Rational design, synthesis, and evaluation of novel 2,4-Chloro- and Hydroxy-Substituted diphenyl Benzofuro[3,2-b]Pyridines: Non-intercalative catalytic topoisomerase I and II dual inhibitor

Park, Seojeong; Magar, Til Bahadur Thapa; Kadayat, Tara Man; Lee, Hwa Jong; Bist, Ganesh; Shrestha, Aarajana; Lee, Eung Seok; Kwon, Young Joo

doi:10.1016/j.ejmech.2017.01.003

Cited by 30 publications

(19 citation statements)

References 38 publications

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“…Topoisomerase II kDNA decatenation assay was performed following the published method [ 33 ]. Briefly, the assay was performed using kDNA (TopoGen, Inc., Buena Vista, CO, USA) and reaction buffer according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

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AK-I-190, a New Catalytic Inhibitor of Topoisomerase II with Anti-Proliferative and Pro-Apoptotic Activity on Androgen-Negative Prostate Cancer Cells

Jeon

Park

Jang

et al. 2021

IJMS

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Castration-resistant prostate cancer (CRPC) is a clinical challenge in treatment because of its aggressive nature and resistance to androgen deprivation therapy. Topoisomerase II catalytic inhibitors have been suggested as a strategy to overcome these issues. We previously reported AK-I-190 as a novel topoisomerase II inhibitor. In this study, the mechanism of AK-I-190 was clarified using various types of spectroscopic and biological evaluations. AK-I-190 showed potent topoisomerase II inhibitory activity through intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in significantly less DNA toxicity than etoposide, a clinically used topoisomerase II poison. AK-I-190 induced G1 arrest and effectively inhibited cell proliferation and colony formation in combination with paclitaxel in an androgen receptor–negative CRPC cell line. Our results confirmed that topoisomerase II catalytic inhibition inhibited proliferation and induced apoptosis of AR-independently growing prostate cancer cells. These findings indicate the clinical relevance of topoisomerase II catalytic inhibitors in androgen receptor-negative prostate cancer.

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Section: Methodsmentioning

confidence: 99%

“…Band depletion assay was evaluated with etoposide and AK-I-190 according to the previously reported method [ 33 ]. Briefly, DU145 cells were treated with etoposide or AK-I-190 in serum-free medium for 2 h and harvested by trypsin.…”

Section: Methodsmentioning

confidence: 99%

AK-I-190, a New Catalytic Inhibitor of Topoisomerase II with Anti-Proliferative and Pro-Apoptotic Activity on Androgen-Negative Prostate Cancer Cells

Jeon

Park

Jang

et al. 2021

IJMS

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“…In 2017, Kwon's group designed and synthesized a novel series of conformationally constrained 2,4-chloro-and hydroxy-substituted diphenyl benzofuro [3,2-b]pyridines 69 (Scheme 11c). [48] Most of the compounds with phenol moiety at 4-position of the central pyridine exhibit significant dual topoisomerase I and II inhibitory activities and strong antiproliferative activities in the lower micromolar range. This provides a good foundation for research into new drug molecules.…”

Section: α β-Unsaturated Ketonesmentioning

confidence: 99%

Recent Advances in the Cycloaddition Reactions of 2‐Benzylidene‐1‐benzofuran‐3‐ones, and Their Sulfur, Nitrogen and Methylene Analogues

Deng

Meng

2020

Chemistry An Asian Journal

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Benzothiophene, benzofuran, indole, and indene derivatives are privileged heterocyclic motifs. These are present in a wide range of bioactive natural products and pharmaceutical drugs and are the subject of materials science research. However, the construction of benzothiophene, benzofuran, indole, and indene frameworks have been long‐standing challenges to organic chemists. In this review, we classify the derivatives of four structures synthesized from 2‐benzylidene‐1‐benzofuran‐3‐one and their analogues in terms of their ring size (from three‐ to ten‐membered) and type (fused or spiro), as well as summarizing the developments of this field. Finally, we discuss the ring opening and 1,4‐addition reactions.

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“…It was the first example of a natural compound able to act on both the cleavage and religation reactions of human Top1 . Benzofuropyridines 5 (Figure ) are compounds that display dual Top1 and Top2 inhibitory activity and are cytotoxic to several human cancer cell lines. , Based on the aforementioned studies, we envisioned that the indole moiety of Evo could be replaced by quinoline and benzofuran cores using a scaffold-hopping approach to design novel polycyclic heterocycles that selectively inhibit Top1 (Figure ). In addition, previous SAR studies revealed that appending a hydroxyl or methoxyl group to the C-10 position of Evo to form hydrogen bonds with Arg364 of Top1 was important to improve its Top1 inhibitory activity and selectivity …”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer

Yao

Qiu

et al. 2021

J. Med. Chem.

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Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1–DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.

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Rational design, synthesis, and evaluation of novel 2,4-Chloro- and Hydroxy-Substituted diphenyl Benzofuro[3,2-b]Pyridines: Non-intercalative catalytic topoisomerase I and II dual inhibitor

Cited by 30 publications

References 38 publications

AK-I-190, a New Catalytic Inhibitor of Topoisomerase II with Anti-Proliferative and Pro-Apoptotic Activity on Androgen-Negative Prostate Cancer Cells

AK-I-190, a New Catalytic Inhibitor of Topoisomerase II with Anti-Proliferative and Pro-Apoptotic Activity on Androgen-Negative Prostate Cancer Cells

Recent Advances in the Cycloaddition Reactions of 2‐Benzylidene‐1‐benzofuran‐3‐ones, and Their Sulfur, Nitrogen and Methylene Analogues

Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer

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