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      上傳時間:2024-03-13
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簡介:THEREARE18MAMMALIANFIBROBLASTGROWTHFACTORSFGF1–FGF10ANDFGF16–FGF23WHICHAREGROUPEDINTO6SUBFAMILIESBASEDONDIFFERENCESINSEQUENCEHOMOLOGYANDPHYLOGENYFGF1ANDFGF2FGF3,FGF7,FGF10,FGF22FGF4,FGF5ANDFGF6FGF8,FGF17ANDFGF18FGF9,FGF16ANDFGF20ANDFGF19,FGF21ANDFGF23REF1THENUMBERED‘FGFS’THATAREUNASSIGNEDTOSUBFAMILIESTHEFGFHOMOLOGOUSFACTORSPREVIOUSLYKNOWNASFGF11–FGF14HAVEHIGHSEQUENCEIDENTITYWITHTHEFGFFAMILYBUTDONOTACTIVATEFGFRECEPTORSFGFRSANDARETHEREFORENOTGENERALLYCONSIDEREDMEMBERSOFTHEFGFFAMILY2BOX1FGF15ISTHEMOUSEORTHOLOGUEOFHUMANFGF19FGFSARECLASSICALLYCONSIDEREDTOBEPARACRINEFACTORSANDAREKNOWNFORTHEIRROLESINTISSUEPATTERNINGANDORGANOGENESISDURINGEMBRYOGENESISTHEFIRSTFIVESUBFAMILIESFALLINTOTHISCATEGORYBYCONTRAST,THEFGF19,FGF21ANDFGF23SUBFAMILYHASRECENTLYBEENSHOWNTOFUNCTIONINANENDOCRINEMANNER,DEPENDENTONTHEPRESENCEOFKLOTHOPROTEINSINTHEIRTARGETTISSUES,TOREGULATEBILEACID,CHOLESTEROL,GLUCOSE,VITAMINDANDPHOSPHATEHOMEOSTASIS3–6THEINVOLVEMENTOFFGFSIGNALLINGINHUMANDISEASEISWELLDOCUMENTEDDEREGULATEDFGFSIGNALLINGCANCONTRIBUTETOPATHOLOGICALCONDITIONSEITHERTHROUGHGAINORLOSSOFFUNCTIONMUTATIONSINTHELIGANDSTHEMSELVESFOREXAMPLE,FGF23GAINOFFUNCTIONINAUTOSOMALDOMINANTHYPOPHOSPHATAEMICRICKETS7,FGF10LOSSOFFUNCTIONINLACRIMOAURICULODENTODIGITALSYNDROMELADDSYNDROME8,FGF3LOSSOFFUNCTIONINDEAFNESS9ANDFGF8LOSSOFFUNCTIONINKALLMANNSYNDROME10ORTHROUGHGAINORLOSSOFFUNCTIONMUTATIONSINFGFRS,WHICHCONTRIBUTETOMANYSKELETALSYNDROMES41,KALLMANNSYNDROME36,LADDSYNDROME54ANDCANCERTHERAPEUTICAPPROACHESUSINGEXOGENOUSFGFS,ANTIBODIESORSMALLMOLECULESARESTILLRELATIVELYNEW,ANDMANYAVENUESOFINVESTIGATIONREMAINOPENRECOMBINANTFGF7ISALREADYINUSEFORTHETREATMENTOFCHEMORADIATIONINDUCEDORALMUCOSITISFUTUREAPPLICATIONOFTHEFGFSINRENALDISEASE,GLUCOSEANDPHOSPHATEHOMEOSTASIS,STEMCELLRESEARCH,TISSUEREPAIRANDBIOENGINEERING,ANDANGIOGENESISISEXPECTEDCONTINUEDEFFORTSTOUNDERSTANDTHESTRUCTURALBIOLOGYOFFGF–FGFRINTERACTIONSWILLPLAYAKEYPARTINDRIVINGTHEDISCOVERYOFNEWTHERAPIESINTHISARTICLE,WEBRIEFLYREVIEWCURRENTKNOWLEDGEREGARDINGFGF–FGFRSIGNALLINGANDTHENFOCUSONTHEBIOLOGY,PATHOLOGYANDRECENTDEVELOPMENTSREGARDINGTHEPHARMACOLOGICALAPPLICATIONSOFEACHLIGANDTHEFGF–FGFRSIGNALLINGSYSTEMFGFSALLFGFS,EXCEPTTHOSEINSUBFAMILIESFGF1ANDFGF2,ANDFGF9,FGF16ANDFGF20,HAVESIGNALPEPTIDESTHEFGF9,FGF16ANDFGF20SUBFAMILYISNONETHELESSSECRETEDTHROUGHTHETRADITIONALENDOPLASMICRETICULUMER–GOLGISECRETORYPATHWAY11,WHEREASTHEFGF1ANDFGF2SUBFAMILYISSECRETEDINDEPENDENTLY12FGFSHAVEAHOMOLOGOUSCOREREGIONTHATCONSISTSOF120–130AMINOACIDSORDEREDINTO12ANTIPARALLELΒSTRANDSΒ1–Β12FLANKEDBYDIVERGENTAMINOANDCARBOXYLTERMINIFIG1AINGENERAL,PRIMARYSEQUENCEVARIATIONOFTHENANDCTERMINALTAILSOFFGFSACCOUNTSFORTHEDIFFERENTBIOLOGYOFTHELIGANDS13FIG1BTHEHEPARANSULPHATEGLYCOSAMINOGLYCANHSGAGBINDINGSITEHBSWITHINTHEFGFCOREISCOMPOSEDOFTHEΒ1–Β2LOOPANDPARTSOFTHEREGIONSPANNINGΒ10ANDΒ12FORPARACRINEFGFS,DEPARTMENTOFPHARMACOLOGY,NEWYORKUNIVERSITYSCHOOLOFMEDICINE,NEWYORK,NEWYORK10016,USAEMAILSANDREWBEENKENMEDNYUEDUMOOSAMOHAMMADINYUMCORGDOI101038/NRD2792AUTOSOMALDOMINANTHYPOPHOSPHATAEMICRICKETSAHEREDITARYDISORDEROFPHOSPHATEWASTINGCHARACTERIZEDBYRICKETS,LOWEREXTREMITYDEFORMITIESANDOSTEOMALACIALACRIMOAURICULODENTODIGITALSYNDROMELADDASYNDROMECHARACTERIZEDBYABNORMALITIESOFTHEDIGITSANDTEETH,LOWSETEARSANDAPLASIAOFTHELACRIMALANDSALIVARYGLANDSMUTATIONSINFGFR2ANDFGF10AREKNOWNTOCAUSELADDKALLMANNSYNDROMETHISSYNDROMERESULTSFROMADEFICIENCYOFGONADOTROPINRELEASINGHORMONE,WHICHLEADSTOHYPOGONADISMMUTATIONSINFGFR1CANDFGF8AREKNOWNTOCAUSEKALLMANNSYNDROMETHEFGFFAMILYBIOLOGY,PATHOPHYSIOLOGYANDTHERAPYANDREWBEENKENANDMOOSAMOHAMMADIABSTRACT|THEFAMILYOFFIBROBLASTGROWTHFACTORSFGFSREGULATESAPLETHORAOFDEVELOPMENTALPROCESSES,INCLUDINGBRAINPATTERNING,BRANCHINGMORPHOGENESISANDLIMBDEVELOPMENTSEVERALMITOGENIC,CYTOPROTECTIVEANDANGIOGENICTHERAPEUTICAPPLICATIONSOFFGFSAREALREADYBEINGEXPLORED,ANDTHERECENTDISCOVERYOFTHECRUCIALROLESOFTHEENDOCRINEACTINGFGF19SUBFAMILYINBILEACID,GLUCOSEANDPHOSPHATEHOMEOSTASISHASSPARKEDRENEWEDINTERESTINTHEPHARMACOLOGICALPOTENTIALOFTHISFAMILYTHISREVIEWDISCUSSESTRADITIONALAPPLICATIONSOFRECOMBINANTFGFSANDSMALLMOLECULEFGFRECEPTORKINASEINHIBITORSINTHETREATMENTOFCANCERANDCARDIOVASCULARDISEASEANDTHEIREMERGINGPOTENTIALINTHETREATMENTOFMETABOLICSYNDROMEANDHYPOPHOSPHATAEMICDISEASESREVIEWSNATUREREVIEWS|DRUGDISCOVERYVOLUME8|MARCH2009|235?2009MACMILLANPUBLISHERSLIMITEDALLRIGHTSRESERVEDCANATUREREVIEWS|DRUGDISCOVERYFGF1FGF2FGF3FGF7FGF10FGF22FGF4FGF5FGF6FGF8FGF17FGF18FGF9FGF16FGF20FGF19FGF21FGF23