Molecular and cellular toxicological profiling of DNA bis-intercalator, quinoxaline compounds: echinomycin as the versatile lead

Park, Yoon Sun; Shin, Wan Seon; Kim, Cheol Su; Ahn, Chan Mug; Qi, Xu; Kim, Soo Ki

doi:10.1007/s13273-018-0002-8

Cited by 12 publications

(12 citation statements)

References 36 publications

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“…The first compounds of this class isolated, the aforementioned echinomycins, 30 possess potent antitumor activity in vivo, 31 and have undergone clinical trials, 32,33 though their toxicological profile has limited their usefulness as systemically delivered small molecules. 34 Other members of this class of natural products (over 18 additional members) include quinaldopeptin, 35 sandramycin, 36 SW-163C-E, 37,38 luzopeptin, 39 triostins, 40 and the quinoxapeptins 41 (Figure 1). The primary mechanism of action of this class of compounds involves, as the name suggests, intercalation via hydrogen bonding associations with the base pairs of DNA directed by the polypeptide core of the compound into the minor groove.…”

Section: ■ Introductionmentioning

confidence: 99%

Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody–Drug Conjugates

et al. 2018

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A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody–drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline-p-aminobenzyl alcohol-N,N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.

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Section: ■ Introductionmentioning

confidence: 99%

Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody–Drug Conjugates

et al. 2018

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“…Overall, this class of compounds is at an earlier stage of development compared to the aforementioned HIF-1 inhibitors, with only limited testing as part of a combined treatment modality with IR. Echinomycin is a DNA intercalator for which the original clinical trials in the early 1990s failed to demonstrate an anti-tumor effect in an acceptable dose range [ 247 ]. Despite these setbacks, preclinical research on echinomycin continued, and in 2005 echinomycin was revealed to act as a potent inhibitor of HIF-1 DNA-binding [ 248 ].…”

Section: Radiotherapy and Tumor Hypoxiamentioning

confidence: 99%

“…Despite these setbacks, preclinical research on echinomycin continued, and in 2005 echinomycin was revealed to act as a potent inhibitor of HIF-1 DNA-binding [ 248 ]. In parallel, to overcome toxicities, novel derivatives and formulations of echinomycin are being developed, such as the YK-2000 and liposome-encapsulated echinomycin [ 247 , 249 ]. There are currently no clinical trials investigating echinomycin or its derivatives.…”

Section: Radiotherapy and Tumor Hypoxiamentioning

confidence: 99%

Interfering with Tumor Hypoxia for Radiotherapy Optimization

Telarovic

Wenger

Pruschy

2021

J Exp Clin Cancer Res

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Hypoxia in solid tumors is an important predictor of treatment resistance and poor clinical outcome. The significance of hypoxia in the development of resistance to radiotherapy has been recognized for decades and the search for hypoxia-targeting, radiosensitizing agents continues. This review summarizes the main hypoxia-related processes relevant for radiotherapy on the subcellular, cellular and tissue level and discusses the significance of hypoxia in radiation oncology, especially with regard to the current shift towards hypofractionated treatment regimens. Furthermore, we discuss the strategies to interfere with hypoxia for radiotherapy optimization, and we highlight novel insights into the molecular pathways involved in hypoxia that might be utilized to increase the efficacy of radiotherapy.

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“…The novel anticancer discovering or developing DNA intercalators is one of the extremely significant objectives in medicinal chemistry 27 . Quinoxaline derivatives were reported to have high anticancer activities through intercalation of DNA 28 e.g. echinomycin.…”

Section: Introductionmentioning

confidence: 99%

Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations

Elwan

Sakr

El‐Helby

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives 7e , 7c and 7b exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, 7e , 7c and 7b exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives 7e , 7c, 7b, 7g and 6e were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative 7e exhibited the highest binding affinity. It intercalates DNA at IC 50 = 29.06 µM. Moreover, compound 7e potently intercalates DNA at an IC 50 value of 31.24 µM. Finally, compound 7e demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound 7c exhibited an equipotent IC 50 value (0.940 µM) to that of doxorubicin. Furthermore, derivatives 7b, 7c, 7e and 7g displayed a high ADMET profile.

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Molecular and cellular toxicological profiling of DNA bis-intercalator, quinoxaline compounds: echinomycin as the versatile lead

Cited by 12 publications

References 36 publications

Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody–Drug Conjugates

Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody–Drug Conjugates

Interfering with Tumor Hypoxia for Radiotherapy Optimization

Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations

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