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Polysulfide compounds as inhibitors of the key base excision repair enzymes

Keywords: DNA polymerase β , poly(ADP-ribose)polymerase 1 , apurinic/apyrimidinic endonuclease 1 , polysulfide , pentathiepine , inhibitor.

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Abstract:

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 tests in the presence of compounds versus their absence. Results. Benzopentathiepine derivative bearing trifluoromethyl group at the 1st position was shown to be a weak inhibitor of PARP1. Cyclic substituents at the 1st position attached through amide bond bring about moderate enhancement of pol β inhibition. Each studied substituent at the 1st 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.

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