Molecular design, synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase 1 inhibitors

Lee, Suh Hee; Van, Hue Thi My; Yang, Suhui; Lee, Kyung Tae; Kwon, Young Joo; Cho, Won Jea

doi:10.1016/j.bmcl.2009.03.058

Cited by 41 publications

(9 citation statements)

References 19 publications

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“…Previously, our research group synthesized various rigid analogues of 2,4,6-trisubstituted pyridines and evaluated thse analogues for their topoisomerase inhibitory activity, as well as cytotoxicity, in order to determine the effects of rigid structure on anticancer activity (8)(9)(10). Rigid structures are commonly considered to have little conformational entropy compared to flexible structures, and can be more efficiently fitted into the active site of a receptor (11). It has been reported that planar molecules are able to intercalate into the DNA helix and stabilize the topoisomerase-DNA covalent cleavage, converting topoisomerase into a lethal DNA-damaging agent.…”

Section: Introductionmentioning

confidence: 99%

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Park

Kim

et al. 2014

International Journal of Molecular Medicine

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Abstract. The inhibition of topoisomerase can suppress the growth of cancer cells and induce apoptosis. The aim of this study was to evaluate the anticancer effects and mechanisms of action of a novel topoisomerase inhibitor, 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1,10-phenanthroline (FPDHP). FPDHP suppressed the growth of Caki, A549, HT29 and MDA-MB-231 cells, and induced caspase-dependent apoptosis in the Caki cells. In particular, FPDHP also induced caspase-dependent apoptosis and the downregulation of the protein expression levels of cellular FLICE-like inhibitory protein (cFLIP) and the phosphorylation of Akt in Caki cells. Notably, the overexpression of cFLIP, but not that of Akt, in part, blocked the FPDHP-mediated apoptosis in Caki cells. In addition, FPDHP was further shown to induce the caspase-independent detachment of Caki cells from the culture dish; higher populations of apoptotic cells were observed in the detached cells than in the attached cells. To the best of our knoweledge, these results collectively demonstrate for the first time that FPDHP has a killing effect on Caki cells, which is mediated through both caspase-dependent apoptosis and caspase-independent cell detachment.

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Section: Introductionmentioning

confidence: 99%

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Park

Kim

et al. 2014

International Journal of Molecular Medicine

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“…S urflex‐ D ock (11) is a classical protein–ligand docking program associated with a specific empirical scoring function and search engine pair. Its usefulness as a drug design tool has already been demonstrated in several cases (12). Protomol is used to guide molecular docking.…”

Section: Methodsmentioning

confidence: 99%

Docking and 3D‐QSAR investigations of pyrrolidine derivatives as potent neuraminidase inhibitors

Sun

Mei

2012

Chem Biol Drug Des

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Docking studies of pyrrolidine derivatives indicated that Trp178, Arg371, and Tyr406 were the key residues in the active pocket of influenza neuraminidase (NA). Hydrogen bond and electrostatic factors mainly influenced interactions between pyrrolidine derivatives and NA. Moreover, there was a significant correlation between binding affinity (total scores) and the experimental pIC(50) . Meanwhile, 3D-QSAR models of 87 pyrrolidine derivatives were developed to understand chemical-biological interactions governing their activities toward NA. Furthermore, R(2) , Q(2) , , and of the models were from 0.731 to 0.830, from 0.560 to 0.611, from 0.762 to 0.875, and from 0.649 to 0.856, respectively. QSAR modeling results elucidated that hydrogen bonds and electrostatic factors highly contributed to inhibitory activity, which was unanimous in the docking results.

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“…Surflex-Dock is a classic protein-ligand docking program associated to a specific empirical scoring function and search engine pair [24]. Its usefulness as a drug design tool has already been demonstrated in several cases [25].…”

Section: Molecular Dockingmentioning

confidence: 99%

QSAR and molecular mechanism analysis of N-substituted oseltamivir derivatives as potent avian influenza H5N1 neuraminidase inhibitors

Sun

Mei

2015

Chemometrics and Intelligent Laboratory Systems

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Molecular design, synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase 1 inhibitors

Cited by 41 publications

References 19 publications

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Docking and 3D‐QSAR investigations of pyrrolidine derivatives as potent neuraminidase inhibitors

QSAR and molecular mechanism analysis of N-substituted oseltamivir derivatives as potent avian influenza H5N1 neuraminidase inhibitors

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