinsky G.A. , Tretyakov E.V.
Phosphonium betaines derived from hexafluoro-1,4-naphthoquinone: Synthesis and cytotoxic and antioxidant activities
Journal of Fluorine Chemistry. 2016. V.192. P.68-77. DOI: 10.1016/j.jfluchem.2016.10.014 WOS Scopus РИНЦ

Dates:

Published print:

Dec 1, 2016

Identifiers:

Web of science	WOS:000390073300008
Scopus	2-s2.0-84993933876
Elibrary	27583493
OpenAlex	W2543305016

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