代表讲稿2-Doripenem-ANewBroa

Doripenem-ANewBroad-SpectrumCarbapenemAntibioticGroupMember0440213044021604415150441523SARofdoripenemFromPenicillinsToCarbapenems从青霉素到碳青霉烯——沙纳霉素（硫霉素，Thienamycin）的发现CarbapenembeforeDoripenemStructureofDoripenem(1R,5S,6S)-2-[(3S,5S)-5-substitutedpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylicacidsAnalysisofSARMechanismStabilityb-lactamasestabilitystabilityagainsthumanrenaldehydropeptidaseI(DHPI)AntimicrobialfeaturesToxiceffectsMechanismLikeallbeta-lactamantimicrobialagents,carbapenemsactbyinhibitingbacterialcellwallsynthesisbybindingtoandinactivatingpenicillin-bindingproteins(PBPs).b-lactamasestabilitydoripenemhasatrans-configured6-hydroxyethylgroup,whichprotectsitagainstbeta-lactamases.ResistancetocarbapenemsdevelopswhenbacteriaacquireordevelopstructuralchangeswithintheirPBPs,whentheyacquiremetallo-beta-lactamasesthatarecapableofrapidlydegradingcarbapenems,orwhenchangesinmembranepermeabilityariseasaresultoflossofspecificoutermembraneporins.B-内酰胺环与二氢吡咯环反式拼合对B-内酰胺酶高度稳定。顺式则易被酶水解。6-位引入立体因素较大的反式a-羟乙基侧链，降低了钝化酶对结构的适应性，保护B-内酰胺环不被B-内酰胺酶进攻。Humanrenaldehydropeptidase1(DHP1)stability1-beta-methylsidechainprovidesresistancetotherenalenzymeDHP1.AntimicrobialFeaturesI.由于B-内酰胺环的张力较大，其中羰基氮原子上的孤对电子不能完全共轭，易受亲核进攻，且1位用亚甲基取代了硫原子，亚甲基sp3杂化的键角小于硫醚的键角，并由于C2与C3间双键的存在，使二氢吡咯趋于平面结构，活化了B-内酰胺环的反应活性，这是碳青霉烯类抗生素抗菌活性强的的化学基础II.2位具有碱性烷基硫醚基团，使其更易进入G-杆菌的细胞外膜。III.C-3羧基使碱性下降，且是亲水基团可扩大抗菌谱，提高对G-的抑制作用和与蛋白的亲和力。Aparticularfeature,thesidechainatposition2—sulfamoylaminomethylgroup.ToxicEffectsDoripenemdisplaysfavorablepharmacokinetic,pharmacodynamicandtoxicologicalfeatures,similartothoseofmeropenem.Doripenemhasnoconvulsiveactivity.DoripenemdidnotcauseanyinhibitionmuscimolbindingtotheGABAreceptor.So,itsneurotoxicitymaybenegligibleinclinicaluse.Synthesisofdoripenem(1R,5S,6S)-6-[(1R)-1-羟乙基]-2-[(3S,5S)-5-氨磺酰胺基甲基吡咯烷-3-基]巯基-1-甲基-1-碳代-2-青霉烯-3-羧酸(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacidmonohydrateDoripenemwassynthesizedbythecondensationof(2S,4S)-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-sulfamoylamido)methyl-4-mercaptopyrrolidone(7)and(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphonyloxy-1-methyl-1-carba-2-penem-3-carboxylicacidp-nitrobenzylester(8),followedbydeprotectionwithayieldof50.5%.Compound7wasobtainedfromtrans-4-hydroxy-L-prolinebyesterification,protection,reduction,SN2substitution,Mitsunobureactionandalcoholysiswithayieldof50.8%.Theoverallyieldwasabout26%(basedontrans-4-hydroxy-L-proline).