Concise total synthesis of largazole

Xiao, Qiong; Wang, Liping; Jiao, Xiaozhen; Liu, Xiaoyu; Wu, Qian; Xie, Ping

doi:10.1080/10286020.2010.510114

Cited by 24 publications

(14 citation statements)

References 14 publications

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“…As a result, a mixture of Z - and E -isomer 4 was subjected to the reduction condition, giving the fluoro unsaturated aldehyde 5 in 86% yield. The asymmetric aldol condensation of 5 with acetyl Nagao’s auxiliary afforded 4-fluoro derivatives of chiral 3-hydroxy-7-mercaptohept-4-enoic acid ( 8 and 9 ) under Xie’s conditions [31,32] at a low temperature (−90 °C). The two diastereomers with 2:1 ratio as determined by 19 F-NMR, were readily separated by silica gel column chromatography.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

et al. 2019

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Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

et al. 2019

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“…13 To date, eleven total syntheses of largazole have appeared in the literature, 13,14,18–21,27–31 and they have been extensively reviewed. 32–34 The synthetic challenges it presents include the preparation of the β-hydroxy carboxylic acid subunit, the formation of the 16-membered cyclic depsipeptide core, and the incorporation of the fairly labile thioester.…”

Section: Total Synthesis Of Largazolementioning

confidence: 99%

Largazole: From discovery to broad-spectrum therapy

2012

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The cyclic depsipeptide largazole from a cyanobacterium of the genus Symploca is a marine natural product with novel chemical scaffold and potently inhibits class I histone deacetylases (HDACs). Largazole possesses highly differential growth-inhibitory activity, preferentially targeting transformed over non-transformed cells. The intriguing structure and biological activity of largazole have attracted strong interest from the synthetic chemistry community to establish synthetic routes to largazole and to investigate its potential as a cancer therapeutic. This highlight surveys recent advances in this area with a focus on the discovery, synthesis, target identification, structure–activity relationships, HDAC8–largazole thiol crystal structure, and biological studies, including in vivo anticancer and osteogenic activities.

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“…Luesch and Hong reported the first total synthesis of largazole, identified histone deacetylases (HDACs) as the molecular targets, and demonstrated antitumor activity in a xenograft mouse model 2,3. Following our initial report, additional total and formal syntheses, further studies on its HDAC inhibition, and structure–activity relationship studies have appeared in the literature 4–17…”

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confidence: 90%

In Vitro and In Vivo Osteogenic Activity of Largazole

Lee

Kwak

et al. 2011

ACS Med. Chem. Lett.

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Due to their capability of modifying chromatin structure and thereby regulating gene transcription, histone deacetylases (HDACs) have been reported to play important roles in osteogenesis and considered a promising potential therapeutic target for bone diseases, including osteoporosis. We showed that the novel marine-derived HDAC inhibitor largazole exhibits in vitro and in vivo osteogenic activity. Largazole significantly induced the expression of ALP and OPN. The osteogenic activity of largazole was mediated through the increased expression of Runx2 and BMPs. Importantly, largazole showed in vivo bone-forming efficacy in the mouse calvarial bone formation assay and the rabbit calvarial bone fracture healing model. The dual action of largazole to stimulate bone formation and inhibit bone resorption would be a useful feature in drug development for bone-related disorders.

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Concise total synthesis of largazole

Abstract: The concise total synthesis of largazole was accomplished. The key step included the use of the Nagao thiazolidinethione auxiliary for the diastereoselective acetate aldol reaction and it acts as an acylating agent for the peptide formation.

Cited by 24 publications

References 14 publications

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

Largazole: From discovery to broad-spectrum therapy

In Vitro and In Vivo Osteogenic Activity of Largazole

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