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Anthony crasto colchinine
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COLCHININE MOLECULE REVIEW BY DR ANTHONY MELVIN CRASTO N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7, 9-tetrahydrobenzo[a]heptalen-7-yl]acetamide
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Anthony crasto presents colchinine review
Transcript of Anthony crasto colchinine
COLCHININE MOLECULE REVIEW
BY DR ANTHONY MELVIN CRASTO
N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide
Dedicated to my son Lionel Crasto,
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MOL MODEL
Colchicine
Systematic(IUPAC)name
N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide
AmajoralkaloidfromColchicumautumnaleL.andfoundalsoinotherColchicumspecies.Itsprimarytherapeuticuseisinthetreatmentofgout,butithasbeenusedalsointhetherapyoffamilialMediterraneanfever(periodicdisease)
CASnumber 64-86-8
Identifiers
CASnumber 64-86-8
ATCcode M04AC01
PubChem CID6167
IUPHARligand 2367
DrugBank DB01394
ChemSpider 5933
UNII SML2Y3J35T
KEGG D00570
ChEBI CHEBI:27882
ChEMBL CHEMBL107
Chemicaldata
Formula C22H25NO6
Mol.mass 399.437
SMILES eMolecules & PubChem
Colchicine isamedicationusedfor gout.Itisatoxic naturalproduct and secondarymetabolite,originallyextractedfromplantsofthegenus Colchicum (autumncrocus, Colchicum autumnale,alsoknownas"meadowsaffron").Itwasusedoriginallytotreatrheumaticcomplaints,especially gout,andstillfindsuseforthesepurposestodaydespitedosingissuesconcerningitstoxicity.[1] Itwasalsoprescribedforits cathartic and emetic effects.Colchicine'spresentmedicinaluseisinthetreatmentof gout, familialMediterraneanfever, pericarditis and Behçet'sdisease.Itisalsobeinginvestigatedforitsuseasan anticancer drug.
Oralcolchicinehasbeenusedformanyyearsasanunapproveddrugwithnoprescribinginformation,dosagerecommendations,ordruginteractionwarningsapprovedbytheU.S. FoodandDrugAdministration (FDA).[2] OnJuly30,2009theFDAapprovedcolchicineasamonotherapyforthetreatmentofthreedifferentindications:familialMediterraneanfever,acutegoutflares,andfortheprophylaxisofgoutflares,[2] andgaveURLPharmaathree-yearmarketingexclusivityagreement[3] inexchangeforURLPharmadoing17newstudiesandinvesting$100millionintotheproduct,ofwhich$45millionwenttotheFDAfortheapplicationfee.URLPharmaraisedthepricefrom$0.09pertabletto$4.85,andtheFDAremovedtheolderunapprovedcolchicinefromthemarketinOctober2010bothinoralandIVform,butgavepharmaciestheopportunitytobuyuptheolderunapprovedcolchicine.[4] Colchicineincombinationwith probenecid hasbeenFDAapprovedpriorto1982.[3]
References^ a b "Colchicineforacutegout:updatedinformationaboutdosinganddruginteractions". National Prescribing Service.14May2010.Retrieved14May2010.^ a b "FDAApprovesColchicineWithDrugInteractionandDoseWarnings".July2009.^ a b [1] FDAOrangeBook;searchforcolchicine^ QuestionsandAnswersforPatientsandHealthcareProvidersRegardingSingle-ingredientOralColchicineProducts
Severalexperimentshaveshownthatthebiosynthesisofcolchicineinvolvestheaminoacidsphenylalanineandtyrosineasprecursors.Indeed,thefeedingof Colchicum autumnale withradioactiveaminoacid,tyrosine-2-C14,causedthelattertobepartiallyincorporatedintheringsystemofcolchicine.Theinducedabsorptionofradioactivephenylalanine-2-C14by Colchicum byzantinum,anotherplantoftheColchicaceaefamily,resultedinitsefficientabsorptionbycolchicine.[19] However,itwasproventhatthe tropolone ringofcolchicineresulted,inessence,fromtheexpansionofthetyrosinering.Furtherradioactivefeedingexperimentsof Colchicum autumnale revealedthatColchicinecanbesynthesizedbiosyntheticallyfrom (S)-Autumnaline.Thatbiosynthesicpathwayoccursprimarilythroughapara-paraphenoliccouplingreactioninvolvingtheintermediateisoandrocymbine.Theresultingmoleculeundergoes O-methylationdirectedby S-Adenosylmethionine (SAM).Twooxidationstepsfollowedbythecleavageofthecyclopropaneringleadstotheformationofthe tropolone ringcontainedby N-formyldemecolcine. N-formyldemecolcinehydrolyzesthentogeneratethemoleculedemecolcine,whichalsogoesthroughanoxidativedemethylationthatgeneratesdeacetylcolchicine.Themoleculeofcolchicineappearsfinallyafteradditionofacetyl-CoenzymeAtodeacetylcolchicine.,[20][21]
