Sesterterpene MHO7 suppresses breast cancer cells as a novel estrogen receptor degrader

Zhao, Yue; Zhao, Chenxi; Lu, Jin Song; Wu, Jun; Li, Changhao; Hu, Zhigang; Tian, Wei; Xiang, Jin; Zhou, Haibin; Deng, Zixin; Huang, Jian; Hong, Kui

doi:10.1016/j.phrs.2019.104294

Cited by 23 publications

(17 citation statements)

References 39 publications

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“…To rationalize the distinct regioselectivity of OleT JE towards 2 and 3,w ep erformed molecular docking using Sybyl-X 2.0 software. [9] As shown in Figure 2a,t he docking conformation of the cis-isomer 2 in the active site of OleT JE is analogous to the cis-like configuration seen both in the cocrystal structure of OleT JE and the C 20 substrate arachidic acid (PDB ID code:4 L40) [10] and the docking structure of 1 in OleT JE (Figure S53). These results suggest that the C2 À C3 cisconfiguration might be favored by the architecture of OleT JE active site.Inthis binding mode,the shorter distance between the pro-4R CÀHbond (relative to the pro-4S CÀHbond) and the heme-iron may also explain the stereoselectivity of OleT JE towards 2 (Figure 2a).…”

Section: Methodsmentioning

confidence: 71%

“…To rationalize the distinct regioselectivity of OleT JE towards 2 and 3 , we performed molecular docking using Sybyl‐X 2.0 software [9] . As shown in Figure 2 a, the docking conformation of the cis ‐isomer 2 in the active site of OleT JE is analogous to the cis ‐like configuration seen both in the co‐crystal structure of OleT JE and the C 20 substrate arachidic acid (PDB ID code: 4L40) [10] and the docking structure of 1 in OleT JE (Figure S53).…”

Section: Resultsmentioning

confidence: 99%

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Unexpected Reactions of α,β‐Unsaturated Fatty Acids Provide Insight into the Mechanisms of CYP152 Peroxygenases

Jiang

Peng

et al. 2021

Angewandte Chemie

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CYP152 peroxygenases catalyzed ecarboxylation and hydroxylation of fatty acids using H 2 O 2 as cofactor.T o understand the molecular basis for the chemo-and regioselectivity of these unique P450 enzymes,weanalyzethe activities of three CYP152 peroxygenases (OleT JE ,P 450 SPa ,P 450 BSb ) towards cis-and trans-dodecenoic acids as substrate probes. The unexpected 6S-hydroxylation of the trans-isomer and 4Rhydroxylation of the cis-isomer by OleT JE ,a nd molecular docking results suggest that the unprecedented selectivity is due to OleT JE spreference of C2ÀC3 cis-configuration. In addition to the common epoxideproducts,undecanal is the unexpected major product of P450 SPa and P450 BSb regardless of the cis/ trans-configuration of substrates.The combined H 2 18 O 2 tracing experiments,M Ds imulations,a nd QM/MM calculations unravel an unusual mechanism for Compound I-mediated aldehyde formation in whichthe active site water derived from H 2 O 2 activation is involved in the generation of af ourmembered ring lactone intermediate.T hese findings provide new insights into the unusual mechanisms of CYP152 peroxygenases.

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Section: Methodsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Unexpected Reactions of α,β‐Unsaturated Fatty Acids Provide Insight into the Mechanisms of CYP152 Peroxygenases

Jiang

Peng

et al. 2021

Angewandte Chemie

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“…At 1 h after oral administration of MHO7, highest concentration levels were observed in liver (3.01 ± 1.53 µg•g −1 ), followed by brain (0.95 ± 0.80 µg•g −1 ) and reproductive organs (0.88 ± 0.68 µg•g −1 ). At 4 h, the MHO7 was concentrated in fat ( The results indicate that MHO7 was widely distributed in most tissues and decreased obviously after 20 h. In our previous study, MHO7 exhibited antitumor activity against breast cancer cells (MCF-7) by the mechanism of down regulating ERα [11]. Breast cancer occurs in female animals; in the pharmacokinetics experiments, especially tissue distribution, we studied whether MHO7 has potential for the treatment of breast cancer in female mice.…”

Section: Pharmacokinetics and Tissue Distribution After Oral Administmentioning

confidence: 98%

“…In our previous study, MHO7 (6-epi-ophiobolin G, the structure is shown in Figure 1), which was produced by a mangrove fungus Aspergillus ustus 094102 [10], demonstrated potent antitumor activity against breast cancer cells (MCF-7) by the mechanism of down regulating estrogen receptor alpha (ERα) acting as a novel estrogen receptor degrader different from the known ERα inhibitors [11]. Although the family of Ophs have shown anticancer activity in some cancer cell lines [5], no toxicity and pharmacokinetics studies have been reported on these compounds.…”

