title: Fluorescein hydrazones as novel nonintercalative topoisomerase catalytic inhibitors with low DNA toxicity.
abstract: Fluorescein hydrazones (3a-3l) were synthesized in three steps with 86-91% overall yields. Topo I- and IIα-mediated relaxation and cell viability assay were evaluated. 3d inhibited 47% Topo I (camptothecin, 34%) and 20% Topo II (etoposide 24%) at 20 μM. 3l inhibited 61% Topo II (etoposide 24%) at 20 μM. 3d and 3l were further evaluated to determine their mode of action with diverse methods of kDNA decatenation, DNA-Topo cleavage complex, comet, DNA intercalating/unwinding, and Topo IIα-mediated ATP hydrolysis assays. 3d functioned as a nonintercalative dual inhibitor against the catalytic activities of Topo I and Topo IIα. 3l acted as a Topo IIα specific nonintercalative catalytic inhibitor. 3d activated apoptotic proteins as it increased the level of cleaved capase-3 and cleaved PARP in a dose- and time-dependent manner. The dose- and time-dependent increase of G1 phase population was observed by treatment of 3d along with the increase of p27(kip1) and the decrease of cyclin D1 expression.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia.
authors.forename: A F M Motiur
authors.initials: AF
authors.lastname: Rahman
authors.forename: So-Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Kadi
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D019793:Fluorescein / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis*; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D006835:Hydrazones; D059003:Topoisomerase Inhibitors; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D004250:DNA Topoisomerases, Type II; D019793:Fluorescein