Biosynthesis
Colchicineinhibitsmicrotubulepolymerizationbybindingto tubulin,oneofthemainconstituentsof microtubules.Availabilityoftubulinisessentialto mitosis,andthereforecolchicineeffectivelyfunctionsasa"mitoticpoison"or spindlepoison.[10]
The mitosis inhibitingfunctionofcolchicinehasbeenofgreatuseinthestudyofcellular genetics.Toseethe chromosomes ofacellunderalightmicroscope,itisimportantthattheybeviewednearthepointinthe cellcycle inwhichtheyaremostdense.Thisoccursnearthemiddleof mitosis,somitosismustbestoppedbeforeitcompletes.Addingcolchicinetoacultureduringmitosisispartofthestandardprocedurefordoing karyotype studies.
Apartfrominhibitingmitosis(aprocessheavilydependentoncytoskeletalchanges),colchicinealsoinhibits neutrophil motilityandactivity,leadingtoanet anti-inflammatory effect.
Mechanism of Action
３．コルヒチンの生合成 コルヒチン(Colchicine)はユリ科イヌサフランに含まれ、トロポロン(tropolone)骨格を有する珍しい構造をもつ含窒素化合物である。３環性でありながら窒素原子が環の中に含まれない非複素環化合物であり、しかもアミドであるため塩基性を示さない。典型的なアルカロイドには見えないが、生合成的見地からすればコルヒチンは純然たる真正アルカロイドの１種である。標識化合物を用いた投与実験で、コルヒチンの A環部および C-5、 C-6、 C-7はフェニルアラニンに由来することが明らかにされている。その結果、コルヒチンのユニークな基本骨格は図４に示すようにドーパミン（またはチラミン）とケイヒ酸が縮合してできるフェネチルイソキノリンが酸化カップリング、転位、環拡大反応を経て生合成されると推定されている。この生合成スキームで中間体とされるフェネチルイソキノリン誘導体アウタムナリン (Autamnaline)はイヌサフランの同属近縁種 Colchicumcornigerumから実際に単離されている。ベンジルイソキノリンアルカロイドが比較的広く分布するのに対してコルヒチンなどフェネチルイソキノンアルカロイドは天然界では極めて稀な存在である。 イヌサフランの種子は欧州において 17世紀から通風治療に用いられていたが、その活性成分としてコルヒチンが単離されたのは 1886年のことであった。コルヒチンは今日でも抗通風薬として用いられるが、その他、細胞分裂において紡錘糸の形成を阻害するというユニークな生物活性が知られている。一方で染色体分裂は阻害しないので、コルヒチン処理により倍数体の細胞ができる。これを利用して農業分野において種なし果実などをつくるのに利用されている。
Colchicine (Colchicine)isthelilyfamily dogsaffron isincludedin,whichisanitrogen-containingcompoundhavingaskeletonwithanunusualstructure(tropolone)tropolone. Isanon-heterocycliccompoundsthatarenotincludedinthenitrogenatomintheringyetringof3,donotshowbecauseitisabasicamideaddition. Thetypicalalkaloidisnotvisible,colchicineispurefromthestandpointofbiosynthesis genuinealkaloid whichisakindof.Intheexperimentusingthelabeledcompoundadministration,C-5,C-6,C-7canbederivedfromphenylalaninehasbeenfoundtopartandtheAringofcolchicine. Asaresult,thebasicskeletonuniquecolchicine Figure 4 isbiosynthesizedthroughoxidativecoupling,dislocationphenethylisoquinolinecanbefusedcinnamicacidand(tyramine)ordopamine,asshownin,thering-expansionreactionhasbeenestimated. (Autamnaline)actuallyhavebeenisolatedfromrelatedspeciesofgenusColchicumcornigerumdogsaffronAutamunarinphenethylisoquinolinederivativesthatareintermediatesinthisbiosyntheticscheme. Phenethyliso-quinoneintheworldofnaturalalkaloidssuchascolchicineisextremelyrareisthepresenceasopposedtoarelativelywidedistributionbenzylisoquinolinealkaloid. Saffronseedsofdogshavebeenusedtotreatventilationfromthe17thcenturyinEurope,itwasisolatedcolchicineastheactiveingredientofwhichwasthatof1886. Colchicineisusedasananti-drugventilationEventoday,otheruniquebiologicalactivity,thatinhibittheformationofspindlefibersincelldivisionareknown. Chromosomedivisionbecauseitdoesnotinhibittheotherhand,canbeofpolyploidcellsbycolchicinetreatment. Hasbeenusedtomake,suchasseedlessfruitinthefieldofagriculturetotakeadvantageofthis
Translation
ThispaperpresentedaveryneatuseofRCMandquitecleverstrategytoconstructthe7,7-fusedcoreofcolchicine.
