Synthesis and Biological Evaluation of New (−)‐Englerin Analogues

López-Suárez, Laura; Riesgo, Lorena; Bravo, Fernando; Ransom, Tanya T.; Beutler, John A.; Echavarren, Antonio M.

doi:10.1002/cmdc.201600040

Cited by 13 publications

(17 citation statements)

References 48 publications

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“…Most of the shortest asymmetric syntheses (<20 steps) rely on the use of prebuilt five‐membered rings derived from the chiral pool and already equipped with key stereocenters of the product . Although some of these approaches are efficient, the types of analogues that can be assembled are inherently restricted, in particular with respect to the substitution at the five‐membered ring . The groups of Ma and Echavarren independently developed synthetic routes that allow the direct assembly of the bicarbocyclic scaffold of 1 by using a gold‐catalyzed cycloisomerization of enantiomerically enriched ketoenynes ,.…”

Section: Methodsmentioning

confidence: 99%

Concise, Enantioselective, and Versatile Synthesis of (−)‐Englerin A Based on a Platinum‐Catalyzed [4C+3C] Cycloaddition of Allenedienes

et al. 2016

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Abstract:A practical synthesis of (-)-englerin A was accomplished in 17 steps and 11% global yield from commercially available achiral precursors. The key step consists of a Pt-catalyzed [4C+3C] allenediene cycloaddition that directly delivers the trans-fused guaiane skeleton with complete diastereoselectivity. The high enantioselectivity (99% ee) stems from an asymmetric Ru-catalyzed transfer hydrogenation of a readily assembled diene-ynone. The synthesis also features a highly stereoselective oxygenation, and a late-stage cuprate alkylation that enables the preparation of previously inaccessible structural analogues.Along the last years, the guaiane sesquiterpene (−)-englerin A (1, Figure 1) has attracted the attention of chemists, biologists and physicians because of its potent and highly selective activity as inhibitor of renal cancer growth. [1] Recent work carried out independently by Waldmann, Beech and Christmann, [2] as well as by a Novartis' team, [3] identified the transient receptor potential Ca 2+ channel TRPC4 as its main target. [4] TRPC channels are complex membrane proteins that are implicated in multiple biological functions, but they are unusual targets for antitumoral compounds. [5] The activation of this particular channel by 1 has been shown to induce cell death by elevated Ca 2+ influx, [2] however, the general mechanisms that govern TRPC4 activation remains elusive. [5] In this context, the development of efficient and versatile approaches to englerin A and related structural analogues is of major current interest.Since its isolation, [1] several synthesis of englerin have been accomplished, [6,7] some of which are asymmetric. [8] Most of the shortest (<20 steps) asymmetric synthesis rely on the use of prebuilt five-membered rings derived from the chiral pool, and already equipped with key stereocenters of the product. [8b] Although some of these approaches are efficient, the types of analogues that can be assembled are inherently restricted, in particular with respect to the substitution at the five membered ring. [9,10] The groups of Ma and Echavarren independently developed synthetic routes that allow the direct assembly of the bicarbocyclic scaffold of 1 by using a gold-catalyzed cycloisomerization of enantioenriched ketoenynes. [7d,e] The Ma route makes use of the chiral pool to prepare the ketoenyne, whereas Echavarren's approach relies on a Sharpless asymmetric epoxidation to generate the key stereocenter of the annulation precursor. While these approaches are very elegant, the cycloisomerization yields are moderate and the generation of the correct stereochemistry at the ring fusion requires the destruction and regeneration of stereocenters.Herein, we report an enantioselective synthesis of (−)-englerin A that allows to overcome many of the above limitations. The approach relies on a Pt-catalyzed [4C+3C] cycloaddition, and allows to build the bicyclic skeleton of 1 with the correct stereochemistry at the ring fusion, from a readily available allenediene precursor (Figure 1). ...

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Section: Methodsmentioning

confidence: 99%

Concise, Enantioselective, and Versatile Synthesis of (−)‐Englerin A Based on a Platinum‐Catalyzed [4C+3C] Cycloaddition of Allenedienes

et al. 2016

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“…[2][3][4][5][6] Further work in several groups has explored structure activity relationships. [7][8][9][10][11][12][13][14][15] Plausible molecular mechanisms of action for englerin A have been proposed, including agonism of protein kinase C θ, 16 and agonism of the ion channels transient receptor potential canonical (TRPC) 4 and 5. [17][18] In the case of TRPC4/5, it appears that englerin A may bind to an allosteric site on the ion channel complex, thereby facilitating entry of sodium and/or calcium ions into the cell.…”

Section: Takedownmentioning

confidence: 99%

“…The synthesis protocols were based on the total syntheses published by the Chain 6,11 and Echavarren groups. 3,10 Analogues 2-5 had been prepared following a simplified route that provides 50% of an unwanted and unreactive diastereomer, and which was therefore less efficient in terms of overall yield, but simplified the scale up of the chemical steps. Those analogues possessed an unnatural 4,5 double bond, 10 therefore going forward we chose to prepare the corresponding saturated natural analogues 6 and 7 by the route in Scheme 1.…”

Section: Takedownmentioning

confidence: 99%

Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

Suppo

Tumova

et al. 2020

ACS Med. Chem. Lett.

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Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells.Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product.Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.

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“…51 Another unusual modification involved esterification with cinnamate at a C-4 hydroxy group in two compounds ( 42 and 43 ), but these compounds were inactive. 51 …”

Section: Englerin Analoguesmentioning

confidence: 99%

Englerins: A Comprehensive Review

Zhao

Fash

et al. 2017

J. Nat. Prod.

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Graphical Abstract In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.

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Synthesis and Biological Evaluation of New (−)‐Englerin Analogues

Cited by 13 publications

References 48 publications

Concise, Enantioselective, and Versatile Synthesis of (−)‐Englerin A Based on a Platinum‐Catalyzed [4C+3C] Cycloaddition of Allenedienes

Concise, Enantioselective, and Versatile Synthesis of (−)‐Englerin A Based on a Platinum‐Catalyzed [4C+3C] Cycloaddition of Allenedienes

Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

Englerins: A Comprehensive Review

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