Relative and Absolute Configuration of Versipelostatin, a Down-Regulator of Molecular Chaperone GRP78 Expression

Park, Hae-Ryong; Chijiwa, Shuhei; Furihata, Kazuo; Hayakawa, Yoichi; Shin‐ya, Kazuo

doi:10.1021/ol070042t

Cited by 42 publications

(38 citation statements)

References 18 publications

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“…12 The deduced absolute configuration was identical with that known for this antibiotic family. 13,14 Spirotetronates represented by kijanimicin 15 feature a trans-D 1 -octalin unit and a tetronic acid moiety spiro-linked with a cyclohexene ring. To date, over 50 related metabolites have been discovered from actinomycetes.…”

Section: Resultsmentioning

confidence: 99%

Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura

et al. 2012

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Nomimicin (1), a new spirotetronate-class polyketide, was isolated from the culture broth of an actinomycete of the genus Actinomadura. Its structure was established by spectroscopic methods, and the absolute configuration was determined by a combination of NOESY experiment, J-based configuration analysis and the modified Mosher method. Nomimicin (1) showed antimicrobial activity against Micrococcus luteus, Candida albincans and Kluyveromyces fragilis. Keywords: Actinomadura; polyketide; spirotetronate INTRODUCTION Microbial secondary metabolites have been the most productive source of small molecules for the development of drugs. 1 Almost a half of the known microbial bioactive compounds are derived from actinomycetes, and specifically Streptomyces accounts for more than 70% of the actinomycete-derived metabolites. 2 Among the nonStreptomyces species, Micromonospora is the leading producer of secondary metabolites, including polyketides, peptides and glycosides, whereas Actinomadura is known as a producer of chemically and biologically unique polyketides such as antitumor enediynes, 3 mannose-binding quinone glycosides with antifungal and anti-HIV activities 4 and anticoccidial polyethers, 5 accounting for up to 350 compounds reported as of 2005. 2 During our continuing investigation on the metabolites from actinomycetes of nonStreptomyces group, 6,7 a new spirotetronate antibiotic of polyketide origin, nomimicin (1, Figure 1), was isolated from the culture extract of Actinomadura sp. TP-A0878. In this paper, we describe the isolation, structural determination and biological properties of 1.

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Section: Resultsmentioning

confidence: 99%

Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura

et al. 2012

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“…Versipelostatin, a Grp78/BiP inhibitor shows promise in solid tumour cell lines, 38,52 particularly as the levels Grp78/BiP are commonly raised in solid tumours and cancer cell lines. [53][54][55] A number of groups are also working on specific inhibitors of the IRE1α/XBP1 pathways, with Irestatin being developed to inhibit IRE1α activity 56 and Trierixin, a new member of the triene-ansamycin group, being shown to be a novel inhibitor of ER-stress induced cleavage of XBP1.…”

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confidence: 99%

Untangling the unfolded protein response

Davenport¹,

Morgan²,

Davies³

2008

Cell Cycle

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“…The 2R-hydroxy-propyl group of maklamicin is attached on the cyclohexene ring, whereas other spirotetronates have an achiral substituent at the same position, such as a methyl, a formyl, an ethyl, or an n-propyl group (Shimotohno et al 1993;Hegde et al 1997;Momose et al 1999;Park et al 2007). The attachment of a hydroxy group to the alkyl chain to form a peripheral moiety of a polyketide compound has been known to be catalyzed by specific enzymes in the post-PKS tailoring step (Rix et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the biosynthetic gene cluster for maklamicin, a spirotetronate-class antibiotic of the endophytic Micromonospora sp. NBRC 110955

Daduang

Kitani

Hashimoto

et al. 2015

Microbiological Research

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Maklamicin, which is produced by the endophytic Micromonospora sp. NBRC 110955, is a spirotetronate-class antibiotic possessing anti-microbial activity against Gram-positive bacteria, and has several unique structural features different from other spirotetronates. Here we describe identification and characterization of the maklamicin biosynthetic (mak) gene cluster through draft genome sequencing, genomic library screening, and gene disruption. Sequence analysis revealed that a plausible maklamicin cluster resides in a 152 kb DNA region encoding 46 open reading frames, 24 of which can be assigned roles in the biosynthesis of polyketide backbone, spirotetronate or peripheral moieties, self-resistance and the regulation of maklamicin production. Disruption of the polyketide synthase (PKS) genes makA1 or makA4 resulted in a complete loss of maklamicin production, indicating that the type I modular PKS system is responsible for the biosynthesis of maklamicin. The mak gene cluster contained a set of biosynthetic genes for the formation of a tetronate moiety, which were found to be highly conserved in the gene clusters for spirotetronate antibiotics. Based on the estimated biosynthetic genes, we propose the biosynthetic pathway for maklamicin. Our findings provide not only insights on the biosynthetic mechanism of the unique structures in maklamicin, but also useful information to facilitate a comparative analysis of the spirotetronate biosynthetic pathways to expand the structural repertoire.

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Relative and Absolute Configuration of Versipelostatin, a Down-Regulator of Molecular Chaperone GRP78 Expression

Cited by 42 publications

References 18 publications

Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura

Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura

Untangling the unfolded protein response

Characterization of the biosynthetic gene cluster for maklamicin, a spirotetronate-class antibiotic of the endophytic Micromonospora sp. NBRC 110955

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