Fluorescein hydrazones as novel nonintercalative topoisomerase catalytic inhibitors with low DNA toxicity

A. F.M.Motiur Rahman, So Eun Park, Adnan A. Kadi, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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 p27kip1 and the decrease of cyclin D1 expression.

Original languageEnglish
Pages (from-to)9139-9151
Number of pages13
JournalJournal of Medicinal Chemistry
Volume57
Issue number21
DOIs
StatePublished - 13 Nov 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

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