Syntheses of Englerin A, a Potent Renal Cancer Inhibitor

Abstract

Mankind has been searching for anticancer drugs from nature and artificial compounds. Since the discovery of englerin A, a guaiane sesquiterpene possessing the characteristic tricyclic 5-6-5 fused ring framework with contiguous seven stereogenic centers and isolated from Phyllanthus engleri, many synthetic groups have enthusiastically launched and accomplished its the chemical synthesis. All the synthetic groups focused on how to efficiently construct the tricyclic framework containing oxygen bridge with various approaches. In this review, the total and formal syntheses of englerin A reported to date are summarized. . Theodrakis' formal synthesis of (À )-englerin A (1) via [4 + 3] cycloaddition.Scheme 6. Chain's total synthesis of (À )-englerin A (1) via Michael addition and reductive carbonyl-enone cyclization. . Parker's formal synthesis of (À )-englerin A (1) via relay RCM.Scheme 8. Cook's formal synthesis of (�)-englerin A (1) via reductive Mizoroki-Heck cyclization.

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

“…[19][20][21] Two recent reviews have summarized progress. [22][23] One barrier to development of englerin A as a drug candidate has been its potent intravenous toxicity and lethality, observed by both our group and the Novartis group. 17 A recent report identified TRPC4 and TRPC5 ion channels as mediating this adverse response to englerin A.…”

“…Englerin A ( 1 ) was discovered in extracts of the root and stem bark of the Tanzanian tree Phyllanthus engleri on the basis of its nanomolar activity against most renal cancer cell lines and concomitant inactivity against most other cell types in the NCI 60 cell screen . Total syntheses of the molecule established its absolute configuration and have provided multiple synthetic pathways to the natural product. − Further work in several groups has explored structure activity relationships. − Plausible molecular mechanisms of action for englerin A have been proposed, including agonism of protein kinase C θ and agonism of the ion channels transient receptor potential canonical (TRPC) 4 and 5. , 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. − Two recent reviews have summarized progress. , One barrier to development of englerin A as a drug candidate has been its potent intravenous toxicity and lethality, observed by both our group and the Novartis group . A recent report identified TRPC4 and TRPC5 ion channels as mediating this adverse response to englerin A …”

Biological Effects of Modifications of the Englerin A Glycolate

“…Subsequent total syntheses of the molecule established its absolute configuration and have provided multiple synthetic pathways to the natural product. − Further work in several groups including our own has explored structure–activity relationships. − Plausible molecular mechanisms of action for englerin A in renal cancer cells have been proposed, including agonism of protein kinase C θ, as well as the ion channels transient receptor potential canonical (TRPC) 4 and 5. , While TRPC channels have been viewed as primarily gating the calcium ion, recent work has linked the cytotoxicity of englerins to entry of sodium ions in TRPC4 channels. , Other work has investigated englerin A activity in triple negative breast cancer cells, also implicating TRPC channels, while englerin A has also been found to be active in analgesic and anti-inflammatory models independent of TRPC 4 and 5 . Two recent reviews have summarized the progress. , …”

“…29 Two recent reviews have summarized the progress. 30,31 The most sensitive site for modification of englerin A is the glycolate ester C-9. Loss of the glycolate, e.g., englerin B, 1b, completely abrogates cell growth inhibition, 1,4 and most modifications of the glycolate generally lead to a precipitous decline in activity in cells.…”

Syntheses of Epoxyguaiane Sesquiterpenes (−)-Englerin A, (−)-Oxyphyllol, (+)-Orientalol E, and (+)-Orientalol F: A Synthetic Biology Approach

“…Since its isolation by Beutler and co-workers from Phyllanthus engleri found in East Africa, englerin A ( 1 ) has attracted extensive attention from chemists, biologists, and physicians . Englerin A demonstrates potent and selective inhibitory activity toward renal cancer cell lines, whereas englerin B ( 2 ), lacking the glycolic ester moiety, shows no significant cell growth inhibition .…”