Enantioselective Synthesis of Pladienolide B and Truncated Analogues as New Anticancer Agents

Kumar, Vemula Praveen; Chandrasekhar, Srivari

doi:10.1021/ol401458d

Cited by 42 publications

(39 citation statements)

References 52 publications

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“…We were inspired by the seminal work of Chandrasekhar et al in their disclosure of simplified pladienolide analogs wherein they rigidified the side chain with an aryl isostere and we determined that a similar replacement was feasible based on computational modeling (Figure 1). 17 We and others 18 have been drawn to this substitution as it would both simplify the synthesis and effectively evaluate the importance of the elaborate side chain. Herein, we report the DTS of 16 simplified carolacton-inspired analogs that have resulted in the discovery of three independent biofilm phenotypes: (1) inhibition of their formation, (2) inhibition of their maturation, and (3) acid-mediated cell death during formation, akin to carolacton, by an analog coined “carylacton”.…”

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confidence: 99%

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

et al. 2017

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The oral microbiome is a dynamic environment inhabited by both commensals and pathogens. Among these is Streptococcus mutans, the causative agent of dental caries, the most prevalent childhood disease. Carolacton has remarkably specific activity against S. mutans, causing acid-mediated cell death during biofilm formation; however, its complex structure limits its utility. Herein, we report the diverted total synthesis and biological evaluation of a rationally designed library of simplified analogs that unveiled three unique biofilm phenotypes further validating the role of natural product synthesis in the discovery of new biological phenomena.

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confidence: 99%

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

et al. 2017

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“…As a result, several total synthesis routes to pladienolide, spliceostatin, and herboxidiene classes of natural products have been reported (for the most recent, see refs. [14][15][16]. For spliceostatins, the shortest described synthetic route contains 20 total steps, with the longest linear sequence being 10 steps (14).…”

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confidence: 99%

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

Eustáquio

Janso

Ratnayake

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Spliceostatins are bacterial natural products that show promising anticancer activity. Understanding how the bacterium makes spliceostatins will aid efforts toward a sustainable route for their production. Moreover, altering the chemical structure of a natural product is usually necessary to improve its pharmaceutical properties. For example, the parent spliceostatin molecule contains an unstable hemiketal chemical group. Contrary to previous hypotheses, we report on the identification of a dioxygenase enzyme responsible for hemiketal biosynthesis. Deletion of the corresponding dioxygenase gene led to a strain that produces exclusively spliceostatin congeners that are more stable than, and as active as, the parent compound, when derivatized to increase cell permeability. The strain generated in this study will be the basis for future development.

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“…Oxone was used in DME under basic buffered conditions at 0 °C in the presence of only 5-10 mol% of the chiral ketone [94]. More recently, a comparable methodology was applied by Chandrasekhar and Kumar to the total synthesis of pladienolide B, a natural anticancer macrolide [95]. The key step of the synthesis was the epoxidation of homoallylic alcohol 105 performed in the presence of superstoichiometric amounts of ketone 106 and oxone to give epoxide 107 in 64% yield and 95% de (Scheme 43).…”

Section: Asymmetric Organocatalyzed Epoxidations As Key Stepsmentioning

confidence: 99%

Applications of Chiral Three-membered Rings for Total Synthesis: A Review

Dalpozzo¹,

Lattanzi

Pellissier

2017

COC

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This review updates recent applications of asymmetric aziridination, azirination, thiirination, epoxidation, and cyclopropanation in the total synthesis of biologically active compounds, including natural products, using chiral substrates or chiral catalysts, covering the literature since 2000. The interest towards these synthetic methodologies of chiral three-membered rings has increased in the last decade, dictated either by the biological activities that display many naturally occurring products bearing a three-membered unit or by the ring strain of three-membered rings making them useful precursors of many more complex interesting molecules. Classic as well as modern protocols in asymmetric aziridinations, azirinations, epoxidations, thiirinations, and cyclopropanations have been widely applied as key steps of a number of syntheses of important products. Although the use of chiral substrates and auxiliaries is still highly employed particularly in asymmetric aziridination and cyclopropanation, the development of enantioselective catalytic methodologies has witnessed exponential growth during the last decade. The present review is subdivided into three parts, dealing successively with the use of chiral nitrogen-containing three-membered rings, chiral epoxides and thiiranes, and chiral cyclopropanes in total synthesis.

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Enantioselective Synthesis of Pladienolide B and Truncated Analogues as New Anticancer Agents

Cited by 42 publications

References 52 publications

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

Applications of Chiral Three-membered Rings for Total Synthesis: A Review

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