Two New Neo-debromoaplysiatoxins—A Pair of Stereoisomers Exhibiting Potent Kv1.5 Ion Channel Inhibition Activities

Fan, Tao; Zhang, Huihui; Tang, Yang-Hua; Zhang, Fan-Zhong; Han, Bingnan

doi:10.3390/md17120652

Cited by 22 publications

(11 citation statements)

References 39 publications

(68 reference statements)

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“…Kv1.5 channels, a possible pivotal target for new treatment of atrial tachyarrhymias with minimal potential for deleterious side effect [150,153,154]. Although further studies are still ongoing to establish the Kv1.5 inhibition mechanism by these various bioactive compounds, researchers suggested two mechanisms.…”

Section: Aplysiatoxin Derivativesmentioning

confidence: 99%

“…The other proposed mechanism is the indirect modulation of the Kv channel by activating protein kinase C [153]. In addition to their various structures, ATX derivatives exhibit selectivity and potency against Kv1.5 channels, a possible pivotal target for new treatment of atrial tachyarrhymias with minimal potential for deleterious side effect [151,154,155]. Although further studies are still ongoing to establish the Kv1.5 inhibition mechanism by these various bioactive compounds, researchers suggested two mechanisms.…”

Section: Aplysiatoxin Derivativesmentioning

confidence: 99%

“…One is the direct ion channel modulation by direct blocking of the pore. The other proposed mechanism is the indirect modulation of the Kv channel by activating protein kinase C [154].…”

Section: Aplysiatoxin Derivativesmentioning

confidence: 99%

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Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

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Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

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Section: Aplysiatoxin Derivativesmentioning

confidence: 99%

Section: Aplysiatoxin Derivativesmentioning

confidence: 99%

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Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

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“…The absolute configurations of this kind of secondary metabolites were difficult to determine because the alkyl chains were flexible and there were no conjugated chromophores in the compounds. Thus, we combined DP4+ probability analysis [12,13], electronic circular dichroism (ECD)…”

Section: Introductionmentioning

confidence: 99%

Three New Sesquiterpenoids from the Algal-Derived Fungus Penicillium chermesinum EN-480

Yang

et al. 2020

Marine Drugs

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Secondary metabolites obtained from marine-derived fungi are rich sources of drug candidates. Three new sesquiterpenoids, chermesiterpenoids A–C (1–3), along with four known alkaloids (4–7), were isolated and identified from the marine red algal-derived fungus Penicillium chermesinum EN-480. The structures of these new sesquiterpenoids were elucidated using detailed analysis of the NMR data and their relative configurations were elucidated using nuclear overhauser effect spectroscopy (NOESY) spectra as well as gauge-independent atomic orbital (GIAO) NMR shift calculations and DP4+ probability analysis. Their absolute configurations were determined using electronic circular dichroism (ECD) calculations and modified Mosher’s method. Compounds 2 and 3 exhibited potent activities against human and aquatic pathogenic bacteria and plant pathogenic fungi.

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“…ATXs are a class of biologically active dermatoxins with tumor-promoting properties, anti-proliferative activity, antiviral activity, antileukemia activity, and pro-inflammatory actions [ 11 , 15 , 16 , 17 , 18 ]. So far, about 45 ATXs were identified from marine cyanobacteria, and mainly existed in Lyngbya [ 19 , 20 , 21 , 22 , 23 , 24 ]. Thus, the blooms of Lyngbya were often concerned with negative impacts on human health and economic implications [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Chemical and Biological Study of Novel Aplysiatoxin Derivatives from the Marine Cyanobacterium Lyngbya sp.

Zhang

et al. 2020

Toxins

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Since 1970s, aplysiatoxins (ATXs), a class of biologically active dermatoxins, were identified from the marine mollusk Stylocheilus longicauda, whilst further research indicated that ATXs were originally metabolized by cyanobacteria. So far, there have been 45 aplysiatoxin derivatives discovered from marine cyanobacteria with various geographies. Recently, we isolated two neo-debromoaplysiatoxins, neo-debromoaplysiatoxin G (1) and neo-debromoaplysiatoxin H (2) from the cyanobacterium Lyngbya sp. collected from the South China Sea. The freeze-dried cyanobacterium was extracted with liquid–liquid extraction of organic solvents, and then was subjected to multiple chromatographies to yield neo-debromoaplysiatoxin G (1) (3.6 mg) and neo-debromoaplysiatoxin H (2) (4.3 mg). They were elucidated with spectroscopic methods. Moreover, the brine shrimp toxicity of the aplysiatoxin derivatives representing differential structural classifications indicated that the debromoaplysiatoxin was the most toxic compound (half inhibitory concentration (IC50) value = 0.34 ± 0.036 µM). While neo-aplysiatoxins (neo-ATXs) did not exhibit apparent brine shrimp toxicity, but showed potent blocking action against potassium channel Kv1.5, likewise, compounds 1 and 2 with IC50 values of 1.79 ± 0.22 µM and 1.46 ± 0.14 µM, respectively. Therefore, much of the current knowledge suggests the ATXs with different structure modifications may modulate multiple cellular signaling processes in animal systems leading to the harmful effects on public health.

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Two New Neo-debromoaplysiatoxins—A Pair of Stereoisomers Exhibiting Potent Kv1.5 Ion Channel Inhibition Activities

Cited by 22 publications

References 39 publications

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Three New Sesquiterpenoids from the Algal-Derived Fungus Penicillium chermesinum EN-480

Chemical and Biological Study of Novel Aplysiatoxin Derivatives from the Marine Cyanobacterium Lyngbya sp.

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