Synthesis of a stable and orally bioavailable englerin analogue

Fash, David M.; Peer, Cody J.; Li, Zhenwu; Talisman, Ian Jamie; Hayavi, Sima; Sulzmaier, Florian J.; Ramos, Joe W.; Sourbier, Carole; Neckers, Leonard Μ.; Figg, William D.; Beutler, John A.; Chain, William J.

doi:10.1016/j.bmcl.2016.04.016

Cited by 10 publications

(30 citation statements)

References 35 publications

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“…was determined with the new formulation; however, on intravenous administration, doses decreasing to 0.1 mg/kg were immediately lethal. 52 The extreme intravenous lethality is consistent with data reported by the Novartis group, while the Novartis workers were unable to deliver 1 by the intraperitoneal route, even at doses as low as 1 mg/kg. Note that a Cremophor emulsion was used by Novartis.…”

Section: Preclinical Studiessupporting

confidence: 87%

“…50 Conversion to a glycolamide shows some promise, but the low intrinsic activity this series has shown so far is puzzling. 52 …”

Section: Discussionmentioning

confidence: 99%

“…52,61 However, the Novartis group was unable to administer 1 to mice by the intraperitoneal route without toxicity. 65 It is possible that the Cremophor vehicle used by the Novartis group somehow potentiates the toxic effect of 1 by this route.…”

Section: Discussionmentioning

confidence: 99%

“…52 In mice, a maximum tolerated dose of 10 mg/kg i.p. was determined with the new formulation; however, on intravenous administration, doses decreasing to 0.1 mg/kg were immediately lethal.…”

Section: Preclinical Studiesmentioning

confidence: 99%

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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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Section: Preclinical Studiessupporting

confidence: 87%

“…50 Conversion to a glycolamide shows some promise, but the low intrinsic activity this series has shown so far is puzzling. 52 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Preclinical Studiesmentioning

confidence: 99%

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Englerins: A Comprehensive Review

Zhao

Fash

et al. 2017

J. Nat. Prod.

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“…Currently approved treatments for renal cell carcinoma are of limited efficacy and are often toxic. Therefore, there has been keen interest in the discovery of (−)-EA and methods for its synthesis (2–5). A larger screen revealed that (−)-EA kills cells from a wide range of lineages but again supported the absence of adverse effects on normal, non-cancerous cells (6).…”

Section: Introductionmentioning

confidence: 99%

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

Ludlow

Gaunt

Rubaiy

et al. 2017

Journal of Biological Chemistry

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(−)-Englerin A ((−)-EA) has a rapid and potent cytotoxic effect on several types of cancer cell that is mediated by plasma membrane ion channels containing transient receptor potential canonical 4 (TRPC4) protein. Because these channels are Ca2+-permeable, it was initially thought that the cytotoxicity arose as a consequence of Ca2+ overload. Here we show that this is not the case and that the effect of (−)-EA is mediated by a heteromer of TRPC4 and TRPC1 proteins. Both TRPC4 and TRPC1 were required for (−)-EA cytotoxicity; however, although TRPC4 was necessary for the (−)-EA-evoked Ca2+ elevation, TRPC1 was not. TRPC1 either had no role or was a negative regulator of Ca2+ entry. By contrast, both TRPC4 and TRPC1 were necessary for monovalent cation entry evoked by (−)-EA, and (−)-EA-evoked cell death was dependent upon entry of the monovalent cation Na+. We therefore hypothesized that Na+/K+-ATPase might act protectively by counteracting the Na+ load resulting from sustained Na+ entry. Indeed, inhibition of Na+/K+-ATPase by ouabain potently and strongly increased (−)-EA-evoked cytotoxicity. The data suggest that (−)-EA achieves cancer cell cytotoxicity by inducing sustained Na+ entry through heteromeric TRPC1/TRPC4 channels and that the cytotoxic effect of (−)-EA can be potentiated by Na+/K+-ATPase inhibition.

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Gold(I)‐Catalysis for the Synthesis of Terpenoids: From Intramolecular Cascades to Intermolecular Cycloadditions

Mayans

Armengol-Relats

Calleja

et al. 2018

Israel Journal of Chemistry

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Gold(I)‐catalyzed cycloisomerizations of 1,n‐enynes proceed through electrophilic intermediates that can be trapped intra‐ or intermolecularly by a variety of hetero‐ and carbon nucleophiles to form complex skeletons in a single step. This review covers the efforts of our group towards the development of new reactions that have been successfully applied in the total synthesis of several natural terpenoids and related carbocyclic structures, as well as for the ready access to challenging linear acenes.

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Synthesis of a stable and orally bioavailable englerin analogue

Abstract: Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice.

Cited by 10 publications

References 35 publications

Englerins: A Comprehensive Review

Englerins: A Comprehensive Review

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

Gold(I)‐Catalysis for the Synthesis of Terpenoids: From Intramolecular Cascades to Intermolecular Cycloadditions

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