Formal Catalytic Asymmetric Total Synthesis of Fostriecin

Fujii, Kunihiko; Maki, Kazuhiro; Kanai, Motomu; Shibasaki, Masakatsu

doi:10.1021/ol027528o

Cited by 120 publications

(47 citation statements)

References 33 publications

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“…Cloning of the PLM biosynthetic gene cluster and creation of a strain producing only PLM-B also set the stage for the generation of novel compounds with improved stability, activity, and selectivity. As such, this work represents a complementary approach to the widespread synthetic approaches directed toward this class of compounds (5,(17)(18)(19)(20)(21). One of the key structural differences between PLMs and fostriecin is the C-8 ethylamine substituent, which may contribute to less potent activity (15).…”

Section: Pcr-targeted Gene Disruption Of Plmsmentioning

confidence: 99%

“…Phase I clinical trials of fostriecin were suspended before either dose-limiting toxicities or therapeutic plasma levels were attained because of inherent drug instability and unpredictable purity in the clinical supply of the natural product (1,4). In an attempt to address these limitations and further develop this class of novel antitumor agents, no less than six elegant total syntheses of fostriecin have been developed over a short 2-year period (5,(17)(18)(19)(20)(21). A complementary approach for developing these agents can come through gene manipulation of the natural biosynthetic process.…”

mentioning

confidence: 99%

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Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

Palaniappan

Kim

Sekiyama

et al. 2003

Journal of Biological Chemistry

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Section: Pcr-targeted Gene Disruption Of Plmsmentioning

confidence: 99%

mentioning

confidence: 99%

Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

Palaniappan

Kim

Sekiyama

et al. 2003

Journal of Biological Chemistry

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“…A cis-selective reduction of the triple bond in 16 was achieved with a diimine that was generated in situ from o-nitrobenzenesulfonylhydrazide 17 [17] in THF/iPrOH in the presence of NEt 3 under strict exclusion of light. [18] A subsequent halogen-lithium exchange and quenching with Bu 3 SnCl gave the target precursor 10 in 75 % yield. The Stille coupling [19] of 10 with hydroxyornithine 8 provided compound 19 in 51 % yield.…”

Section: Synthesis Of Cyclopentane Analogue 4 By Route Bmentioning

confidence: 99%

Synthesis and Biological Properties of Cylindramide Derivatives: Evidence for Calcium‐Dependent Cytotoxicity of Tetramic Acid Lactams

et al. 2008

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To gain insight into the biological properties of tetramic acid lactam cylindramide 1, the analogues 4 a-d bearing a cyclopentane ring instead of the pentalene unit were prepared by tandem conjugate addition/enolate trapping of cyclopentenone 10; a Sonogashira or Stille coupling, followed by a Julia-Kocienski olefination, macrolactamisation and Lacey-Dieckmann cyclisation were the key steps. The previous NMR structure of cylindramide 1, which was based on NOE and J coupling restraints, could be refined by including residual dipolar coupling data measured for a sample of cylindramide that was aligned in polyacrylonitrile (18 %). Biological screening of cylindramide 1 and its analogues 2-epi-1, 20 and 4 revealed promising antiproliferative activity against several tumour cell lines. It turned out that the activity is strongly correlated to the functionalised pentalene system. The configuration of the cyclopentane ring and an intact tetramic acid lactam with the correct configuration seem to play an equal role in the cytotoxicity. The antiproliferative activity was found to be calcium dependent. Phenotypic characterisation of the mode of action showed vacuolisation and vesicle formation in the endoplasmic reticulum.

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“…Phase I clinical trials of fostriecin were reportedly halted due to inherent drug instability and unpredictable purity in the clinical supply of the natural products [22]. In an attempt to address these limitations and further develop this class of novel antitumor agents, no less than six total syntheses of fostriecin were developed over a short period of 2 years [1,6,7,26,33,50]. A total synthesis of LSN B has also been accomplished [39].…”

Section: Biological Activity Of the Plm And Related Compoundsmentioning

confidence: 99%

Genetic manipulation of the biosynthetic process leading to phoslactomycins, potent protein phosphatase 2A inhibitors

Ghatge

Palaniappan

Choudhuri

et al. 2006

J IND MICROBIOL BIOTECHNOL

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Phoslactomycins (PLMs) represent an unusual structural class of natural products secreted by various streptomycetes, containing an alpha,beta-unsaturated delta-lactone, an amino group, phosphate ester, conjugated diene and a cyclohexane ring. Phosphazomycins, phospholines and leustroducsins contain the same structural moieties, varying only in the acyl substituent at the C-18 hydroxyl position. These compounds possess either antifungal or antitumor activities or both. The antitumor activity of the PLM class of compounds has been attributed to a potent and selective inhibition of protein phosphatase 2A (PP2A). The cysteine-269 residue of PP2Ac-subunit has been shown to be the site of covalent modification by PLMs. In this article, we review previous work on the isolation, structure elucidation and biological activities of PLMs and related compounds and current status of our work on both PLM stability and genetic manipulation of the biosynthetic process. Our work has shown that PLM B is surprisingly stable in solution, with a pH optimum of 6. Preliminary biosynthetic studies utilizing isotopically labeled shikimic acid and cyclohexanecarboxylic acid (CHC) suggested PLM B to be a polyketide-type antibiotic synthesized using CHC as a starter unit. Using a gene (chcA) from a set of CHC-CoA biosynthesis genes from Streptomyces collinus as a probe, a 75 kb region of 29 ORFs encoding PLM biosynthesis was located in the genome of Streptomyces sp. strain HK803. Analysis and subsequent manipulation of plmS2 and plmR2 in the gene cluster has allowed for rational engineering of a strain that produces only one PLM analog, PLM B, at ninefold higher titers than the wild type strain. A strain producing PLM G (the penultimate intermediate in PLMs biosynthesis) has also been generated. Current work is aimed at selective in vitro acylation of PLM G with various carboxylic acids and a precursor-directed biosynthesis in a chcA deletion mutant with the aim of generating novel PLM analogs.

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Formal Catalytic Asymmetric Total Synthesis of Fostriecin

Abstract: The common synthetic intermediate of a potent and promising anticancer agent, fostriecin, was synthesized using a unique method that combines four catalytic asymmetric reactions as shown above.

Cited by 120 publications

References 33 publications

Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

Synthesis and Biological Properties of Cylindramide Derivatives: Evidence for Calcium‐Dependent Cytotoxicity of Tetramic Acid Lactams

Genetic manipulation of the biosynthetic process leading to phoslactomycins, potent protein phosphatase 2A inhibitors

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