Novel indolo-sophoridinic scaffold as Topo I inhibitors: Design, synthesis and biological evaluation as anticancer agents

Xu, Yiming; Wu, Li; Rashid, Haroon Ur; Jing, Dewang; Liang, Xiao-Le; Wang, Haodong; Liu, Xu; Jiang, Jun; Wang, Lisheng; Xie, Peng

doi:10.1016/j.ejmech.2018.07.028

Cited by 13 publications

(6 citation statements)

References 29 publications

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“…Compound 6j was synthesized as reported previously [ 30 ]. Ferrostatin-1 (Fer-1, HY-100579), Z-VAD-FMK (HY-16658B), 3-Methyladenine (3-MA, HY-19312), Necrostatin-1 (Nec-1, HY-15760), and odium 4-phenylbutyrate (4-PBA, HY-A0281) were purchased from MedChem Express (New Jersey, USA).…”

Section: Methodsmentioning

confidence: 99%

“…In our previous study, series of sophoridine derivatives were synthesized and derivative 6j exhibited the strongest cytotoxic effects against liver cancer, lung cancer, and nasopharyngeal carcinoma without affecting the activity of Top I (Fig. 1A ) [ 30 ], indicating that there might be an alternative anticancer mechanism for 6j. In the present study, the anti-liver cancer effects and mechanism of 6j was explored.…”

Section: Introductionmentioning

confidence: 99%

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Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

Tian

Wang

et al. 2023

Cell Death Discov.

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Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

Tian

Wang

et al. 2023

Cell Death Discov.

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“…In this paper, a 2D-QSAR study was performed using a support vector regression (SVR) model described by the radial basis kernel function and the designed arti cial neural network (ANN) model, and a 3D-QSAR study using comparative molecular eld analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)-based models was also undertaken. The structures of the 64 sophoridine derivatives and their activity data against HepG-2 cells were collected from Yiming Xu's article [20,21] and PhD thesis [22] for the QSAR study.…”

Section: Qsar Studymentioning

confidence: 99%

Novel N-Substituted Sophoridine Derivatives: Design, QSAR, Synthesis and Anticancer Activities

Zhu

Shi

et al. 2023

Preprint

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Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives were designed and synthesized. 2D and 3D-QSAR anticancer activity prediction models of the sophoridine derivatives were established to predict the IC50 values of the 28 designed compounds, and the results showed that the introduction of appropriate substituents on the nitrogen atom at the 12-position of sophoridinic acid may enhance their anticancer activities. The structures of 28 novel N-substituted sophoridine derivatives were confirmed by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry, and their anticancer activities against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B) were evaluated by MTT assay. In particular, Compound 26 presented the most significant inhibitory activity, with an IC50 of 15.6 μM against HepG-2 cells, indicating that it has potential anticancer activity. Cell cycle analysis with 26 showed that this designed sophoridine derivative could arrest cells in G0/G1 phase. This study provides a new pathway for the structural modification of this class of compounds and the research and development of anticancer drugs.

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“…Therefore, compound 93 deserves further study as a potential anti-tumor drug agent. 140 Derivative 94 (Fig. 12, Table 12, IC 50 : 0.93-1.44 μM) exhibited promising anti-tumor activity against HepG2, SMMC-7721, HeLa and MCF-7 cancer cell lines.…”

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%

Research status of indole-modified natural products

Duan,

Song,

Guo

et al. 2023

RSC Med. Chem.

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Novel indolo-sophoridinic scaffold as Topo I inhibitors: Design, synthesis and biological evaluation as anticancer agents

Cited by 13 publications

References 29 publications

Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

Novel N-Substituted Sophoridine Derivatives: Design, QSAR, Synthesis and Anticancer Activities

Research status of indole-modified natural products

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