Progress in the Chemistry of Organic Natural Products 102 PDF
Preview Progress in the Chemistry of Organic Natural Products 102
Progress in the Chemistry of Organic Natural Products A. Douglas Kinghorn Heinz Falk Simon Gibbons Jun’ichi Kobayashi Editors 102 Progress in the Chemistry of Organic Natural Products Progress in the Chemistry of Organic Natural Products FoundedbyLa´szlo´ Zechmeister SeriesEditors A.DouglasKinghorn,Columbus,OH,USA HeinzFalk,Linz,Austria SimonGibbons,London,UK Jun’ichiKobayashi,Sapporo,Japan HonoraryEditor WernerHerz,Tallahassee,FL,USA EditorialBoard GiovanniAppendino,Novara,Italy VerenaDirsch,Vienna,Austria NicholasH.Oberlies,Greensboro,NC,USA YangYe,Shanghai,PRChina More information about this series at http://www.springer.com/series/10169 A. Douglas Kinghorn (cid:129) Heinz Falk (cid:129) Simon Gibbons (cid:129) Jun’ichi Kobayashi Editors Progress in the Chemistry of Organic Natural Products Volume 102 With contributions by G. Appendino (cid:1) (cid:1) M. Harizani E. Ioannou V. Roussis Editors A.DouglasKinghorn HeinzFalk Div.MedicinalChemistry& InstituteofOrganicChemistry Pharmacognosy JohannesKeplerUniversityLinz TheOhioStateUniversity Linz,Austria CollegeofPharmacy Columbus,Ohio USA SimonGibbons Jun’ichiKobayashi ResearchDepartmentof GraduateSchoolofPharmaceutical Pharmaceuticaland Science BiologicalChemistry HokkaidoUniversity UCLSchoolofPharmacy Sapporo,Japan London,UnitedKingdom ISSN2191-7043 ISSN2192-4309 (electronic) ProgressintheChemistryofOrganicNaturalProducts ISBN978-3-319-33170-6 ISBN978-3-319-33172-0 (eBook) DOI10.1007/978-3-319-33172-0 LibraryofCongressControlNumber:2016943631 ©SpringerInternationalPublishingSwitzerland2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexempt fromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthis book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained hereinorforanyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper ThisSpringerimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAGSwitzerland Contents IngenaneDiterpenoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 GiovanniAppendino TheLaurenciaParadox:AnEndlessSourceofChemodiversity. . . . . . . . 91 MariaHarizani,EfstathiaIoannou,andVassiliosRoussis ListedinPubMed v Ingenane Diterpenoids GiovanniAppendino Contents 1 Introduction................................................................................... 2 2 Phytochemistry............................................................................... 5 2.1 StructureandSpectroscopicProperties................................................ 5 2.2 Biogenesis.............................................................................. 9 2.3 Isolation................................................................................. 17 2.4 DistributionandDiversity............................................................. 20 2.4.1 Ingenol3-Monoesters......................................................... 26 2.4.2 Ingenol5-Monoesters......................................................... 28 2.4.3 Ingenol20-Monoesters....................................................... 29 2.4.4 Ingenol3,5-Diesters.......................................................... 30 2.4.5 Ingenol3,20-Diestersand5,20-Diesters..................................... 30 2.4.6 Ingenol3,5,20-Triesters...................................................... 31 2.4.7 13-HydroxyingenolEsters.................................................... 32 2.4.8 16-HydroxyingenolEstersand17-HydroxyingenolEsters................. 33 2.4.9 13,17-DihydroxyingenolEsters.............................................. 35 2.4.10 13,19-DihydroxyingenolEsters.............................................. 36 2.4.11 TetrahydroingenolEsters..................................................... 36 2.4.12 20-DeoxyingenolEsters...................................................... 37 2.4.13 16-and17-Hydroxy-20-deoxyingenolEsters............................... 38 2.4.14 16-and17-Hydroxy-20-deoxy-13-hydroxyingenolEsters.................. 39 2.4.15 5-DeoxyingenolEstersandMiscellaneousIngenoids....................... 40 2.5 Ecology................................................................................. 40 3 Chemistry..................................................................................... 41 3.1 Reactivity............................................................................... 