诺维糖新合成路线探索及新生霉素类似物的合成
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摘要
通过抑制热休克蛋白90(Hsp90)而抑制肿瘤细胞增殖活性,已成为近年来新的癌症治疗方向。有关Hsp90氮端抑制剂的研究比较成熟,部分化合物已进入Ⅱ期临床阶段。由诺维糖和香豆素构成的香豆素类抗生素是一类新近发现的Hsp90碳端抑制剂,其抑制机制与氮端有所不同:Novobiocin结合于Hsp90的碳端ATP结合位点,而同型二聚体Coumermycin A1能够抑制Hsp90碳端的二聚。新的抑制机制提示,香豆素类抗生素有可能成为一类新的具有抑制肿瘤细胞增殖活性的化学治疗药物。
本论文立足于发现具有抑制肿瘤细胞增殖活性的Hsp90碳端抑制剂,设计并合成了同系列六个新生霉素类似物。新生霉素类化合物的分子结构分为香豆素苷元和诺维糖片段,因此,论文工作围绕两个片段分为以下三部分进行:
1.诺维糖的合成路线探索及诺维糖的合成
已有诺维糖的合成方法或无法实现3'位的区域选择性,或不具备经济性和原子经济性。因此,本部分工作主要集中在寻找一条新的合成路线,解决限制糖片段构效关系研究的瓶颈。论文设计两种方案实现3'位选择性修饰,成功的实现了其中一条路线,首次实现了区域选择性的修饰3'位羟基得到目标糖片段。从起始物L-阿拉伯糖开始,共17步反应,总收率10%。
2.香豆素的合成
借鉴已有碳端抑制剂有关香豆素结构改造的研究,设计了六个不同取代的香豆素结构片段,即3位乙酰胺、苯甲酰胺,8位氯代、甲基取代和无取代。六个化合物均能通过经典的缩合成香豆素的方法顺利制得,并且达到了克级,收率16-36%。
3.新生霉素类似物的合成
借鉴文献方法,通过Mitsunobu方法在端基羟基成糖苷键,且主产物为预期的α糖苷结构。依据底物结构差异,产物β/α在0-1/2之间,缩合一步收率10-34%。Mitsunobu反应条件较好的控制了α、β产物的比例,并且对于2'位羟基没有保护的糖片段也能选择性的在端基羟基成键。对某些反应和核磁共振谱进行了讨论。
本论文共合成和鉴定了新化合物31个(包括目标物,中间体和副产物)。
The molecular chaperone Hsp90(Heat shock protein 90) is a promising target for cacer therapy.Preclinical and clinical evaluations of a variety of Hsp90 inhibitors have shown anti-tumor effects as a single agent and in combination with other chemotheraputics.All Hsp90 inhibitors fall into two classes:the N-terminal inhibitors and the C-terminal inhibitors.The structure-activity relatioship of N-terminal inhibitors has been extensively studied,and some derivatives of these compounds are in phaseⅡclinic trial.Meanwhile,number of known C-terminal inhibitors,representated by Novobiocin and Coumermycin,is still very limited.
This thesis was focused on discovery of potent novobiocin analogues,which are a glycoside consisting of noviose and coumarin with improved tumor inhibition activity. Research work described here includes:
1.Design and de novo synthesis of noviose-1,2-acetonide
(+)-Noviose is the only chiral moiety presenting in the moleculars of these antibiotics, and hence constitutes the most important building block for their syntheses.Because this unusual monosaccharide is not available from other natural soure,it has been subject for numerous synthetic studies.However,no synthetic studies achieve the region-selectivity of 3'-OH,which is the limit in expanding research range of the C-terminal inhibitors.In this work,we designed two strategies and one of them was completed successfully.Starting with L-arabinose,we successfully prepared the key intermediate 1,2-acetyl-noviose with 17 steps in 10%yield.
2.Coumarin synthesis
According to previous SAR study,six coumarins with different substitutes at the 3-and 8-position were prepared by Perkin and Pechmann condensation in 16~36%yield.
3.Synthesis of novobiocin analogues
With obtained noviose and coumarins,we prepared six novobiocin analogues with Mitsunobu reaction,and yielded a-glycoside as the predominat isomer.
Totally,54 compounds have been prepared and characterized by~1 HNMR,~13 CNMR,IR, El,HRMS,among which are 31 new compounds.
