Dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines: Topoisomerase I and IIα dual inhibitors with DNA non-intercalative catalytic activity

Bist, Ganesh; Park, Seojeong; Song, Chanju; Magar, Til Bahadur Thapa; Shrestha, Aarajana; Kwon, Young Joo; Lee, Eung-Seok

doi:10.1016/j.ejmech.2017.03.048

Cited by 22 publications

(10 citation statements)

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“…The mechanism of action of triarylpyridines has been shown to be non-intercalative catalytic inhibition of topo I and topo II. Example compound 24 is shown in Figure . , Park et al designed and synthesized diphenyl benzofuro[3,2- b ]pyridines as new dual-target human topoisomerase inhibitors that structurally resemble triarylpyridines. Structure–activity relationship studies were performed to determine the optimal substitution patterns of both phenyl moieties attached to the central scaffold, which identified the phenol substituent at position 4 of the pyridine ring as being essential for dual topo I/II inhibition, as well as for the activity in cancer cell lines.…”

Section: Dual Inhibitors Of Topoisomerase II and Other Cancer-related...mentioning

confidence: 99%

Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets

et al. 2019

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Human DNA topoisomerase II is an important target in anticancer therapy. Despite the clinical success of drugs that target topoisomerase II, the development of resistant cancer cells can limit their clinical efficacy. To maximize the therapeutic potential of anticancer drugs, combination therapies and multitarget drugs have been suggested in many studies, where the use of multitarget drugs is advantageous from a pharmacokinetic point of view. There are various different options for the preparation of dual-target or multiple-target inhibitors, as topoisomerase II is both structurally (e.g., topoisomerase I, Hsp90, and kinases) and functionally (e.g., histone deacetylases and proteasome) connected to many validated anticancer targets. In this Perspective, we discuss the scientific background behind targeting topoisomerase II together with a number of other targets important in cancer therapy, review the present status, and discuss further options in the field.

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Section: Dual Inhibitors Of Topoisomerase II and Other Cancer-related...mentioning

confidence: 99%

Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets

et al. 2019

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“…All the test compounds were dissolved in DMSO at 10 mM to produce stock solutions, which were stored at −20 °C. DNA topo I and IIα inhibitory activities were measured as previously reported . A mixture of 100 ng of supercoiled pBR322 plasmid DNA (Thermo Scientific, USA) and 0.2–1 units of recombinant human DNA topo I (TopoGEN INC., USA) or topo IIα (Usb Corp., USA) were incubated with or without the prepared compounds in assay buffer (for topo I, 10 mM Tris-HCl (pH 7.9), 150 mM NaCl, 0.1% BSA, 0.1 mM spermidine, and 5% glycerol; and for topo IIα, 10 mM Tris-HCl (pH 7.9), 50 mM NaCl, 50 mM KCl, 5 mM MgCl 2 , 1 mM EDTA, 1 mM ATP, and 15 mg/mL BSA) in a final reaction volume of 10 μL for 30 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The cleavage complex of topoisomerase IIα/DNA in cells were evaluated with or without etoposide or compound 89 , as previously described . T47D cells were seeded in a 60 mm cell culture plate at a density of 2 × 10 5 cells.…”

Section: Methodsmentioning

confidence: 99%

“…TLC (ethyl acetate/n-hexane = 2:5) R f = 0. (32). The procedure described for compound 1 was employed with 7-hydroxy-1-indanone (0.296 g, 2 mmol), 2chlorobenzaldehyde (0.23 mL, 2 mmol), 2-hydroxyacetophenone (0.272 g, 2 mmol), and ammonium acetate (0.385 g, 5 mmol) mixed with DMF (5 mL) to yield 176 mg (0.46 mmol, 22.8%) as a light-yellow solid.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…The cleavage complex of topoisomerase IIα/DNA in cells were evaluated with or without etoposide or compound 89, as previously described. 32 T47D cells were seeded in a 60 mm cell culture plate at a density of 2 × 10 5 cells. Two days later, cells were treated with 50 μM each compound for 2 h as shown in the legend of Figure 10.…”

Section: Notesmentioning

confidence: 99%

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Discovery and Biological Evaluations of Halogenated 2,4-Diphenyl Indeno[1,2-b]pyridinol Derivatives as Potent Topoisomerase IIα-Targeted Chemotherapeutic Agents for Breast Cancer

et al. 2019

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With the aim of developing new effective topoisomerase IIα-targeted anticancer agents, we synthesized a series of hydroxy- and halogenated 2,4-diphenyl indeno[1,2-b]pyridinols using a microwave-assisted single step synthetic method and investigated structure–activity relationships. The majority of compounds with chlorophenyl group at 2-position and phenol group at the 4-position of indeno[1,2-b]pyridinols exhibited potent antiproliferative activity and topoisomerase IIα-selective inhibition. Of the 172 compounds tested, 89 showed highly potent and selective topoisomerase IIα inhibition and antiproliferative activity in the nanomolar range against human T47D breast (2.6 nM) cancer cell lines. In addition, mechanistic studies revealed compound 89 is a nonintercalative topoisomerase II poison, and in vitro studies showed it had promising cytotoxic effects in diverse breast cancer cell lines and was particularly effective at inducing apoptosis in T47D cells. Furthermore, in vivo administration of compound 89 had significant antitumor effects in orthotopic mouse model of breast cancer.

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Design and Synthesis of Fluorinated and/or Hydroxylated 2‐Arylidene‐1‐indanone Derivatives as an Inhibitor of LPS‐stimulated ROS Production in RAW 264.7 Macrophages with Structure–Activity Relationship Study

Katila

Shrestha

et al. 2018

Bulletin Korean Chem Soc

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A new series of thirty‐two fluorinated and/or hydroxylated 2‐arylidene‐1‐indanone derivatives were systematically designed, synthesized, and evaluated for their inhibitory activity against LPS‐stimulated ROS production in RAW 264.7 macrophages. 5/6‐Fluoro‐1‐indanone or 4‐, 5‐, 6‐, or 7‐hydroxyindanone moiety along with ortho‐, meta‐, or para‐hydroxyphenyl, furanyl or thiophenyl moiety was prepared and evaluated. Among the synthesized compounds, compound 11 possessing 6‐hydroxy‐1‐indanone moiety along with 5‐chlorothiophenyl moiety was found to have the most potent inhibitory effect on the production of ROS in LPS‐stimulated RAW 264.7 macrophages with an IC50 value of 3.29 μM.

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Dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines: Topoisomerase I and IIα dual inhibitors with DNA non-intercalative catalytic activity

Cited by 22 publications

References 50 publications

Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets

Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets

Discovery and Biological Evaluations of Halogenated 2,4-Diphenyl Indeno[1,2-b]pyridinol Derivatives as Potent Topoisomerase IIα-Targeted Chemotherapeutic Agents for Breast Cancer

Design and Synthesis of Fluorinated and/or Hydroxylated 2‐Arylidene‐1‐indanone Derivatives as an Inhibitor of LPS‐stimulated ROS Production in RAW 264.7 Macrophages with Structure–Activity Relationship Study

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