Biopolym. Cell. 2012; 28(3):239-241.
Short Communications
Polysulfide compounds as inhibitors of the key base excision repair enzymes
1Kutuzov M. M., 1Zakharenko A. L., 1Sukhanova M. V., 1Khodyreva S. N., 2Khomenko T. M., 2Volcho K. P., 2Salakhutdinov N. F., 1Lavrik O. I.
  1. Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
    8, Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090
  2. N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences
    9, Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090


Aim. To increase the capacity of antitumor therapy based on DNA damage it is important to minimize the repair of DNA lesions that can be achieved by inhibiting the activity of key DNA repair enzymes. To this end several benzopentathiepine and benzo[1,3]dithiol derivatives were synthesized and tested as inhibitors of the key base excision repair (BER) enzymes, PARP1, DNA polymerase β, and APE1. Methods. The procedure of synthesis of several new compounds was developed. The inhibitory capacity of the compounds was estimated by comparison of the enzyme activities in specific testsin the presence of compounds versustheir absence. Results. Benzopentathiepine derivative bearing trifluoromethyl group at the 1-st position was shown to be a weak inhibitor of PARP1. Cyclic substituents at the 1-st position attached through amide bond bring about moderate enhancement of pol β inhibition. Each studied substituent at the 1-st position considerably increases the inhibition of APE1-catalyzed hydrolysis of AP sites as compared to parent compound. Conclusions. Several new inhibitors of BER enzymes were revealed. The directions for further modification of compounds to improve their inhibitory activity were found out.
Keywords: DNA polymerase &beta, poly(ADP-ribose)polymerase 1, apurinic/apyrimidinic endonuclease 1, polysulfide, pentathiepine, inhibitor


[1] Reed A. M., Fishel M. L., Kelley M. R. Small-molecule inhibitors of proteins involved in base excision repair potentiate the antitumorigenic effect of existing chemotherapeutics and irradiation Future Oncol 2009 5, N 5:713–726.
[2] Davidson B. S., Molinski T. F., Barrows L. R., Ireland C. M. Varacin: a novel benzopentathiepin from Lissoclinum vareau that is cytotoxic toward a human colon tumor J. Am. Chem. Soc 1991 113, N 12:4709–4710.
[3] Khomenko T. M., Tolstikova T. G., Bolkunov A. V., Dolgikh M. P., Pavlova A. V., Korchagina D. V., Volcho K. P., Salakhutdinov N. F. 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine: novel aminobenzopentathiepine having in vivo anticonvulsant and anxiolytic activities Lett. Drug Des. Discov 2009 6, N 6:464–467.
[4] Sukhanova M. V., Khodyreva S. N., Lavrik O. I. Poly(ADP-ribose) polymerase-1 inhibits strand-displacement synthesis of DNA catalyzed by DNA polymerase beta Biochemistry (Mosc) 2004 69, N 5:558–568.
[5] Drachkova I. A., Petruseva I. O., Safronov I. V., Zakharenko A. L., Shishkin G. V., Lavrik O. I., Khodyreva S. N. Reagents for modification of protein-nucleic acids complexes. II. Site-specific photomodification of DNA-polymerase beta complexes with primers elongated by the dCTP exo-N-substituted arylazido derivatives Bioorg. Khim 2001 27, N 3:197–204.
[6] Lebedeva N. A., Khodyreva S. N., Favre A., Lavrik O. I. AP endonuclease 1 has no biologically significant 3'-5'-exonuclease activity Biochem. Biophys. Res. Commun 2003 300, N 1:182–187.
[7] Zakharenko A. L., Sukhanova M. V., Khodyreva S. N., Novikov F. N., Stroilov V. S., Nilov D. K., Chilov G. G., Shviadas V. K., Lavrik O. I. Improved procedure of the search for poly(ADP-Ribose) polymerase-1 potential inhibitors with the use of the molecular docking approach Mol. Biol. (Mosk) 2011 45, N 3:565–569.