One-pot synthesis of natural-product inspired spiroindolines with anti-cancer activities

Li, Shi-Qiang; Yan, Wei; He, Liu‐Jun; Zhang, Ming; Tang, Dianyong; Li, Hongyu; Chen, Zhong-Zhu; Xu, Zhigang

doi:10.1039/d1qo01694f

Cited by 6 publications

(3 citation statements)

References 38 publications

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“…Previously, we have demonstrated that compound 6d can significantly reduce the cell proliferation efficiency of a panel of human tumor cell lines, including glioma cell U87, pancreatic cancer cell PANC-1, prostate cancer cell PC3, hepatoma cell Hep3B, lung adenocarcinoma cell A549, and breast cancer cell MCF7 [ 27 ]. The chemical structure of compound 6d is shown in Figure 1 A.…”

Section: Resultsmentioning

confidence: 99%

“…Natural and synthetic spiroindolines with indole derivatives are an important class of heterocyclic compounds that exert a wide range of biological properties, such as anticancer and insecticidal activities [ 26 ]. In our previous report, a diverse suite of spiroindolines were synthesized using a metal-free, one-pot post-Ugi/diastereoselective domino cyclization in acidic conditions under microwave irradiation, and it was found that compound 6d exhibits antiproliferative capability against several types of cancer cell lines [ 27 ]. However, the underlying mechanism of this compound-mediated inhibitory capability in cancer cells, the potential target, and the effect on colorectal cancer (CRC) cells remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer

Yang

et al. 2023

IJMS

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Compound 6d, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory capability remains unclear. Here, we showed that compound 6d is an inhibitor of Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis of mitochondria. Regarding the underlying mechanism, we identified HDAC6 as a direct substrate for caspase 3, and caspase 3 activation induced by compound 6d directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound 6d promoted autophagy initiation by inhibiting interaction between Bcl-2 and Beclin 1, while it led to the accumulation of ubiquitinated proteins and the reduction of autophagic flux. Collectively, our findings reveal that the Bcl-2-caspase 3-HDAC6 cascade is a crucial regulatory pathway of autophagy and identify compound 6d as a novel lead compound for disrupting the balance between apoptosis and autophagy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer

Yang

et al. 2023

IJMS

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“…In 2022, a similar procedure for the production of spiroindolines 72 was reported by Xu and co‐workers by a metal‐free one‐pot intramolecular dearomatization of Ugi adducts 71 in the presence of TFA under microwave irradiation (Scheme 30). [38] A broad range of starting materials 71 performed efficiently in this tandem 5‐ exo‐dig indole cyclization/C−N bond formation, leading to the naturally existing frameworks 72 in good yields.…”

Section: Brønsted Acid‐ or Base‐promoted Dearomatization Reactionsmentioning

confidence: 99%

Application of Metal‐Free Dearomatization Reaction as a Sustainable Strategy to Direct Access Complex Cyclic Compounds

Zhong

Feng

et al. 2023

The Chemical Record

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The highly efficient construction of complicated heterocyclic frameworks in an atom‐ and step‐economic manner is still one of the cores of synthetic chemistry. Dearomatization reactions show the unique advantage for the construction of functionalized heterocycles and have attracted widespread attention over the past two decades. The metal‐free approach has proved to be a green and sustainable paradigm for the synthesis of spirocyclic, polycyclic and heterocyclic scaffolds, which are widely present in natural products and bioactive molecules. In this review, the advances in the recent six years (2017–2023) in metal‐free dearomatization reactions are highlighted. Emphasis is placed on developments in the field of organo‐catalyzed dearomatization reactions, oxidative dearomatization reactions, Brønsted acid‐ or base‐promoted dearomatization reactions, photoredox‐catalyzed dearomatization reactions, and electrochemical oxidation dearomatization reactions.

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Diversity‐Oriented Catalytic Asymmetric Dearomatization of Indoles with o‐Quinone Diimides

Gao,

Miao,

Sun

et al. 2023

Advanced Science

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Herein, the first diversity‐oriented catalytic asymmetric dearomatization of indoles with o‐quinone diimides (o‐QDIs) is reported. The catalytic asymmetric dearomatization (CADA) of indoles is one of the research focuses in terms of the structural and biological importance of dearomatized indole derivatives. Although great achievements have been made in target‐oriented CADA reactions, diversity‐oriented CADA reactions are regarded as more challenging and remain elusive due to the lack of synthons featuring multiple reaction sites and the difficulty in precise control of chemo‐, regio‐, and enantio‐selectivity. In this work, o‐QDIs are employed as a versatile building block, enabling the chemo‐divergent dearomative arylation and [4 + 2] cycloaddition reactions of indoles. Under the catalysis of chiral phosphoric acid and mild conditions, various indolenines, furoindolines/pyrroloindolines, and six‐membered‐ring fused indolines are collectively prepared in good yields with excellent enantioselectivities. This diversity‐oriented synthesis protocol enriches the o‐quinone chemistry and offers new opportunities for CADA reactions.

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One-pot synthesis of natural-product inspired spiroindolines with anti-cancer activities

Abstract: A post-Ugi/diastereoselective cascade reaction was developed to construct naturally existing spiroindolines via a facile and metal-free one-pot protocol. During the construction, a new C-C bond was formed through a selective...

Cited by 6 publications

References 38 publications

Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer

Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer

Application of Metal‐Free Dearomatization Reaction as a Sustainable Strategy to Direct Access Complex Cyclic Compounds

Diversity‐Oriented Catalytic Asymmetric Dearomatization of Indoles with o‐Quinone Diimides

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