Phoenistatin, A New Gene Expression-Enhancing Substance Produced by Acremonium fusigerum.

Masuoka, Yuhta; Shin‐ya, Kazuo; Furihata, Kazuo; Nagai, Koji; Suzuki, Kenichi; Hayakawa, Yoichi; Seto, Haruo

doi:10.7164/antibiotics.54.187

Cited by 12 publications

(4 citation statements)

References 7 publications

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“…As discussed for compound 8 , examples of the naturally occurring cyclotetrapeptides ( 14 a , 15 , 17 , 22 b , 24 c , 24 d , 24 g , and 24 i ) have not been tested for HDAC inhibitory activity, but are generally assumed to inhibit HDAC enzymes due to the structural resemblance to other known HDAC inhibitors. Furthermore, cytostatic activity has been reported for phoenistatin ( 17 ), and cytotoxic activities against cancer cells have been reported for WF3161 ( 15 ) and microsporin B ( 22 b ); this is consistent with HDAC inhibition but naturally not evidence that they target HDACs.…”

Section: Naturally Occurring Macrocyclic Hdac Inhibitorsmentioning

confidence: 77%

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

et al. 2016

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Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen. Nevertheless, it has been speculated that using macrocyclic compounds to target HDAC enzymes might hold an advantage over the use of traditional hydroxamic‐acid‐containing inhibitors, which rely on chelation to the conserved active‐site zinc ion. Here we review the literature on macrocyclic HDAC inhibitors obtained from natural sources and on structure–activity relationship studies inspired by these molecules, as well as on efforts aimed at fully synthetic macrocyclic HDAC inhibitors.

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Section: Naturally Occurring Macrocyclic Hdac Inhibitorsmentioning

confidence: 77%

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

et al. 2016

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“…FR235222 possesses a unique structural feature that makes it different from the other cyclotetrapeptides showing the same activity: in addition to the rare amino acids Ahoda and isovaline, the novel 4-methylproline replaces the more common proline or pipecolinic acid [119]. These rare amino acids are also present in phoenistatin [120], isolated in 2001 as fungal metabolite (Acremonium fusigerum), and TAN-1746, identified in 1995 as neoplasm inhibitor in the culture broth of Verticillium chlamydosporium [121].…”

Section: Cyclic Peptidesmentioning

confidence: 99%

Chemistry and Biology of Chromatin Remodeling Agents: State of Art and Future Perspectives of HDAC Inhibitors

Rodriquez¹,

Aquino²,

Bruno³

et al. 2006

CMC

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Chromatin remodeling is a fundamental phenomenon in the life of eukaryotic cells, bearing implications to numerous physiological and pathological phenomena. This review outlines the chemistry of natural and synthetic agents endowed with the ability to interfere with such biological function, with a particular emphasis on histone deacetylase (HDAC) inhibitors. Other aspects covered in this article comprise structure activity relationships (SAR) and modes of action at molecular level, including the description of crystal structures of enzyme-inhibitor complexes.

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“…In our previous study, we showed that the β ‐turn unit D‐Phe‐Pro of gramicidin S (GS) is nicely mimicked by a suitably functionalized tetrahydrofuran amino acid (TAA) having a ( R )‐benzyl substituent at its C6‐position mimicking the D‐Phe unit [23] . In addition, many naturally occurring cyclic tetrapeptide based HDAC inhibitors like trapoxin B, chlamydocin, [24] AS1387392, [25] phoenistatin [26] and, some synthetic HDACis such as CHAP1 [17] carry Phe‐Pro in their core structures. These reports on the cyclic peptide‐based HDACis carrying proline or pipecolic acids [17,22] and our own work on GS analogs [23] prompted us to explore if the TAA‐based CTPs shown in Figure 2 could serve as a new class of HDAC inhibitors in which the TAA unit in the CAP segment was expected to mimic the proline‐mediated turn structures of natural peptides and the Orn side chain with hydroxamic acid at the end was to serve as the ZBG.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Conformational Studies of Cyclic Tetrapeptides having βγ Fused Turns as HDAC Inhibitors

et al. 2021

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Histone deacetylases (HDACs) belong to a class of major targets for the development of anticancer drugs for which cyclic peptide-based molecules are attracting wide attention. Here we show the synthesis, conformational and in silico analysis of tetrahydrofuran amino acid (TAA) based 15-membered cyclic tetrapeptides (CTPs) containing hydroxamic acid side chain as potential HDAC inhibitors. NMR based solution studies in protected and deprotected forms reveal that the macrocycles are stabilized by 10-membered β-turn as well as a 7-membered γ-turn. This type of fused structures within the same macrocycle is not frequently sighted. Our initial in silico docking results indicated that the hydroxamic acid protected CTPs show promising binding with the class-1 HDACs. We also noticed that the C-chain with hydroxamic functional group attached on the ornithine sidechain did not affect the core structure of the peptide ring. Moreover, some of these cyclic tetrapeptides with hydroxamic acid side chain exhibited an induction of acetylation of histones on preliminary cell-based experiments. Our initial results provide an insight into the development of HDAC inhibitors based on the CTPs with novel βγ fused turns which have not been explored yet.

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Phoenistatin, A New Gene Expression-Enhancing Substance Produced by Acremonium fusigerum.

Cited by 12 publications

References 7 publications

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

Chemistry and Biology of Chromatin Remodeling Agents: State of Art and Future Perspectives of HDAC Inhibitors

Design, Synthesis and Conformational Studies of Cyclic Tetrapeptides having βγ Fused Turns as HDAC Inhibitors

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