Forthefirsttime,the7,7-fusedbicyclicsystemcouldbeaccessedveryquicklyinasinglestep.
Thismainstrategyissummarizedintheretrosyntheticanalysisbelow.
http://pubs.acs.org/doi/abs/10.1021/ol070708j
Thekeyreactionswereformylationof 6 mediatedbySnCl4togive 7andthesynthesisofpropargylicalcohol 14 whichwasachievedinthreestepsfrom 5,usingtheOhira-Bestmanreagentinthelaststep.
Next,sequentialRCMreactionswereperformedon 14 usingGrubbs'secondgenerationcatalyst(15)aftertheprotectionoftheOHgroupwithTMS.
Thereactionprovedtobeveryefficient,providingthedesired 16 in74%yieldfrom 14.
Thisintermediate 16 wasfurtherelaboratedasshowninScheme4viaoxidativerearrangement.
Compound 18 couldbeobtainedinhighyield.However,goingalongamorewell-knownrouteofprevioustotalsynthesesofcolchicine,intermediate 19 couldbeobtainedinmodestyield,alongwith 20,from 17.
Thislatterrouteeffectivelyconstitutedaformalsynthesisofcolchicine.
Thefinalcompletionofthismoleculebyanovelsequenceiscurrentlyunderinvestigation
Theplantsourceofcolchicine,the autumncrocus (Colchicum autumnale),wasdescribedfortreatmentof rheumatism and swelling inthe EbersPapyrus (ca.1500B.C.),an Egyptianmedical papyrus.[5]
Theuseofthebulb-like corms of Colchicum forgoutprobablytracesbacktoca.550A.D.,asthe"hermodactyl"recommendedby AlexanderofTralles.
Colchicumextractwasfirstdescribedasatreatmentfor gout in De Materia Medica by PedaniusDioscorides inthefirstcentury CE. Colchicum cormswereusedbythe Persian physician ibnSina(Avicenna) andother Islamic physicians,wererecommendedby AmbroisePare inthesixteenthcentury,andappearedinthe LondonPharmacopoeia of1618.
Colchicum plantswerebroughtto Americaby BenjaminFranklin,whosufferedfromgouthimselfandhadwrittenhumorous doggerel aboutthediseaseduringhisstintas Envoy to France.
History
SPECTROSCOPY
FT-IRspectraofColchicine(4000-400)cm-1
FT-Raman spectra of Colchicine (4000-100) cm-1
KEGGDrugD00570 KEGGCompoundC07592 PubChemCompound6167 PubChemSubstance46505639 ChemSpider5933 ChEBI23359 ChEMBL23359 TherapeuticTargetsDatabaseDAP001254 PharmGKBPA449092 IUPHAR2367 GuidetoPharmacology2367 HETLOC DrugProductDatabase396 RxListhttp://www.rxlist.com/cgi/generic/colch.htm Drugs.comhttp://www.drugs.com/cdi/colchicine.html Wikipediahttp://en.wikipedia.org/wiki/Colchicine
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