Antitumor Activity of Phenylahistin<i>in Vitro</i>and<i>in Vivo</i>

Kanoh, Kaneo; Kohno, Shinkichi; Katada, Jun; Hayashi, Yoshio; Muramatsu, Michiko; Uno, Isao

doi:10.1271/bbb.63.1130

Cited by 85 publications

(63 citation statements)

References 7 publications

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“…In contrast to various carcinoma cell lines for which cytotoxic effects can be observed in the 0.1 M range (Kanoh et al, 1999b), no significant toxicity was observed using (Ϯ)-PHL in the 1 to 5 M range on human hepatocytes [using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium test or protein amounts in the cellular layer] (data not shown). In these hepatocyte preparations, metabolite formation was observed in the culture medium at 1-h incubation (approximately 60% of (Ϯ)-PHL metabolized).…”

Section: Detection Of At Least Two Dihydroxy Metabolites ([M-h]mentioning

confidence: 80%

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Metabolism of Phenylahistin Enantiomers by Cytochromes P450: A Possible Explanation for Their Different Cytotoxicity

Perrin¹,

Aninat²,

Hamon³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Phenylahistin is a fungal diketopiperazine derived from isoprenylated (Phe-⌬His) cyclodipeptide. The (؊)-enantiomer is a cell cycle inhibitor, which can be potentially used as an antitumor agent. By contrast, the (؉)-enantiomer exhibits no antimicrotubule activity. To better understand the differences that could arise from a difference of bioavailability, we investigated the interaction and metabolism of both enantiomers with mammalian cytochromes P450 (P450s). We found that both enantiomers were metabolized by various isoforms of mammal P450 with a noticeable activity for the (؉)-enantiomer. P450 3A isoforms were mainly responsible for this metabolism, the bioactive (؊)-enantiomer being 1.5 to 8 times less metabolized than the (؉)-enantiomer. Spectral analysis of the interaction with P450s revealed that (؊)-phenylahistin led to a hydrophobic type I signature, whereas the (؉)-isomer yielded a Fe-N type II one. Structural analysis of metabolites by liquid chromatography-tandem mass spectrometry allowed us to characterize two major metabolites (P1 and P3) for both enantiomers. In human liver microsomal preparations, P1 was predominant in the (؊)-phenylahistin metabolic profile. In contrast, (؉)-phenylahistin mainly produced P3 in human microsomes and CYP3A human expressed P450s. (؊)-Phenylahistin proved to be less toxic on P450-rich hepatocytes than on P450-deprived KB lines. The slower metabolism of this enantiomer could account for its higher toxicity. This is strengthened by the fact that isolated metabolites of (؊)-phenylahistin showed no toxic effects toward KB lines. Finally, differences of metabolism and interaction mode between both phenylahistin enantiomers and CYP3A4 were supported by in silico molecular docking calculations.

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Section: Detection Of At Least Two Dihydroxy Metabolites ([M-h]mentioning

confidence: 80%

“…In the present work, we studied the recognition Woehlecke et al, 2003. b Usui et al, 1998. c Hayashi et al, 2000. d Kanoh et al, 1999a. e Kanoh et al, 1999b. f Kanoh et al, 1999c.…”

mentioning

confidence: 99%

Metabolism of Phenylahistin Enantiomers by Cytochromes P450: A Possible Explanation for Their Different Cytotoxicity

Perrin¹,

Aninat²,

Hamon³

et al. 2008

Drug Metab Dispos

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“…Furthermore, 242 was evidenced to be a cell cycle inhibitor and exhibited in vivo activity against P388 leukemia and Lewis lung carcinoma cells (Kanoh et al 1997(Kanoh et al , 1999. [262][263][264][265][268][269][270], each featuring two sulfur bridges, exhibited extreme activity against P388 cells with ED 50 values ranging from 0.0023 to 0.0057 μM (Table 6) (Takahashi et al 1994a(Takahashi et al , b, 1995aYamada et al 2002Yamada et al , 2004.…”

Section: Peptidesmentioning

confidence: 99%

Mycochemistry of marine algicolous fungi

Wang

2016

Fungal Diversity

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Marine algicolous fungi refer to the fungi inhabiting or associated with marine algae, which have attracted a great attention for natural product researchers due to their chemical diversity and biological activity during the past two decades. Up to the end of 2014, a total of 366 new natural products, including polyketides, terpenoids, polyketide-terpenoids, peptides, alkaloids, and shikimate derivatives, have been characterized from them. Among these metabolites, 240 compounds feature cytotoxic, antibacterial, antifungal, antimicroalgal, zooplankton-toxic, antiprotozoal, antioxidative, enzyme-modulatory, and/or some other activities. This review gives a comprehensive coverage of both chemical and biological aspects of the secondary metabolites from marine algicolous fungi.

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“…2 They also occur in a variety of peptide antibiotics of microbial origin (including important lantibiotics such as: nisin, subtilin, epidermin and gallidermin), 3 neurotoxins (roquefortin, oxaline and phomopsin), 4 hepatotoxins (microcystins and nodularins), 5 and phytotoxic (tentoxin and AM toxins) 6,7 and antitumor agents (phenylahistin, telomestatin). 8,9 Dehydropeptides might be also considered as a class of promising foldamers 10 because of their ability to take specific three-dimensional structure forms resulting from the presence of a double bond between the Cα and Cβ atoms, which causes the coupling of this double bond with flanking amide fragments and results in rigid structure of the peptide chain. [11][12][13][14] Numerous studies dealing with dehydropeptide structure and conformation have used Z ΔPhe containig peptides owing to their easy chemical synthesis and substantial stability upon storage, [15][16][17][18] whereas peptides containing E ΔPhe are scarcely described in the literature.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of photochemical isomerization of TFA-Gly-ZΔPhe into TFA-Gly-EΔPhe

Makowski¹,

Jewgiński²,

Hurek³

et al. 2017

Arkivoc

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The kinetics of photoisomerization of trifluoroacetyl-(Z)-dehydrophenylalanylglycine into trifluoroacetyl-(E)-dehydrophenylalanylglycine was studied in the hope that light-induced reaction could be useful as a means of preparation of the E-dehydropeptides. The obtained results indicate that if this reaction carried out under irradiation with light of wavelength 360 nm it is practically irreversible and gave nearly quantitatively pure Eisomer Significantly, expected cyclic side-products were not observed in the reaction mixture, thus proving the preparative potential of the elaborated procedure.

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Antitumor Activity of Phenylahistinin Vitroandin Vivo

Cited by 85 publications

References 7 publications

Metabolism of Phenylahistin Enantiomers by Cytochromes P450: A Possible Explanation for Their Different Cytotoxicity

Metabolism of Phenylahistin Enantiomers by Cytochromes P450: A Possible Explanation for Their Different Cytotoxicity

Mycochemistry of marine algicolous fungi

Kinetics of photochemical isomerization of TFA-Gly-ZΔPhe into TFA-Gly-EΔPhe

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