Effect of some bis Mannich bases and corresponding piperidinols on DNA topoisomerase I.

Some acetophenone (CAS 98-86-2) derived bis Mannich bases, bis-(3-aryl-3-oxo-propyl)-methylamine hydrochlorides (B1-B5) and representative piperidinols, 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides (C1, C2 and C5), which are the structural isomers of B1, B2 and B5, were synthesized and their effects on DNA topoisomerase I were tested. Aryl part was phenyl in B1 and C1, p-methylphenyl in B2 and C2, p-methoxyphenyl in B3, p-chlorophenyl in B4, and 2-thienyl in B5 and C5. The compounds' chemical structures were confirmed by UV, IR, 1H NMR, 13C NMR, ESI-MS spectra. The purity levels of the compounds were determined by elemental analysis. Among the compounds, B1-B5 and C5 were found to inhibit DNA topo isomerase I at varying degrees. The compounds B1-B5 and C5 manifested an average of 46%, 20%, 40%, 22%, 24% and 22% inhibition on topoisomerase I, respectively, suggesting that the cytotoxic actions of the compounds may be linked to DNA topoisomerase I inhibition. There was a significant negative correlation between the LC50 values reported and topoisomerase I inhibition among the compounds studied. The topoisomerase inhibiting effects of the compounds of the B series may be attributed to the linear structures of the compounds and the possible formation of the hydrogen bonds with the DNA nucleotides. Among the compounds studied, the most potent topoisomerase I inhibiting compounds B1 (46%) and B3 (40%) may serve as model compounds to develop new more potent topoisomerase inhibitors in future studies.