Section: Introductionmentioning

confidence: 99%

Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus

Tian

Deng

et al. 2019

Marine Drugs

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Sesterterpene MHO7 derived from mangrove fungus is a novel estrogen receptor degrader for the treatment of breast cancer. To explore its safety and pharmacokinetics in vivo, Log P/D values, stability in simulated gastric/intestinal (SGF/SIF), toxicity, and pharmacokinetics studies were carried mainly by liquid chromatography technique coupled with tandem mass spectrometry (LC–MS/MS) method in mice, and the effect of MHO7 on mice gut microbiota at different time points was revealed by 16S rRNA sequencing. Log P/D values ranged 0.93–2.48, and the compound in SGF and SIF is stable under the concentration of 5 mM·L−1. The maximum tolerance dose (MTD) of oral administration in mice was 2400 mg·kg−1. The main pharmacokinetics parameters were as following: Cmax of 1.38 μg·mL−1, Tmax of 8 h, a half-life (t1/2) of 6.97 h, an apparent volume of mean residual time (MRT) of 8.76 h, and an area under the curve (AUC) of 10.50 h·μg·mL−1. MHO7 displayed a wide tissue distribution in mice, with most of the compound in liver (3.01 ± 1.53 μg·g−1) at 1 h, then in fat (5.20 ± 3.47 μg·g−1) at 4 h, and followed by reproductive organs with the concentrations of 23.90 ± 11.33 μg·g−1,13.69 ± 10.29 μg·g−1, 1.46 ± 1.23 μg·g−1, and 0.36 ± 0.46 μg·g−1 at 8, 12, 20 and 30 h, respectively. The most influenced genera of gut microbiome belonged to phylum Firmicutes (21 of 28), among which 18 genera originated from the order Clostridiales, class Clostridia, and families of Ruminococcaceae (11 of 18) and Lachnospiraceae (4 of 18). These results provide that MHO7 is suitable for oral administration in the treatment of breast cancer with the target organs of reproductive organs and regulation on Ruminococcaceae and Lachnospiraceae.

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“…Most of ophiobolins show the significant inhibitory activity of tumor cell proliferation and are considered potential antitumor drugs [86]. MHO7 (6-epi-ophiobolin G) can suppress breast cancer cells by downregulating estrogen receptor alpha (ERα), which acts as a novel estrogen receptor degrader [87]. Further research of MHO7 showed that it is appropriate for oral administration according to the target reproductive organs and influences the metabolic pathways via short-chain fatty acids by regulating the levels of the gut microbiome (Ruminococcaceae and Lachnospiraceae) [88].…”

Section: Sesterterpenesmentioning

confidence: 99%

A Review of Terpenes from Marine-Derived Fungi: 2015–2019

Jiang

Guo

et al. 2020

Marine Drugs

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Marine-derived fungi are a significant source of pharmacologically active metabolites with interesting structural properties, especially terpenoids with biological and chemical diversity. In the past five years, there has been a tremendous increase in the rate of new terpenoids from marine-derived fungi being discovered. In this updated review, we examine the chemical structures and bioactive properties of new terpenes from marine-derived fungi, and the biodiversity of these fungi from 2015 to 2019. A total of 140 research papers describing 471 new terpenoids of six groups (monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, and meroterpenes) from 133 marine fungal strains belonging to 34 genera were included. Among them, sesquiterpenes, meroterpenes, and diterpenes comprise the largest proportions of terpenes, and the fungi genera of Penicillium, Aspergillus, and Trichoderma are the dominant producers of terpenoids. The majority of the marine-derived fungi are isolated from live marine matter: marine animals and aquatic plants (including mangrove plants and algae). Moreover, many terpenoids display various bioactivities, including cytotoxicity, antibacterial activity, lethal toxicity, anti-inflammatory activity, enzyme inhibitor activity, etc. In our opinion, the chemical diversity and biological activities of these novel terpenoids will provide medical and chemical researchers with a plenty variety of promising lead compounds for the development of marine drugs.

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Sesterterpene MHO7 suppresses breast cancer cells as a novel estrogen receptor degrader

Cited by 23 publications

References 39 publications

Unexpected Reactions of α,β‐Unsaturated Fatty Acids Provide Insight into the Mechanisms of CYP152 Peroxygenases

Unexpected Reactions of α,β‐Unsaturated Fatty Acids Provide Insight into the Mechanisms of CYP152 Peroxygenases

Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus

A Review of Terpenes from Marine-Derived Fungi: 2015–2019

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