Newly discovered chroman-2,4-diones neutralize DNA alkylation damage in vivo on topIIa level: A story behind the molecular modeling approach

Abstract

Eight chroman-2,4-diones, namely 2a-h, were evaluated as in vivo genotoxic agents in Wistar rats livers and kidneys using the alkaline comet assay. Compounds 2a, (E)-3- (1-(2-aminoethylamino) ethylidene) chroman-2,4-dione,2b,(E)-3-( 1-(2-hydroxyethylamino) ethylidene) chroman-2,4-dione, and 2f, (3E,3'E) - 3,3'-( l, l '-(ethane-1,2-diylbis (azanediyl)) bis (ethan-1-yl-l-ylidene)) dichroman-2,4- dione showed no genotoxic potential and were tested as antigenotoxic agents by application prior to ethyl methanesulfonate (EMS), a proven mutagen. As antigentotoxics, compounds significantly diminished EMS-induced DNA damage in both organs. The reduction of liver DNA damage amounted 86.93% (2b), 77.23% (2f), and 64.52% (2a), respectively, while the reduction in kidney DNA damage was 89.52 (2b), 82.50% (2f) and 68.14% (2a). Since EMS produce harmful d-ethylguanine lesion which is incorporated in aberrant genotoxic G=T and T=G pairing after rat Topoisomerase Ila (rToplla) catalyzed ATP-dependent DNA strand breaks, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on enzyme level using molecular docking and molecular dynamics simulations. According to molecular docking studies, those compounds occupy the A TPase region proximal to rGlu86, catalytic amino acid involved in the hydrolysis of y-pbosphate group of ATP via water bridges. Molecular dynamics simulations showed that 2a, 2b, and 2f are a barrier for the formation of ATP-H20-rGlu86 bridge. Since compounds inhibit the hydrolysis of ATP, they prohibit the energy for the DNA double strand ligation, and therefore neutralize any possible damage that can arise after the formation of 06-ethylguanine harmful lesion. Consequently, compounds 2a, 2b, and 2f prevent EMS mutagenic and carcinogenic effects, and can be applied in the cancer treatment to control the rate of anticancer alkylation drugs.