Asperspiropene A, a novel fungal metabolite as an inhibitor of cancer-associated mutant isocitrate dehydrogenase 1

He, Yan; Zheng, Mengzhu; Li, Qin; Hu, Zhengxi; Zhu, Hucheng; Liu, Junjun; Wang, Jianping; Xue, Yongbo; Li, Hua; Zhang, Yonghui

doi:10.1039/c6qo00847j

Cited by 18 publications

(14 citation statements)

References 34 publications

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“…The in‐house NPs database are a collection of fungal metabolites isolated by our group. Based on their structural novelty, the molecules in the database may have promising biological activities . Structure‐based virtual ligand screening facilitated the early stage small‐molecule inhibitor discovery.…”

Section: Resultsmentioning

confidence: 99%

“…In this work, we applied in silico screening techniques to identify PI3K α inhibitors from the in‐house NPs library, and wortmannolol ( 1 ) was identified as a promising candidate which showed significant PI3K α inhibitory activity in vitro and in vivo. Our work suggested, for the first time, that wortmannolol, as a PI3K α inhibitor, is selectively cytotoxic to cancer cells and has potential to become a novel agent for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Wortmannolol Induces Breast Cancer Cell Death In Vitro and In Vivo by Targeting Phosphoinositide 3‐Kinaseα

Sun

Qin

et al. 2020

ChemistrySelect

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In silico screening of an in‐house natural products database by targeting PI3Kα and confirmatory bioassays led to the identification of wortmannolol (1) as a novel inhibitor of PI3Kα. In vitro enzymological assay revealed that 1 showed specific inhibitory activity on PI3Kα. Compound 1 inhibited PI3 K activation in a concentration‐dependent manner. Inhibition of the PI3 K/AKT signaling pathway by 1 also led to apoptosis of MCF‐7 cells and activation of the pro‐apoptotic signals. Furthermore, 1 displayed potent anti‐tumor activity in MCF‐7 xenograft CB‐17/SCID mice. Intraperitoneal injection of 5 mg/kg per bodyweight almost fully suppressed tumor growth within 14 days without gross toxicity. Importantly, PI3 K/AKT activation was suppressed in tumor tissues from 1‐treated mice, which was consistent with delayed tumor growth.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wortmannolol Induces Breast Cancer Cell Death In Vitro and In Vivo by Targeting Phosphoinositide 3‐Kinaseα

Sun

Qin

et al. 2020

ChemistrySelect

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“…Isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Neomorphic mutations in IDH1, mostly occurring at arginine 132, are frequently found in several human cancer types, including glioma, acute myeloid leukemia (AML), and myeloproliferative neoplasm [ 17 ]. When our research group screened for the IDH1 inhibitors from our natural product libraries, all the isolates 1 – 5 were evaluated for IDH1 inhibitory activity; unfortunately, none of them was active at a concentration of 20 μM.…”

Section: Resultsmentioning

confidence: 99%

A New Breviane Spiroditerpenoid from the Marine-Derived Fungus Penicillium sp. TJ403-1

et al. 2018

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Marine-derived fungi are a promising and untapped reservoir for discovering structurally interesting and pharmacologically active natural products. In our efforts to identify novel bioactive compounds from marine-derived fungi, four breviane spiroditerpenoids, including a new compound, brevione O (1), and three known compounds breviones I (2), J (3), and H (4), together with a known diketopiperazine alkaloid brevicompanine G (5), were isolated and identified from an ethyl acetate extract of the fermented rice substrate of the coral-derived fungus Penicillium sp. TJ403-1. The absolute structure of 1 was elucidated by HRESIMS, one- and two-dimensional NMR spectroscopic data, and a comparison of its electronic circular dichroism (ECD) spectrum with the literature. Moreover, we confirmed the absolute configuration of 5 by single-crystal X-ray crystallography. All the isolated compounds were evaluated for isocitrate dehydrogenase 1 (IDH1) inhibitory activity and cytotoxicity, and compound 2 showed significant inhibitory activities against HL-60, A-549, and HEP3B tumor cell lines with IC50 values of 4.92 ± 0.65, 8.60 ± 1.36, and 5.50 ± 0.67 µM, respectively.

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“…The theoretical calculations of compounds 1a / 1b and 2a / 2b were performed using Gaussian 09 and figured using GaussView 5.0 (He et al, 2017a , b , c ; Hu et al, 2017 ). Conformation search using molecular mechanics calculations was performed in the Discovery Studio 3.5 Client with MMFF force field with 20 kcal mol −1 upper energy limit (Smith and Goodman, 2010 ).…”

Section: Methodsmentioning

confidence: 99%

α-Glucosidase Inhibitors From the Coral-Associated Fungus Aspergillus terreus

Liu

Sun

et al. 2018

Front. Chem.

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Nine novel butenolide derivatives, including four pairs of enantiomers, named (±)-asperteretones A–D (1a/1b–4a/4b), and a racemate, named asperteretone E (5), were isolated and identified from the coral-associated fungus Aspergillus terreus. All the structures were established based on extensive spectroscopic analyses, including HRESIMS and NMR data. The chiral chromatography analyses allowed the separation of (±)-asperteretones A–D, whose absolute configurations were further confirmed by experimental and calculated electronic circular dichroism (ECD) analysis. Structurally, compounds 2–5 represented the first examples of prenylated γ-butenolides bearing 2-phenyl-3-benzyl-4H-furan-1-one motifs, and their crucial biogenetically related metabolite, compound 1, was uniquely defined by an unexpected cleavage of oxygen bridge between C-1 and C-4. Importantly, (±)-asperteretal D and (4S)-4-decarboxylflavipesolide C were revised to (±)-asperteretones B (2a/2b) and D (4), respectively. Additionally, compounds 1a/1b–4a/4b and 5 were evaluated for the α-glucosidase inhibitory activity, and all these compounds exhibited potent inhibitory potency against α-glucosidase, with IC50 values ranging from 15.7 ± 1.1 to 53.1 ± 1.4 μM, which was much lower than that of the positive control acarbose (IC50 = 154.7 ± 8.1 μM), endowing them as promising leading molecules for the discovery of new α-glucosidase inhibitors for type-2 diabetes mellitus treatment.

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Asperspiropene A, a novel fungal metabolite as an inhibitor of cancer-associated mutant isocitrate dehydrogenase 1

Abstract: In silico screening of an in-house natural product database and confirmatory bioassays led to the identification of asperspiropene A (1) as an inhibitor of cancer-associated mutant IDH1.

Cited by 18 publications

References 34 publications

Wortmannolol Induces Breast Cancer Cell Death In Vitro and In Vivo by Targeting Phosphoinositide 3‐Kinaseα

Wortmannolol Induces Breast Cancer Cell Death In Vitro and In Vivo by Targeting Phosphoinositide 3‐Kinaseα

A New Breviane Spiroditerpenoid from the Marine-Derived Fungus Penicillium sp. TJ403-1

α-Glucosidase Inhibitors From the Coral-Associated Fungus Aspergillus terreus

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