Semisynthesis of Ingenol 3-Angelate (PEP005): Efficient Stereoconservative Angeloylation of Alcohols

Liang, Xifu; Grue-Sørensen, Gunnar; Petersen, Anders K.; Högberg, Thomas

doi:10.1055/s-0032-1317415

Cited by 43 publications

(40 citation statements)

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“…E. lathyris L. contains both esterified lathyrane and ingenane derivatives (known as Euphorbia factors or L-factors) in the seed oil (10). A semisynthesis approach to ingenol mebutate using hydrolysis products of ingenol-based Euphorbia factors as raw material has been developed (11). However, access to the starting material from E. lathyris L. seeds is limited due to natural fluctuations and a biennial life cycle.…”

Section: Significancementioning

confidence: 99%

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Luo

Callari

Hamberger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon-carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved in the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids.terpenoid biosynthesis | transcriptomic analysis | regio-specific oxidation | nonconventional cyclization

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Section: Significancementioning

confidence: 99%

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Luo

Callari

Hamberger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…To circumvent supply problems of ingenol mebutate, two chemical approaches have been investigated. A semisynthetic route has been developed using ingenol extracted from the seeds of Euphorbia lathyris (Liang et al, 2012), and, recently, a 14-step synthetic route was described (Jørgensen et al, 2013). Both of these routes, however, have limitations.…”

Section: Introductionmentioning

confidence: 99%

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

et al. 2014

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The Euphorbiaceae produce a diverse range of diterpenoids, many of which have pharmacological activities. These diterpenoids include ingenol mebutate, which is licensed for the treatment of a precancerous skin condition (actinic keratosis), and phorbol derivatives such as resiniferatoxin and prostratin, which are undergoing investigation for the treatment of severe pain and HIV, respectively. Despite the interest in these diterpenoids, their biosynthesis is poorly understood at present, with the only characterized step being the conversion of geranylgeranyl pyrophosphate into casbene. Here, we report a physical cluster of diterpenoid biosynthetic genes from castor (Ricinus communis), including casbene synthases and cytochrome P450s from the CYP726A subfamily. CYP726A14, CYP726A17, and CYP726A18 were able to catalyze 5-oxidation of casbene, a conserved oxidation step in the biosynthesis of this family of medicinally important diterpenoids. CYP726A16 catalyzed 7,8-epoxidation of 5-keto-casbene and CYP726A15 catalyzed 5-oxidation of neocembrene. Evidence of similar gene clustering was also found in two other Euphorbiaceae, including Euphorbia peplus, the source organism of ingenol mebutate. These results demonstrate conservation of gene clusters at the higher taxonomic level of the plant family and that this phenomenon could prove useful in further elucidating diterpenoid biosynthetic pathways.

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“…Yet, these synthetic endeavors are not reflected in the broad industrial manufacture of natural products. There is at least one total synthesis for each of the plant-derived natural products approved for therapeutic use in the last thirty years, presented in Table 1, with exemplary syntheses of (+)-artemisinin (Zhu and Cook, 2012), (+)-arglabin (Kalidindi et al, 2007), (−)-cannabidiol (Petrzilka et al, 1969), capsaicin (Kaga et al, 1989), (−)-colchicine (Lee et al, 1998), dronabinol ((−)-Δ 9 -trans-tetrahydrocannabinol (THC); (Trost and Dogra, 2007)), (+)-ingenol (as described in greater detail in the next paragraphs, ingenol is chemically converted to ingenol mebutate for therapeutic supply; (Liang et al, 2012)), masoprocol (meso-nordihydroguaiaretic acid; (Gezginci and Timmermann, 2001)), omacetaxine mepesuccinate ((−)-homoharringtonine; (Eckelbarger et al, 2008)), (−)-paclitaxel (Nicolaou et al, 1994), and (−)-solamargine (Wei et al, 2011a). Also found in this list is (−)-galanthamine, which is particularly notable because it is a rather complex plant-derived compound for which an entirely chemical industrial-scale production process exists (as described in detail in the next paragraphs).…”

Section: Organic Synthesismentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

Draw Science

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Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Semisynthesis of Ingenol 3-Angelate (PEP005): Efficient Stereoconservative Angeloylation of Alcohols

Cited by 43 publications

References 1 publication

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

Discovery and resupply of pharmacologically active plant-derived natural products: A review

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