Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer

Hu, De-Xuan; Tang, Wen-Lin; Zhang, Yu; Yang, Hao; Wang, Wenjie; Agama, Keli; Pommier, ﻿Yves; An, Lin‐Kun

doi:10.1021/acs.jmedchem.1c00318

Cited by 17 publications

(20 citation statements)

References 57 publications

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“…The TDP1 inhibition was tested through a fluorescence assay according to a previously reported method [ 29 ]. Detailed procedures are included in the Supporting Information .…”

Section: Methodsmentioning

confidence: 99%

Pyranodipyran Derivatives with Tyrosyl DNA Phosphodiesterase 1 Inhibitory Activities and Fluorescent Properties from Aspergillus sp. EGF 15-0-3

et al. 2022

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Four new benzodipyran racemates, namely (±)-aspergiletals A–D (3–6), representing a rare pyrano[4,3-h]chromene scaffold were isolated together with eurotiumide G (1) and eurotiumide F (2) from the soft-coral-derived fungus Aspergillus sp. EGF 15-0-3. All the corresponding optically pure enantiomers were successfully separated by a chiral HPLC column. The structures and configurations of all the compounds were elucidated based on the combination of NMR and HRESIMS data, chiral separation, single-crystal X-ray diffraction, quantum chemical 13C NMR, and electronic circular dichroism calculations. Meanwhile, the structure of eurotiumide G was also revised. The TDP1 inhibitor activities and photophysical properties of the obtained compounds were evaluated. In the TDP1 inhibition assay, as a result of synergy between (+)-6 and (−)-6, (±)-6 displayed strong inhibitory activity to TDP1 with IC50 values of 6.50 ± 0.73 μM. All compounds had a large Stokes shift and could be utilized for elucidating the mode of bioactivities by fluorescence imaging.

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“…The TDP1 inhibition was tested through a fluorescence assay according to a previously reported method [ 29 ]. Detailed procedures are included in the Supporting Information .…”

Section: Methodsmentioning

confidence: 99%

Pyranodipyran Derivatives with Tyrosyl DNA Phosphodiesterase 1 Inhibitory Activities and Fluorescent Properties from Aspergillus sp. EGF 15-0-3

et al. 2022

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“…The following are available online at, NMR 1 H and 13 C, HRMS of benzyloxy-DCA derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19); Table S1. The influence of the deoxycholic acid derivative 8 at 10 µM on topotecan cytotoxicity; Table S2.…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…Several studies have reported the development of TDP1 inhibitors of organic chemical matter [ 6 , 7 , 8 , 9 ] as well as natural product derivatives: steroids ( A – C ) ( Figure 1 ) [ 10 , 11 , 12 ], coumarins [ 13 , 14 ], usnic acids [ 15 , 16 , 17 , 18 , 19 ], and aminoadamantanes containing monoterpene-derived fragments [ 20 , 21 , 22 , 23 ]. Known TDP2 inhibitors are represented by isoquinoline-1,3-diones ( J ) [ 24 ], deazaflavins ( E ), and toxoflavins ( F ) [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2

et al. 2021

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A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.

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“…Although some CPT-type Top1 inhibitors have been applied clinically, they still suffered from disadvantages such as poor chemical stability, drug resistance, gastrointestinal toxicity or serious side effects [ 7 , 10 ]. Consequently, in the past decades many investigations have focused on the discovery and development of novel non-CPT Top1 inhibitors [ 11 , 12 , 13 ]. It has been reported that several non-CPT Top1 inhibitors including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan) and LMP744 ( Figure 1 ) have been used in clinical trials [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors

et al. 2022

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A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1–DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC50 values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC50 values of 0.78 and 0.62 μM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure–activity relationships of thiazole-based stilbene analogs was also discussed.

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Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer

Cited by 17 publications

References 57 publications

Pyranodipyran Derivatives with Tyrosyl DNA Phosphodiesterase 1 Inhibitory Activities and Fluorescent Properties from Aspergillus sp. EGF 15-0-3

Pyranodipyran Derivatives with Tyrosyl DNA Phosphodiesterase 1 Inhibitory Activities and Fluorescent Properties from Aspergillus sp. EGF 15-0-3

New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2

Design, Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors

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