Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer

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

“…[5] This is reflected by comparing the biological activities of 12-Otetradecanoylphorbol-13-acetate (TPA), bryostatin 1, and ingenol mebutate (2): the first is as trong tumor promoter, the second shows antiproliferative properties,a nd latter has antitumoral properties and represents the active ingredient in Picato,amarketed product for the topical treatment of actinic keratosis (solar keratosis). [6] Thet wo-phase total synthesis of ingenol (1) [7] and the semisyntheses of ingenol mebutate (2) [8] and ingenol 3-amethylcyclohexanecarboxylate (3) [9] were reported previously ( Figure 1A). Tw o-phase terpene synthesis can both enable scalable access to the parent natural product and constitute atemplate for preparation of analogues with deepseated changes.…”

“…Ingenol 3-a-methylcyclohexanecarboxylate (3)was chosen as the reference ester because 3 has previously been shown to be more chemically stable and more potent than ingenol mebutate (2). [9] Thes ynthesis of analogues 3-14 was accomplished by atwo-phase strategy that closely resembles our previous work on the total synthesis of ingenol (1). [7] Since intermediate 15 (prepared from 3-carene in 6s teps including an efficient Pauson-Khand reaction) is now being synthesized in greater than 100 gram batches at Kemxtree,i tw as the most logical point of divergence to access 3-14 in am inimal number of synthetic operations ( Figure 1C).…”

“…Finally,t ransformation of cyclase-phase endpoint 17 into ingenol analogue 14 led to another curious finding in oxidation chemistry (Path E): although 14 did not react under Pd(OH) 2 /TBHP conditions,it was successfully oxidized at C3 when using our recently developed Cr V -based allylic oxidation, [13] giving ingenane 26 with an inverted stereocenter at C3. This inversion of stereochemistry did not obstruct the synthetic plan, since it 26 was easily converted into analogues 11 and 9 in 1a nd 2 steps,respectively.Assuch, 10 new ingenol analogues (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) were synthesized, with most of these products containing an a-methylcyclohexanecarboxylate ester for stability and potency. Thef eat of generating many derivatives with vastly different oxidation states was achieved by embracing the subtleties of CÀHoxidation in complex-molecule synthesis.…”

“…Ap reviously described [9] screening cascade was used to characterize immune response-related effects of C20-hydroxylated ingenol analogues 5, 6, 9, 10, 13 and desmethyl compound 3' '.T hus,s tudies were conducted for in vitro activation of human recombinant PKCd,s timulation of IL-8 release in primary epidermal keratinocytes, and induction of oxidative burst (release of reactive oxygen species) in polymorphonuclear leukocytes (PMN;n eutrophils). PKCd has been shown to be critical for TPA-induced keratinocyte differentiation.…”

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

“…A previously described9 screening cascade was used to characterize immune response‐related effects of C20‐hydroxylated ingenol analogues 5 , 6 , 9 , 10 , 13 and desmethyl compound 3′ . Thus, studies were conducted for in vitro activation of human recombinant PKCδ, stimulation of IL‐8 release in primary epidermal keratinocytes, and induction of oxidative burst (release of reactive oxygen species) in polymorphonuclear leukocytes (PMN; neutrophils).…”