Fluorescein Hydrazones as Novel Nonintercalative Topoisomerase Catalytic Inhibitors with Low DNA Toxicity
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2014
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000113667
- 본문언어 영어
- Published As http://dx.doi.org/10.1021/jm501263m
초록/요약
Fluorescein hydrazones (3a-3l) were synthesized in three steps with 86-91% overall yields. Topo I- and IIa-mediated relaxation and cell viability assay were evaluated. 3d inhibited 47% Topo I (camptothecin, 34%) and 20% Topo II (etoposide 24%) at 20 mu M. 3l inhibited 61% Topo II (etoposide 24%) at 20 mu M. 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 IIa-mediated ATP hydrolysis assays. 3d functioned as a nonintercalative dual inhibitor against the catalytic activities of Topo I and Topo II alpha. 3l acted as a Topo IIa 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.
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