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Fluorescein Hydrazones as Novel Nonintercalative Topoisomerase Catalytic Inhibitors with Low DNA Toxicity

Title
Fluorescein Hydrazones as Novel Nonintercalative Topoisomerase Catalytic Inhibitors with Low DNA Toxicity
Authors
Rahman, A. F. M. MotiurPark, So-EunKadi, Adnan A.Kwon, Youngjoo
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2014
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link1520-4804JCR Link
Citation
vol. 57, no. 21, pp. 9139 - 9151
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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.
DOI
10.1021/jm501263m
Appears in Collections:
약학대학 > 약학과 > Journal papers
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