本论文立足于发现具有抑制肿瘤细胞增殖活性的Hsp90碳端抑制剂,设计并合成了同系列六个新生霉素类似物。新生霉素类化合物的分子结构分为香豆素苷元和诺维糖片段,因此,论文工作围绕两个片段分为以下三部分进行:
1.诺维糖的合成路线探索及诺维糖的合成
已有诺维糖的合成方法或无法实现3'位的区域选择性,或不具备经济性和原子经济性。因此,本部分工作主要集中在寻找一条新的合成路线,解决限制糖片段构效关系研究的瓶颈。论文设计两种方案实现3'位选择性修饰,成功的实现了其中一条路线,首次实现了区域选择性的修饰3'位羟基得到目标糖片段。从起始物L-阿拉伯糖开始,共17步反应,总收率10%。
2.香豆素的合成
借鉴已有碳端抑制剂有关香豆素结构改造的研究,设计了六个不同取代的香豆素结构片段,即3位乙酰胺、苯甲酰胺,8位氯代、甲基取代和无取代。六个化合物均能通过经典的缩合成香豆素的方法顺利制得,并且达到了克级,收率16-36%。
3.新生霉素类似物的合成
借鉴文献方法,通过Mitsunobu方法在端基羟基成糖苷键,且主产物为预期的α糖苷结构。依据底物结构差异,产物β/α在0-1/2之间,缩合一步收率10-34%。Mitsunobu反应条件较好的控制了α、β产物的比例,并且对于2'位羟基没有保护的糖片段也能选择性的在端基羟基成键。对某些反应和核磁共振谱进行了讨论。
本论文共合成和鉴定了新化合物31个(包括目标物,中间体和副产物)。
The molecular chaperone Hsp90(Heat shock protein 90) is a promising target for cacer therapy.Preclinical and clinical evaluations of a variety of Hsp90 inhibitors have shown anti-tumor effects as a single agent and in combination with other chemotheraputics.All Hsp90 inhibitors fall into two classes:the N-terminal inhibitors and the C-terminal inhibitors.The structure-activity relatioship of N-terminal inhibitors has been extensively studied,and some derivatives of these compounds are in phaseⅡclinic trial.Meanwhile,number of known C-terminal inhibitors,representated by Novobiocin and Coumermycin,is still very limited.
This thesis was focused on discovery of potent novobiocin analogues,which are a glycoside consisting of noviose and coumarin with improved tumor inhibition activity. Research work described here includes:
1.Design and de novo synthesis of noviose-1,2-acetonide
(+)-Noviose is the only chiral moiety presenting in the moleculars of these antibiotics, and hence constitutes the most important building block for their syntheses.Because this unusual monosaccharide is not available from other natural soure,it has been subject for numerous synthetic studies.However,no synthetic studies achieve the region-selectivity of 3'-OH,which is the limit in expanding research range of the C-terminal inhibitors.In this work,we designed two strategies and one of them was completed successfully.Starting with L-arabinose,we successfully prepared the key intermediate 1,2-acetyl-noviose with 17 steps in 10%yield.
2.Coumarin synthesis
According to previous SAR study,six coumarins with different substitutes at the 3-and 8-position were prepared by Perkin and Pechmann condensation in 16~36%yield.
3.Synthesis of novobiocin analogues
With obtained noviose and coumarins,we prepared six novobiocin analogues with Mitsunobu reaction,and yielded a-glycoside as the predominat isomer.
Totally,54 compounds have been prepared and characterized by~1 HNMR,~13 CNMR,IR, El,HRMS,among which are 31 new compounds.
引文
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(21) Joseph A,B.,Len,Neckers.,Andrew B,Smith.,Anthony,Maxwell.,Brian S.J.Blagg.,J. Am.Chem.Soc 2006,128,15529-15536.
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(32) Patrick,L.,Didier,Ferroud.,Branislav Musicki.,et al.Bioorganic & Medicinal Chemistry Letters 1999,9,2079-2084.
(33) Renata,T.,Jurij,Svete.,Branko,Stanovnik.,* J.Heterocyclic.Chem 1999,36,225-235.
(2) 郭宗儒 药物化学总论[M].北京:中国医药科技出版社,1994:586.
(3) Didelot,C.,Lanneau,D.,Brunet,M.,et al Curr.Med.Chem.2007,14,2839-2847.
(4) Pearl,L.H.,Prodromou,C.,Workman,P.Bioorg.Med.Chem.Lett.2008,17,6345-6349.