反式-4-羟基-L-脯氨酸经酯化、保护、还原、SN2取代、Mitsunobu反应、醇解得到（2S,4S)-1-叔丁氧羰基氨磺酰胺基）甲基-4-巯基吡咯烷（7），收率50.8%。7与（1R,5S,6S)-6-[(1R)-1-羟乙基]-2-二苯氧磷酰氧基-1-甲基-1-碳代-2-青霉烯-3-羧酸对硝基苄酯（8）缩合、脱保护，得到多尼培南，收率50.5%（以7计）。总收率接近26%（以反式-4-羟基-L-脯氨酸计）。NHCOOHHOCH3OHSOCl2NHCOOMeHO(Boc)2OCH3SO2ClCOOMeNMsONOHMsOKBH4ZnCl2CH3COSKNOHAcS(C6H5)3PBoc-NHSO2NH2NNSO2NH2AcSCH3ONaCH3OHNNSO2NH2HSNCO2PNBOP(OPh)2OHOHOH(i-Pr)2NEtNCO2PNBSOHOHHNNSO2NH2AlCl3/OMeNSOHOHCOOHHNHNHSO2NH2NCO2PNBSOHOHHNHNHSO2NH2Pd/C,.HCl21.2.BocBoc/3Boc54BocBocBocBoc67BocBoc91018Step1Step2Step3Step4Step5Step6NEXTStep1NHCOOHHOCH3OHSOCl2NHCOOMeHO(Boc)2OCH3SO2ClCOOMeNMsO,.HCl21.2.Boc3-Boc:叔丁氧羰基,保护氨基-Ms:甲磺酰基,活化羟基Step2COOMeNMsONOHMsOKBH4ZnCl2CH3COSKNOHAcSBoc3Boc/Boc54酯基还原,还原剂的选择SN2反应,4位发生构型反转Step3(C6H5)3PBoc-NHSO2NH2NNSO2NH2AcSCH3ONaCH3OHNNSO2NH2HSNOHAcSBocBocBocBoc67Boc5Boc-NHSO2NH2:N-叔丁氧羰基氨磺酰胺MitsunobuReaction醇解脱去乙酰基Step4NNSO2NH2HSNCO2PNBOP(OPh)2OHOHOH(i-Pr)2NEtNCO2PNBSOHOHHNNSO2NH2BocBoc7BocBoc98化合物8:(1R,5S,6S)-6-[(1R)-1-羟乙基]-2-二苯氧磷酰氧基-1-甲基-1-碳代-2-青霉烯-3-羧酸对硝基苄酯(MAP,市售)缩合反应Step5NCO2PNBSOHOHHNNSO2NH2AlCl3/OMeNCO2PNBSOHOHHNHNHSO2NH2BocBoc910脱掉-Boc保护基Step6NSOHOHCOOHHNHNHSO2NH2NCO2PNBSOHOHHNHNHSO2NH2Pd/C101脱掉-PNB(对硝基苄基)氢解反应MitsunobuReactionNNEtOOEtOOR'3PNNEtOOEtOOR'3P+HXNNHEtOOEtOOR'3P+R2OHR'3P+OR2NHEtOONHOEtOR'3POR2X-+.X-.X-++Researchisadifficultjobforustochallenge.Fighting!ComparisonofdoripenemandothercarbapenemsComparisonofdoripenemandothercarbapenemsonpharmacologyAntibacterialmechanismsarethesamewithotherbeta-lactamantibiotics:combiningwithbacterialpenicillin-bindingprotein(PBPs)inhibitesbacterialcellwallsynthesis.Doripenemhasstrongantibacterialactivityandstabilityagainstthevastmajorityofbeta-lactamaseandkidneydehydrogenationendopeptidase(DHP)-1.1.AntibacterialactivityagainstG+Methicillin-susceptiblestaphylococcusaureus,Staphylococcusepidermidis:slightlylowerthanimipenem,strongerthanmeropenemandbiapenemMethicillin-resistantStaphylococcusaureus,Staphylococcusepidermidis:2~4timesstrongerthanothercontroldrugsStrongestantibacterialactivitytoStreptococcuspyogenesPenicillin-susceptibleStreptococcuspneumoniae:similartoimipenem,strongerthanmeropenemandbiapenemPenicillin-resistantStreptococcuspneumoniae:identicalwithothersEnterococcusfaecalis:slightlylowerthanimipenem,strongincontrasttootherdrugsComparisonoftheMIC90(μg/ml)fordoripenemandthreeothercarbapenemstestedagainstGram-positivepathogensStrains(NO.)DoripenemImipenemMeropenemBiapenemMethicillin-susceptiblestaphylococcusaureus(30)0.0630.0320.1250.125