Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

Yu, Le-Mao; Zhang, Xiaoru; Li, Xiaobing; Yang, Yuan; Wei, Hongyu; He, Xian-Hui; Gu, Lian‐Quan; Huang, Zhi‐Shu; Pommier, ﻿Yves; An, Lin‐Kun

doi:10.1016/j.ejmech.2015.07.007

Cited by 16 publications

(13 citation statements)

References 20 publications

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“…3, hippeastrine and camptothecin exhibited inhibitory activity on Top I in a similar dose-dependent manner with the IC 50 values at 7.25 ± 0.20 μg/mL and 6.72 ± 0.23 μg/mL, respectively, which clearly implied that hippeastrine was found to be comparable with the well known anticancer drug camptothecin in terms of IC 50 . Other tests on camptothecin against Top I also showed similar inhibitory activity levels with the IC 50 values at 8.71 μg/mL35 or 8.53 μg/mL36, which could further approve our finding in this work. Hence, our result confirmed that hippeastrine could be a potential Top I inhibitor as a very promising anticancer drug candidate, which is in good consistent with the enrichment factors based on UF-LC/MS assay and provides a good validation for its effectiveness.…”

Section: Resultssupporting

confidence: 86%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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Crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity. However, the specific alkaloids responsible for the pharmacodynamic activity and their targets still remain elusive. In this context, we strived to combine affinity ultrafiltration with topoisomerase I (Top I) as a target enzyme aiming to fish out specific bioactive AAs from Lycoris radiata. 11 AAs from Lycoris radiata were thus screened out, among which hippeastrine (peak 5) with the highest Enrichment factor (EF) against Top I exhibited good dose-dependent inhibition with IC50 at 7.25 ± 0.20 μg/mL comparable to camptothecin (positive control) at 6.72 ± 0.23 μg/mL. The molecular docking simulation further indicated the inhibitory mechanism between Top I and hippeastrine. The in vitro antiproliferation assays finally revealed that hippeastrine strongly inhibited the proliferation of HT-29 and Hep G2 cells in an intuitive dose-dependent manner with the IC50 values at 3.98 ± 0.29 μg/mL and 11.85 ± 0.20 μg/mL, respectively, and also induced significant cellular morphological changes, which further validated our screening method and the potent antineoplastic effects. Collectively, these results suggested that hippeastrine could be a very promising anticancer candidate for the therapy of cancer in the near future.

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Section: Resultssupporting

confidence: 86%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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“…Since deletion of Top1 did not unsilence Ube3a , whereas topotecan (which forms TOP1cc’s) did unsilence Ube3a , we hypothesized that TOP1cc’s may be required to unsilence Ube3a in neurons. To test this hypothesis, we compared topotecan to a series of TOP1 catalytic inhibitors that inhibit TOP1 without forming TOP1cc’s ( S5A Fig ) [ 28 , 29 ]. As previously found [ 13 ], topotecan unsilenced the paternal Ube3a-YFP allele in Ube3a m+/pYFP cortical cultures ( S5B and S5C Fig ).…”

Section: Resultsmentioning

confidence: 99%

“…As previously found [ 13 ], topotecan unsilenced the paternal Ube3a-YFP allele in Ube3a m+/pYFP cortical cultures ( S5B and S5C Fig ). However, paternal Ube3a-YFP was not unsilenced after treating with four different TOP1 catalytic inhibitors, including CYB-L10 [ 29 ], over a range of doses ( S5B and S5C Fig ). CYB-L10 did significantly reduce expression of synaptic adhesion molecules in wildtype cells ( S5D and S5E Fig ), suggesting the drug can enter cells and reduce expression of genes that are affected by Top1 deletion.…”

Section: Resultsmentioning

confidence: 99%

Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

et al. 2016

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Topoisomerase 1 (TOP1) inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc’s) that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb) genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR-Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc’s, and a TOP1 mutation (T718A) that stabilizes TOP1cc’s. We found that topotecan treatment significantly alters the expression of many more genes, including long neuronal genes, immediate early genes, and paternal Ube3a, when compared to Top1 deletion. Our data show that topotecan has a stronger effect on neuronal transcription than Top1 deletion, and identifies TOP1cc-dependent and -independent contributions to gene expression.

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“…Generally, CPT derivatives are expected to have improved solubility and stability. Yu et al (18) synthesized a series of 6-substituted indolizinoquinolinedione derivatives and evaluated them for their biochemical and biological activities. Zhou et al (28) evaluated the cytotoxicity of MXN-004 (a small-molecule compound of PEGylated SN38) in vitro and demonstrated that it has good water solubility.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the CPT-11 prodrug group (4-piperidinyl piperidine) causes AchE inhibition, which easily leads to acetylcholine syndrome, resulting in early severe diarrhea and other sideeffects (10). In order to overcome the above drawbacks of CPT-11, scientists have made several attempts to improve it (10,(17)(18)(19). In the present study, we designed and synthesized a novel 10-hydroxy CPT prodrug with a high efficiency and low toxicity (20,21).…”

Section: Antitumor Potential Of a Novel Camptothecin Derivative Zbh-mentioning

confidence: 99%

Antitumor potential of a novel camptothecin derivative, ZBH-ZM-06

Zhao

et al. 2017

Oncol Rep

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Camptothecin (CPT) is a cytotoxic quinoline alkaloid that is used clinically as an anticancer drug. However, the clinical application of CPT is limited due to its low solubility as well as serious and unfathomable side-effects. In the present study, we created a novel 10-hydroxy CPT prodrug, ZBH-ZM‑06. Its cellular cytotoxic activity was analyzed in terms of cellular viability, acetylcholinesterase (AchE) inhibition, DNA relaxation, cellular cycling and apoptosis properties. Our results showed that the AchE inhibition rate of 10 µmol/l ZBH-ZM-06 was 12.5%, compared to 96.5% for carbonyl-oxycamptothecin (CPT-11). In a chemical stability assay, only 4.9% of ZBH-ZM-06 remained after 4 h at pH 7.4. In addition, 10 µmol/l ZBH-ZM-06 significantly inhibited the tumor cell viability of nine tumor cell lines, compared to CPT-11 and the CPT active ingredient, 7-ethyl-10-hydroxy-camptothecin (SN38) (p<0.01-0.05). In the apoptosis assay, ZBH-ZM-06 increased the ratio of annexin V+/propidium iodide (PI)-/+ cells by flow cytometric analysis (p<0.05). Moreover, ZBH-ZM-06 activated caspase-3 and poly(ADP-ribose)polymerase (PARP) expression by immunoblotting. Furthermore, ZBH-ZM-06 induced a greater G2/M phase arrest ratio, compared to CPT-11 and SN38. These results indicated that ZBH-ZM-06 had higher antitumor activity than CPT-11 and SN38, which was shown by its: i) release of the effective ingredient; ii) growth inhibition of a broad spectrum of tumor cells; iii) inhibition of DNA topoisomerase (Topo-1); and iv) promotion of apoptosis through an intrinsic signaling pathway. Thus, ZBH-ZM-06 may be applied in the preclinic study for cancer treatment.

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Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

Cited by 16 publications

References 20 publications

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

Antitumor potential of a novel camptothecin derivative, ZBH-ZM-06

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