EKFNLPPGNYKKPKLLYCGSGAFPPGHFKDPKRLYCGGVYEHLGGAPRRRKLYCRSYDYMEGGDIRVRRLFCVRSYNHLQGDVRWRKLFSPRSYPHLEGDVRWRRLFSSGAGDYLLGIKRLRRLYCQSSFQWSPSGRRTGSLYCNWESGYLVGIKRQRRLYCLVTDQLSRRLIRTYQLYSAMTDQLSRRQIREYQLYSRARDDVSRKQLRLYQLYSVTDLDHLKGILRRRQLYCPTDFAHLKGILRRRQLYCAAQLAHLHGILRRRQLYCPHVHYGWGDPIRLRHLYTSSPLLQFGGQVRQRYLYTNASPLLGSSWGGLIHLYT143734556831726774424343494852333527313451728548898491596060666569505244BΒ1CTERMINUSNTERMINUSΒ9Β8Β6Β4Β7Β5Β3Β2Β10Β11Β1Β12FGFR1ATLEASTTHREEGENETICDISORDERSCANBEATTRIBUTEDTOMUTATIONSINFGFR1KALLMAN’SSYNDROME36,OSTEOGLOPHONICDYPLASIAANDPFEIFFER’SSYNDROME37PATHOLOGICALFGFR1SIGNALLINGALSOOCCURSINV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簡介:JSERBCHEMSOC717733–7442006UDC54728854291361528JSCS–3467ORIGINALSCIENTIFICPAPERSYNTHESISANDANTIBACTERIALACTIVITYOFSOMESCHIFFBASECOMPLEXESRNAIR1,ASHAH2,SBALUJA2ANDSCHANDA11DEPARTMENTOFBIOSCIENCESAND2DEPARTMENTOFCHEMISTRY,SAURASHTRAUNIVERSITY,RAJKOT360005,GUJARAT,INDIAEMAILSUMITRACHANDAYAHOOCOMRECEIVED6JULY,REVISED9NOVEMBER2005ABSTRACTTWOSCHIFFBASESWERESYNTHESIZEDFROMRACEACETOPHENONE1ADS14ETHYL6{E13NITROPHENYLIMINOETHYL}BENZENE1,3DIOLAND2ADS34ETHYL6{E12NITROPHENYLIMINOETHYL}BENZENE1,3DIOLTHENTHEIRMETALCOMPLEXESWEREFORMEDTHEMETALSSELECTEDFORTHEPREPARATIONOFCOMPLEXESWERECOPPER,NICKEL,IRONANDZINCHENCE,INTOTAL8METALCOMPLEXESWERESYNTHESIZEDANDSCREENEDFORANTIBACTERIALACTIVITYAGAINSTSOMECLINICALLYIMPORTANTBACTERIA,SUCHASPSEUDOMONASAERUGINOSA,PROTEUSVULGARIS,PROTEUSMIRABILIS,KLEBSIELLAPNEUMONIAEANDSTAPHYLOCOCCUSAUREUSTHEINVITROANTIBACTERIALACTIVITYWASDETERMINEDBYTHEAGARDITCHTECHNIQUEUSINGDMFPOLARAND1,4DIOXANENONPOLARASSOLVENTSTHESCHIFFBASESSHOWEDGREATERACTIVITYTHANTHEIRMETALCOMPLEXESTHEMETALCOMPLEXESSHOWEDDIFFERENTIALEFFECTSONTHEBACTERIALSTRAINSINVESTIGATEDANDTHESOLVENTUSED,SUGGESTINGTHATTHEANTIBACTERIALACTIVITYISDEPENDENTONTHEMOLECULARSTRUCTUREOFTHECOMPOUND,THESOLVENTUSEDANDTHEBACTERIALSTRAINUNDERCONSIDERATIONTHESCHIFFBASEADS3INTHEPOLARSOLVENTDMFSHOWEDBETTERANTIBACTERIALACTIVITYTOWARDSTHEINVESTIGATEDBACTERIALSTRAINSAMONGSTTHEFOURMETALS,ZNSHOWEDTHEBESTANTIBACTERIALACTIVITYFOLLOWEDBYFEIN1,4DIOXANEWHILENIFOLLOWEDBYZNANDFESHOWEDTHEBESTANTIBACTERIALACTIVITYINDMFPVULGARISWASTHEMOSTRESISTANTBACTERIAKEYWORDSSCHIFFBASECOMPLEXES,ANTIBACTERIALACTIVITY,DMF,1,4DIOXANEINTRODUCTIONTOOVERCOMETHEALARMINGPROBLEMOFMICROBIALRESISTANCETOANTIBIOTICS,THEDISCOVERYOFNOVELACTIVECOMPOUNDSAGAINSTNEWTARGETSISAMATTEROFURGENCYMANYOFTHECRUDEDRUGS,WHICHARESOURCESOFMEDICINALPREPARATIONS,STILLORIGINATEFROMWILDGROWINGMATERIALHOWEVER,PLANTBASEDDRUGSHAVESHORTENEDTHELIFESPANOFTHESOURCEOFMATERIALTHEREISACONTINUOUSSEARCHFORMOREPOTENTANDCHEAPERRAWMATERIALSTOFEEDTHEINDUSTRYCOMPOUNDS,WHICHONDISSOLUTIONDONOTGIVEIONSOFWHICHTHEYAREMADEBUTINSTEADGIVECOMPLEXIONSARECALLEDCOORDINATIONCOMPOUNDSCOORDINATIONCOMPO733DOI102298/JSC0607733NAUTHORFORCORRESPONDENCENOLIC–OHGROUPTHEMETALSSELECTEDFORTHEPREPARATIONOFTHECOMPLEXESWERECOPPER,NICKEL,IRONANDZINCTHESYNTHESISOFMETALCOMPLEXESWASSTUDIEDATDIFFERENTPHVALUESFORDIFFERENTMETALS,THEMAXIMUMYIELDWASOBSERVEDATDIFFERENTPHVALUESTHEPHOFMAXIMUMYIELDWASSELECTEDFORTHESYNTHESISOFEACHCOMPLEXFOREACHMETALCOMPLEX,DIFFERENTMETALSALTSOLUTIONSWEREPREPAREDTHESOLUTIONSUSEDFORTHESYNTHESISOFTHECOPPER,NICKEL,IRONANDZINCCOMPLEXESWERECUPRICCHLORIDE,NICKELCHLORIDE,FERROUSAMMONIUMSULPHATEANDZINCCHLORIDE,RESPECTIVELYSYNTHESISOFCOPPERCOMPLEXES01MSOLUTIONOFLIGANDANDCUPRICCHLORIDEWEREPREPAREDIN1,4DIOXANEANDDISTILLEDWATER,RESPECTIVELYACETICACIDANDSODIUMACETATEWEREADDEDTOTHECUPRICCHLORIDESOLUTIONTOMAINTAINTHEPH65–70THELIGANDSOLUTIONWASADDEDDROPWISETOTHEMETALIONSOLUTIONADARKBROWNPRECIPITATEWASOBTAINEDTHEPHOFSOLUTIONWASMAINTAINEDBYTHEBUFFERSOLUTIONANDTHESOLUTIONWASREFLUXEDFOR4–5HINAWATERBATHTHEPRECIPITATEWASFILTEREDANDWASHED,FIRSTWITH1,4DIOXANEANDTHENWITHHOTWATERTOREMOVEEXCESSLIGANDANDMETALIONS,RESPECTIVELYTHEPRECIPITATEWASTHENDRIEDSYNTHESISOFNICKELCOMPLEXES01MSOLUTIONOFLIGANDANDNICKELCHLORIDEAREPREPAREDIN1,4DIOXANEANDDISTILLEDWATER,RESPECTIVELYTHELIGANDSOLUTIONWASADDEDDROPWISETOTHEMETALIONSOLUTIONTHEPHWASMAINTAINEDBETWEEN10–105BYADDINGAMMONIUMHYDROXIDEAYELLOWISHORANGEPRECIPITATEWASOBTAINEDONREFLUXINGTHESOLUTIONONAWATERBATHFOR4–5HTHEPRECIPITATEWASFILTEREDANDWASHEDWITHHOTWATERAND1,4DIOXANETOREMOVEEXCESSLIGANDANDMETALIONS,RESPECTIVELYTHEPRECIPITATEWASTHENDRIEDSYNTHESISOFIRONCOMPLEXES01MLIGANDSOLUTIONIN1,4DIOXANEWASADDEDDROPWISETOA01MFERROUSAMMONIUMSULPHATESOLUTIONINTHEPRESENCEOFABUFFERSOLUTIONAMMONIUMHYDROXIDEACETICACIDTOMAINTAINTHEPHBETWEEN7–75THESOLUTIONWASREFLUXEDFOR5–6HTHEFORMEDYELLOWISHBROWNPRECIPITATEWASFILTERED,WASHEDWITHHOTWATERAND1,4DIOXANETOREMOVEEXCESSLIGANDANDMETALIONS,RESPECTIVELYTHEPRECIPITATEWASTHENDRIEDSYNTHESISOFZINCCOMPLEXES01MLIGANDSOLUTIONIN1,4DIOXANEWASADDEDDROPWISETOA01MZINCCHLORIDESOLUTIONINPRESENCEOFBUFFERSOLUTIONANDAMMONIUMHYDROXIDETOMAINTAINTHEPHBETWEEN10–11THESOLUTIONWASREFLUXEDFOR4–5HINAWATERBATHTHEFORMEDBROWNPRECIPITATEWASFILTERED,WASHEDWITHHOTWATERAND1,4DIOXANETOREMOVEEXCESSLIGANDANDMETALIONS,RESPECTIVELYTHEPRECIPITATEWASTHENDRIEDANTIBACTERIALACTIVITYANTIBACTERIALACTIVITYWASDETERMINEDBYTHEAGARDITCHMETHOD15THEINVESTIGATEDMICROORGANISMSWEREPSEUDOMONASAERUGINOSA,PROTEUSVULGARIS,PROTEUSMIRABILIS,KLEBSIELLAPNEUMONIAEANDSTAPHYLOCOCCUSAUREUSTHECOMPOUNDSWEREDISSOLVEDINONEOFTHETWOSOLVENTS1,4DIOXANEORDMFTOOBTAINAFINALCONCENTRATION1MG/01MLALOOPFULLOFTHEGIVENTESTSTRAINWASINOCULATEDIN25MLOFNBROTHNUTRIENTBROTHANDINCUBATEDFOR24HINANINCUBATORAT37oCINORDERTOACTIVATETHEBACTERIALSTRAIN28–30MLOFTHENUTRIENTAGARMEDIAWASADDEDINTOA100MMDIAMETERPETRIPLATEINOCULATIONWASDONEBYTHEPOURPLATETECHNIQUE02MLOFTHEACTIVATEDSTRAINWASINOCULATEDINTOTHEMEDIAWHENITREACHEDATEMPERATUREOF40–45oCTHECOMPLETEPROCEDUREOFTHEPLATEPREPARATIONWASDONEINALAMINARAIRFLOWTOMAINTAINSTRIC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      頁數(shù): 12
      11人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大?。?2.81(MB)
      子文件數(shù):
      18人已閱讀
      ( 4 星級)
    • 下載積分: 15 賞幣
      上傳時間:2024-01-07
      大?。?5.72(MB)
      子文件數(shù):
      22人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大小: 2.36(MB)
      子文件數(shù):
      16人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大?。?2.32(MB)
      子文件數(shù):
      21人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大小: 1.01(MB)
      子文件數(shù):
      16人已閱讀
      ( 4 星級)
    • 下載積分: 15 賞幣
      上傳時間:2024-01-07
      大?。?7.57(MB)
      子文件數(shù):
      13人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大小: 2.29(MB)
      子文件數(shù):
      16人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大?。?3.05(MB)
      子文件數(shù):
      8人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大?。?3.26(MB)
      子文件數(shù):
      4人已閱讀
      ( 4 星級)
    • 下載積分: 14 賞幣
      上傳時間:2024-01-07
      大?。?1.07(MB)
      子文件數(shù):
      6人已閱讀
      ( 4 星級)
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