Importance of a 4-Alkyl Substituent for Activity in the Englerin Series

Abstract

The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ tricycle and the 4-oxo Δ tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for englerin A, 4-ethyl englerin A, and 4-isopropyl englerin A. 4-Desmethyl englerin A was less active than the natural product by an order of magnitude, but the 4-ethyl and 4-isopropyl analogues were comparable in activity to englerin A. These results are consistent with the premise that the 4-alkyl group enforces the binding conformation of the cinnamoyl ester substituent. Furthermore, they suggest that 4-alkyl englerin structures may prove to be useful tool compounds.

Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic Stereoselective Reactions of β-Lactams with Aldehydes: The Effect of the N-Methylimidazole Ligand

“…2-((Triisopropylsilyl)­oxy)­acetyl chloride ( xvi ): 10.661 g (85% yield); colorless oil; analytical data were consistent with previously reported values; 1 H NMR (400 MHz, CDCl 3 ) δ 4.62 (s, 2H), 1.18–1.03 (m, 21H); 13 C­{ 1 H} NMR (101 MHz, CDCl 3 ) δ 172.9, 70.3.…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…3) Ring‐closing alkyne metathesis : (+)‐aspicilin core ( 111 ) [173] . 4) Ring‐closing enyne metathesis : 4‐desmethyl englerin ( 112 ), [174] 8‐epi‐xanthatin ( 113 ), [175] and hydroxyl‐kempenone ( 114 ), [176] (Figure 10).…”

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

“…[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.…”

“…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 …”