(5) Chiosis,G.,Neckers,L.ACS Chem.Biol.2006,1,279-284.
(6) Richter,K.,Soroka,J.,Skalniak,L.,Leskovar,A.,Hessling,M.,Reinstein,J.,Buchner,J.J.Biol.Chem 2008,283,17757-17765.
(7) Roe,S.M.,Prodromou,C.,O'Brien,R.,Ladbury,J.E.,Piper,P.W.,Pearl,L.H.J,Med.Chem 1999,42,260-266.
(8) Neckers,L.,Schulte,T.W.,Mimnaugh,E.Invest.New Drugs 1999,17,361-373.
(9) Heath,E.I.,Caskins,M.,Pitot,H.C.,et al.Clin.Prostate Cancer 2005,4,138-141.
(10) Ronnen,E.A.,Kondagunta,G.V.,Ishill,N.,et al.Invest.New Drugs 2006,24,543-546.
(11) Hollingshead,M.,Alley,M.,Buger,A.M.,et al.Cancer Chemother.Pharmacol.2005,56,115-125.
(12) Minaugh,E.G.,Chavany,C.,Neckers,L.J,Biol.Chem 1996,271,22796-22801.
(13) Soga,S.,Shiotsu,Y.,Akinaga,S.,Sharma,S.V.Drug Discov.Today 2003,13,38-43.
(14) Monica G.Marcu.,A.C.,Ilham Bouhouche.,Maria Catelli.,and Leonard M.Neckers.,THE JOURNAL OF BIOLOGICAL CHEMISTRY,2000,275,37181-37186.
(15) Rudi K.Allan,D.M.,Bryan K.Ward,and Thomas Ratajczak The Journal of Biology Chemistry,281,7161-7171.
(16) Albernamm,C.,Soriano,A.,Jiang,J.,Vollmer,H.,Biggins,J.B.,Barton,W.A.,Lesniak,J.,Nikolov,D.B.,Thorson,J.S.Org.Lett 2003,5,933.
(17) Hooper,D.C.,Wolfson,J.S.,McHugh,G L.,Winters,M.B.,Swartz,M.N.Antimicrob.Agents Chemother 1982,22,662.
(18) Maxwell,A.Biochem.Soc.Trans 1999,27,48.
(19) Tanitame,A.,Oyamada,Y.,Ofuji,K.,Fujimoto,M.,Iwai,N.,Hiyama,Y.,Suzuki,K.,Ito,H.,Terauchi,H.,Kawasaki,M.,Nagai,K.,Wachi,M.,Yamagishi,J.J.Med.Chem 2004,47,3593.
(20) Xiao Ming Yu,G.,Shen.,Len Neckers,Helen Blake,Jeff Holzbeierlein,Benjamin Cronk,Brian S.J.Blagg J.Am.Chem.Soc 2005,127 12778-12779.
(21) Joseph A,B.,Len,Neckers.,Andrew B,Smith.,Anthony,Maxwell.,Brian S.J.Blagg.,J. Am.Chem.Soc 2006,128,15529-15536.
(22) Joseph A,B.,Christophe,Avila.,George,Vielhauer.,Donna J,Lubbers.,Jeffrey,Holzbeierlein.,Brian S.J.Blagg J..Org.Chem 2007,73,2130-2137.
(23) Stephen Hanessian,L.A.Organic Letters 2008,10,261-264.
(24) Patrick Laurin,D.F,Branislav Musicki et al.Bioorganic & Medicinal Chemistry Letters 1999,9,2079-2084.
(25) Steven H.Olson,L.H.S.Tetrahedron Letters 2003,44,61-63.
(26) Joseph A.Burlison,L.N.,Andrew B.Smith,Anthony Maxwell,Brian S.J.Blagg J.Am.Chem.Soc 2006,128,15529-15536.
(27) Knoevenagel,E.Ber 1898,31,2585,2596.
(28) Knoevenagel,E.Ber 1904,37,4461.
(29) Pechmann,H.,Duisberg,C.Ber 1883,16,2119.
(30) Perkin,W.H.J.Chem.Soc 1868,58.
(31) Perkin,W.H.J.Chem.Soc 1877,388.
(32) Patrick,L.,Didier,Ferroud.,Branislav Musicki.,et al.Bioorganic & Medicinal Chemistry Letters 1999,9,2079-2084.
(33) Renata,T.,Jurij,Svete.,Branko,Stanovnik.,* J.Heterocyclic.Chem 1999,36,225-235.