41 3.1.1 EpimerizationandIsomerization.............................................. 42 3.1.2 SkeletalRearrangements....................................................... 43 3.1.3 Reduction....................................................................... 46 3.1.4 Oxidation....................................................................... 47 3.1.5 EtherificationandAcetalization............................................... 49 3.1.6 Hydrolysis,Acylation,andAcylRearrangements............................ 50 3.1.7 OtherFunctionalGroupModifications........................................ 53 3.2 TotalSynthesis......................................................................... 53 G.Appendino(*) DipartimentodiScienzedelFarmaco,LargoDonegani2,28100Novara,Italy e-mail:[email protected] ©SpringerInternationalPublishingSwitzerland2016 1 A.D.Kinghorn,H.Falk,S.Gibbons,J.Kobayashi(eds.),ProgressintheChemistry ofOrganicNaturalProducts,Vol.102,DOI10.1007/978-3-319-33172-0_1 2 G.Appendino 3.2.1 TheWinklerSynthesis(2002)................................................. 54 3.2.2 TheKuwajima-TaninoSynthesis(2003)...................................... 55 3.2.3 TheWoodSynthesis(2004)................................................... 56 3.2.4 TheKigoshiSynthesisof13-Hydroxyingenol(2012)........................ 57 3.2.5 TheBaranSynthesis(2013)................................................... 58 4 Bioactivity.................................................................................... 60 4.1 MolecularTargets...................................................................... 60 4.1.1 ProteinKinaseC(PKC)....................................................... 61 4.1.2 TopoisomeraseII............................................................... 65 4.1.3 OtherTargets................................................................... 65 4.1.4 Target-BasedStructure-ActivityRelationshipStudies....................... 66 4.2 PreclinicalPharmacology.............................................................. 67 4.2.1 TumorPromotion.............................................................. 68 4.2.2 AnticancerandImmunostimulatingActivity................................. 68 4.2.3 AntiviralActivity.............................................................. 69 4.2.4 PesticideActivity.............................................................. 71 4.3 ClinicalPharmacology................................................................. 72 4.3.1 DiscoveryoftheAnticancerActivityoftheSapfromEuphorbiapeplus... 72 4.3.2 IdentificationofI3AastheMajorActiveConstituentfromtheSap ofEuphorbiapeplus........................................................... 73 4.3.3 DevelopmentofI3A........................................................... 73 4.3.4 MolecularandClinicalPharmacologyofPicato®............................ 74 4.4 Toxicity................................................................................. 75 4.4.1 SkinIrritancy................................................................... 75 4.4.2 AnimalandHumanExposure................................................. 75 5 Conclusions................................................................................... 78 References........................................................................................ 79 1 Introduction Ingenanediterpenoidsareabiogeneticallyadvancedgroup ofphorboids,afamily ofpolycyclicditerpenoidsstructurallyrelatedtothetiglianeskeletonofphorbol(1) that also includes the tiglianes and daphnanes. A combination of limited distribu- tion,verylowconcentrationinplanttissues,chemicalinstability,anddifficultyof detection delayed the discovery of ingenane derivatives (ingenoids) compared to thetiglianes,themajorclassofphorboids.Thus,whilephorbol(1),thearchetypical tigliane, was first obtained in pure form in 1934 [1], the first ingenol derivative (ingenol-3-hexadecanoate ¼ ingenol 3-palmitate, 2) was only reported in 1968 [2, 3]. On the other hand, while phorbol went into a long series of constitutional and configurational revisions before its structure was clarified unambiguously by X-ray crystallography in1967 [4],the basic ingenane polyol ingenol (3),just like thearchetypicaldaphnanedaphnetoxin(4)[5],benefitedfromanearly(twoyears after the isolation) crystallographic determination of its relative and absolute configuration [6]. In retrospect, the early structure elucidation of ingenol, along