CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation

Abstract

Ingenol derivatives with varying degrees of oxidation were prepared by two‐phase terpene synthesis. This strategy has allowed access to analogues that cannot be prepared by semisynthesis from natural ingenol. Complex ingenanes resulting from divergent C—H oxidation of a common intermediate were found to interact with protein kinase C in a manner that correlates well with the oxidation state of the ingenane core. Even though previous work on ingenanes has suggested a strong correlation between potential to activate PKCδ and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCβII is of key importance while interaction with PKCδ is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCδ‐driven activation of keratinocytes is strongly reduced or even absent while PKCβII‐driven activation of neutrophils is retained.

Gold‐catalyzed [4+2] Annulations of Dienes with Nitrosoarenes as 4 π Donors: Nitroso‐Povarov Reactions

“…Thep roducts 3 correspond to the annulations with the tetrasubstituted alkenes of the dienes 1' ',w hereas 3' ' arises from the trisubstituted alkenes.W et ested the [4+ +2] annulations on various C1-aryl-substituted vinylallenes (1b-e;X= Me,OMe,Brand Cl), giving the compounds 3b-e in satisfactory yields (entries 1-4). With R 1 = phenyl, we varied either the R 2 or R 3 of the vinylallenes 1m-o with alkyl groups, and the resulting products 3m-o were also produced satisfactorily with 59-68 %yields (entries [12][13][14]. For 1i,bearing R 1 = 2-naphthyl, its resulting product 3i was produced smoothly and structurally characterized by X-ray diffraction.…”

“…Notably,the treatment of 3awith SeO 2 (2 equiv) in benzene led to an unknown reaction, yielding 7e as asingle stereoisomer [12] with ay ield was 66 %y ield. Notably,the treatment of 3awith SeO 2 (2 equiv) in benzene led to an unknown reaction, yielding 7e as asingle stereoisomer [12] with ay ield was 66 %y ield.…”

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

“…Some key findings from the structure-activity studies should be pointed out: (1) methylation of the 5- or 20-hydroxyl groups in the rigid ingenol scaffold eliminated the biological effects, (2) ingenol itself lacks biological activity, (3) the carbonyl moiety of the ester groups is essential for biological effects and the activation of PKC, likely via an interaction with the Gly23 NH in the C1 domain, and (4) the 4-, 5-, and 20-hydroxyl groups form a framework for a pH-dependent acyl migration of the ester moiety leading to degradation of ingenol mebutate resulting in limited shelf life [17]. A recent study on a series of ingenol scaffold-modified cyclohexyl esters showed that complete removal of the 4- or 5-hydroxyl groups led to a moderate drop in activity, whereas removal of both hydroxyl groups resulted in a significant loss in activity [19]. The chemical stability could be improved by having substituents flanking the ester group, but this often resulted in reduced potency [17, 18].…”

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

“…The structure and the extremely hindered nature of the C9,C10 olefin was verified by X-ray crystallography. [51] Despite several hundred experiments on 25 and derivatives thereof we were unable to oxidize this olefin in either the presence or absence of oxygen at either C2, C13, or C5 (26). While frustrating, this spectacular failure bolsters the original design of 7 as the ideal synthetic cyclase phase endpoint.…”

“…Acetylation of the secondary alcohols (Ac 2 O, 89 %, gram-scale) set the stage of 12 for chromium(V)-mediated installation of the C13 oxygenation. This CÀH oxidation, invented specifically for this oxidation but finding utility in related contexts, [26] could be used to robustly access the enone 14 (50 % yield, gram-scale) along with 13 [51] (29 %, structure verified by X-ray crystallography). As with the synthesis of 14, this reagent [43] proved essential and was unique in its ability to enable access to C13 oxidized taxane intermediates.…”