AS1387392, a novel immunosuppressive cyclic tetrapeptide compound with inhibitory activity against mammalian histone deacetylase

Sasamura, Satoshi; Sakamoto, Kazutoshi; Takagaki, Shoji; Yamada, Toshiko; Takase, Shigehiro; Mori, Hajime; Fujii, Takashi; Hino, Motohiro; Hashimoto, Michizane

doi:10.1038/ja.2010.51

Cited by 27 publications

(32 citation statements)

References 12 publications

(11 reference statements)

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“…The same strain of fungus that produced metabolite FR235222 was also found to produce demethyl-FR235222, known as AS1387392 (Figure 1b). 9 AS1387392 had an immunosuppressive effect similar to that of FR235222 while maintaining a pharmacokinetic profile approximately two times better than that of FR235222. These findings suggested AS1387392 as a novel immunosuppressive drug candidate for treating acute allograft rejection in organ transplant patients.…”

Section: Introductionmentioning

confidence: 88%

“…These findings suggested AS1387392 as a novel immunosuppressive drug candidate for treating acute allograft rejection in organ transplant patients. 9 However, its paucity of functional groups, essential to synthesizing more derivatives, is a drawback.…”

Section: Introductionmentioning

confidence: 99%

“…12 AS1429716 potently inhibited histone deacetylase activity with an IC 50 value of 22 nM, demonstrating this compound to be as potent as AS1387392 (IC 50 ¼22 nM). 9,12 Given that several biochemical analyses indicated that cytochrome P450 was responsible for this hydroxylation, we attempted to clone a gene encoding bacterial cytochrome P450 that would catalyze the hydroxylation of AS1387392 to AS1429716. Furthermore, to confirm its function, we attempted to produce its expression in a Streptomycetes host.…”

Section: Introductionmentioning

confidence: 99%

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Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

et al. 2010

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Biotransformation technology involving enzymatic modification of original substrates by organisms such as microbes is a valuable tool in improving pharmacokinetics or physicochemical properties of the base compounds. The fungal metabolite AS1387392 is a histone deacetylase inhibitor with potential as a therapeutic immunosuppressant. However, its paucity of functional groups, essential to synthesizing derivatives, is a drawback. Amycolatopsis azurea JCM-3275 catalyzed hydroxylation of AS1387392 to AS1429716, which may facilitate the synthesis of more derivatives by the additional hydroxyl moiety present in AS1429716. This reaction was inhibited by cytochrome P450 inhibitor metyrapone, indicating that cytochrome P450 may be responsible for the transformation. Degenerate PCR primers were subsequently constructed and used to clone genes encoding cytochrome P450 from the genomic DNA of A. azurea JCM-3275. We cloned an entire novel P450 gene (1209 bp) and named it P450Um-1. Its deduced amino acid sequence was homologous with that of the CYP105 subfamily. Further cloning of the upstream region, which may contain the native promoter site, was followed by insertion of the open reading frame with the upstream area into Streptomycetes high copy vector pIJ702, giving the expression plasmid pNUm-1. P450Um-1 was specifically expressed in Streptomyces lividans TK24, and this recombinant strain converted AS1387392 to AS1429716 without any redox partners. These results show that P450Um-1, a novel bacterial P450, catalyzed hydroxylation of AS1387392 to AS1429716. This resultant recombinant strain is expected to be an efficient biocatalyst with application to more suitable redox systems than those tested here.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

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“…(8), bearing a Pro unit instead of (2 R ,4 S )-MePro, was recently isolated from the same Acremonium sp. collection that yielded FR235222, although it had been previously reported as a synthetic compound [87, 88]. Demethylation of the Pro unit was well-tolerated and did not have any detrimental effects on the biological activities of FR235222 while at the same time simplifying the synthesis of this compound [87].…”

Section: Development Of Modulators Of Histone Acetylationmentioning

confidence: 99%

Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation

Salvador¹,

Luesch²

2012

CDT

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Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. This area of research has seen a rapid increase in interest in the past decade, with the structurally diverse natural products-derived compounds at its forefront. These secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.

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“…27082, has been found to exert a strong inhibitory effect against histone deacetylase (HDAC) with a good oral absorption profile. 1 Although AS1429716 (2) (Figure 1) presents an attractive chemical template for synthesizing candidate immunosuppressant compounds subsequent to 1, actually constructing, such a compound is difficult from a chemical stance.…”

Section: Introductionmentioning

confidence: 99%

Bioconversion of AS1387392: bioconversion studies involving Amycolatopsis azurea JCM 3275

et al. 2010

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We screened actinomycetes capable of converting AS1387392 to AS1429716 and identified those strains capable of hydroxylation. Amycolatopsis azurea JCM 3275 was found to be a particularly efficient strain, capable of converting AS1387392 to AS1429716, with a yield of 44% after 9 h. This strain can metabolize not only the hydroxylation of phenylalanine at the meta and para positions but also the reduction of hydroxyketones, as shown by the isolation of bioconversion products. Examination of more suitable conversion conditions showed that pH 7.8 and 25 1C were the optimum pH and temperature for bioconversion, respectively. We also demonstrated the effect of carbon and nitrogen sources in the culture media on hydroxylation. Using this strain, we were able to efficiently produce AS1429716 as a chemical template. Further derivatization studies may provide more effective, safer immunosuppressants than those that are currently on-market.

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AS1387392, a novel immunosuppressive cyclic tetrapeptide compound with inhibitory activity against mammalian histone deacetylase

Cited by 27 publications

References 12 publications

Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation

Bioconversion of AS1387392: bioconversion studies involving Amycolatopsis azurea JCM 3275

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