withthelackofanabundantplantsource,isresponsibleforthelimitedinformation still available on its chemistry compared to phorbol, for which the reactivity was IngenaneDiterpenoids 3 thoroughly investigated in attempts to elucidate its structure by classic studies of chemicaldegradation[7]. HO OH HO O O O O H H O H H OH O 3 O O HO OH 14 O HO OH OH HO HO OH OH O HO OH 1 (phorbol) 2 (ingenol-3-palmitate) 3 (ingenol) 4 (daphnetoxin) To detect the presence, often in trace amounts, of ingenol derivatives in crude extracts and chromatographic fractions, the early studies relied extensively on non-selective bioassays common also to other types of phorboids (e.g. cytotoxicity, fish toxicity, skin irritancy). The improvements in analytical techniques and the introduction of hyphenated chromatographic techniques like HPLC-MS have now simplified the detection and the isolation of ingenol esters. Despite these advancements and the growth of the natural products chemistry community, the diversity of ingenol derivatives has not expanded significantly in terms of chemotypes or euphorbiaceous sources since the pioneering work of the groups of Erich Hecker (Plate 1) in Heidelberg and Fred J. Evans (Plate 2) in Londonduringtheseventiesandtheeightiesofthepastcentury[8],suggestingthat Plate1 ErichHecker (takenfromthebrochure “CancerResearchand Cooperation,German- IsraeliCooperationin CancerResearch–Thefirst 20years”.Deutsches Krebsforschungszentrum (1999) Plate2 FredJ.Evans (1943–2007)(photograph providedcourtesyofProf. ElizabethM.Williamson) 4 G.Appendino this class of compounds has a very narrow distribution in Nature and a limited structuraldiversity. After an initial interest for the oxymoronic tumor-promoting and anticancer properties of ingenol derivatives, activities remained for a long time limited to thechemicalsynthesiscommunityandthetotalsynthesisoftheparentalcohol.On the other hand, the successful and paradoxical development of the (weak) rodent tumor promoter ingenol mebutate (¼ ingenol-3-angelate, I3A, 5) into a topical ® human chemopreventive drug (Picato ) (see Sect. 4.3), has rekindled a multidisciplinaryinterestforthiscompoundanditsbiologicalpotential. O O O O 12 O O HO H H O 3 OH O HO OH OH O HO OH HO HHO 5 (ingenol-3-angelate, I3A) 6 (phorbol-12-myristate-13-acetae, PMA) 7 (lathyrol) Justlikephorbol,ingenoldoesnotoccurinNatureasafreepolyol,butonlyin esterified form, and its direct isolation from plant extracts is associated with the facile hydrolysis of the 3- and 20-monoesters. The first member of the class was reported in 1968 as part of a screening for co-carcinogenic diterpenoids in euphorbiaceous plants and the products obtained thereof [2, 3]. This systematic search for the distribution of co-carcinogenic compounds was undertaken by the GermanCancerResearchCentreinHeidelberginthewakeoftheidentificationof phorbol12-myristate-13-acetate (PMA,6) (¼ tetradecanoylphorbolacetate,TPA) asthemajortumor-promotingprincipleofcrotonoil(CrotontigliumL.)byHecker [7]. The purification of the compound later structurally elucidated as ingenol 3-hexadecanoate (2) was reported in 1968 from the seeds of the caper spurge (Euphorbia lathyris L.) [2] and from the latex of the African candelabra tree (E.ingensE.Mey.)[3].Justlikecrotonoil,amajorsourceofphorbolesters,also the sap ofthe candelabra tree and the oilfromcaper spurgeseeds have long been known for their high irritancy and skin-blistering properties, and the sap of the candelabra tree was also known to display co-carcinogenic properties [9]. Unex- pectedly,bothsourceslackedphorbolesters,containingratheracomplexmixture of ingenol esters and macrocyclic diterpenoids. Hecker, who pioneered studies in this field, assigned codes to diterpenoid constituents obtained in his laboratory, possiblytocopewiththedelaybeforeisolationandstructureelucidationthatused toplaguephytochemistryinthedecadesbeforepre-high-fieldNMRspectroscopic techniques became available. These codes were related to the plant source and to the chromatographic elution order, and the major irritant and co-cocarcinogenic constituents of E. ingens and E. lathyris respectively, dubbed Factors I and L , 5 1 turned out to be the same compound, namely, ingenol-3-hexadecanoate (2), with thestructureoftheparentpolyolbeingeventuallyclarifiedbyX-rayanalysisofits crystalline triacetate [6]. Ingenol was named after E. ingens, possibly because
The list of books you might like
