Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin

Tillotson, Joseph; Bashyal, Bharat P.; Kang, Minjin; Shi, Taoda; Cruz, Fabian De La; Gunatilaka, A. A. Leslie; Chapman, Eli

doi:10.1039/c6ob00560h

Cited by 20 publications

(17 citation statements)

References 21 publications

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“…In addition to the molecules identified by high-throughput screening, the natural products withaferin A and dehydrocurvularin have been shown to inhibit the enzyme [ 176 , 177 ].…”

Section: Therapeutic Potential Of P97 Inhibitorsmentioning

confidence: 99%

The AAA+ ATPase p97, a cellular multitool

Stach

Freemont

2017

Biochemical Journal

123

126

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The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

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“…In addition to the molecules identified by high-throughput screening, the natural products withaferin A and dehydrocurvularin have been shown to inhibit the enzyme [ 176 , 177 ].…”

Section: Therapeutic Potential Of P97 Inhibitorsmentioning

confidence: 99%

The AAA+ ATPase p97, a cellular multitool

Stach

Freemont

2017

Biochemical Journal

123

126

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“…Curvularins are resorcylic acid lactones of considerable biological interest because of their cytotoxic, 9 phytotoxic, 10 antimicrobial, 7b nematicidal, 11 antimycobacterial, 12 and antitrypanosomal 13 activities, their ability to act as spindle poisons, 14 and their role as inhibitors of cell division, 15 microtubule assembly, 16 and components of the ubiquitin proteasome system including the ATPase p97 and the proteasome. 17 Occurrence of altertoxins, epoxyperylenes, and perylenequinones with anti-HIV, 18 anti-leishmanial, 19 antimalarial, 19 and cytotoxic 19 activities has been recently documented in endophytic Alternaria sp. It is noteworthy that the fungal metabolite thioperylenol ( 5 ), structurally related to alterperylenepoxide A ( 4 ) and bearing a 2-hydroxy-3-mercaptopropionic acid moiety at C-6, has been converted into hydroperylene derivatives with therapeutic applications for platelet aggregation.…”

mentioning

confidence: 99%

Chlorinated Dehydrocurvularins and Alterperylenepoxide A from Alternaria sp. AST0039, a Fungal Endophyte of Astragalus lentiginosus

et al. 2017

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Investigation of Alternaria sp. AST0039, an endophytic fungus obtained from the leaf tissue of Astragalus lentiginosus, led to the isolation of (−)-(10E,15S)-4,6-dichloro-10(11)-dehydrocurvularin (1), (−)-(10E,15S)-6-chloro-10(11)-dehydrocurvularin (2), (−)-(10E,15S)-10(11)-dehydrocurvularin (3), and alterperylenepoxide A (4) together with scytalone and α-acetylorcinol. Structures of 1 and 4 were established from their spectroscopic data, and the relative configuration of 4 was determined with the help of nuclear Overhauser effect difference data. All metabolites were evaluated for their cytotoxic activity and ability to induce heat-shock and unfolded protein responses. Compounds 2 and 3 exhibited cytotoxicity to all five cancer cell lines tested and increased the level of the pro-apoptotic transcription factor CHOP, but only 3 induced the heat-shock response and caused a strong unfolded protein response.

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“…Recently, cytotoxicity of compounds 6 – 8 against a small panel of human tumor cell lines has been observed, and this was partially linked to their suppressive effect on the activation of the TNFα-induced NF-κB pathway [ 28 ]. It was also reported that 8 acts as a covalent inhibitor of p97, interfering with its ATPase activity [ 29 ]. Furthermore, the antibacterial activity inhibiting the growth of E. coli of 11-hydroxylcurvularin ( 4 – 5 ) was also demonstrated [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Effects of Curvularin-Type Metabolites from a Marine-Derived Fungal Strain Penicillium sp. SF-5859 in Lipopolysaccharide-Induced RAW264.7 Macrophages

Lee

et al. 2017

Marine Drugs

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Chemical study on the extract of a marine-derived fungal strain Penicillium sp. SF-5859 yielded a new curvularin derivative (1), along with eight known curvularin-type polyketides (2–9). The structures of these metabolites (1–9) were established by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). In vitro anti-inflammatory effects of these metabolites were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Among these metabolites, 3–9 were shown to strongly inhibit LPS-induced overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) with IC50 values ranging from 1.9 μM to 18.1 μM, and from 2.8 μM to 18.7 μM, respectively. In the further evaluation of signal pathways involved in these effects, the most active compound, (10E,15S)-10,11-dehydrocurvularin (8) attenuated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 macrophages. Furthermore, compound 8 was shown to suppress the upregulation of pro-inflammatory mediators and cytokines via the inhibition of the nuclear factor-κB (NF-κB) signaling pathway, but not through the mitogen-activated protein kinase (MAPK) pathway. Based on the comparisons of the different magnitude of the anti-inflammatory effects of these structurally-related metabolites, it was suggested that the opening of the 12-membered lactone ring in curvularin-type metabolites and blocking the phenol functionality led to the significant decrease in their anti-inflammatory activity.

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Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin

Cited by 20 publications

References 21 publications

The AAA+ ATPase p97, a cellular multitool

The AAA+ ATPase p97, a cellular multitool

Chlorinated Dehydrocurvularins and Alterperylenepoxide A from Alternaria sp. AST0039, a Fungal Endophyte of Astragalus lentiginosus

Anti-Inflammatory Effects of Curvularin-Type Metabolites from a Marine-Derived Fungal Strain Penicillium sp. SF-5859 in Lipopolysaccharide-Induced RAW264.7 Macrophages

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