海洋天然产物Largazole的全合成研究
摘要
Largazole是从弗罗里达的海洋蓝藻Smploca sp.中分离得到的具有十六元环肽内酯结构的HDACs抑制剂,它能够选择性抑制癌细胞的生长。该天然产物骨架结构新颖,其结构包括:4-甲基取代的二氢噻唑环与噻唑环的偶联部分,L-缬氨酸和(3S,4E)-3-羟基-7-巯基-4-庚烯酸。本论文采用“最少保护策略”研究了Largazole的全合成,并通过4-甲基取代的二氢噻唑环与噻唑环的偶联反应,以Nagao Evans辅剂诱导的不对称Aldol反应,苄基取代的四氢噻唑硫酮与羰基形成的活性酰胺直接与偶联片段上的氨基发生的氨交换反应,以及大环内酰胺的合成等关键步骤,成功完成了该天然产物的全合成。合成的天然产物Largazole的结构,经~1H-NMR,~(13)C-NMR,EI-MS谱确定,与文献报道的天然产物数据一致。此外,本论文以Largazole为先导化合物,设计出两个结构简化物。目前,其合成工作正在进行。
Largazole is a cyclic depsipeptide, isolated from a cyanobacterium of Floridian marine cyanobacterium Symploca sp.. This compound exhibited potent growth-inhibitory activety in several cancer cell lines. It possesses a dense combination of unusual structural features, including a substituted 4-methylthiazoline fused to a thiazole, L-valine and (3S,4E)-3-hydroxyl-7-thio-4-heptenoic acid. The thesis described less-protection synthesis of Largazole, in which the key steps included thiazoline-thiazole formation, the use of the Nagao thiazolidinethione auxiliary for a diastereoselective actetate aldol reaction, the amino-exchange reaction of the amino of thiazoline-thiazole derivative and active amide which was formed with Nagao thiazolidinethione and carbonyl, and macrolactamization. The molecular structure of the product was determined by ~1H-NMR, ~(13)C-NMR, ESI-MS and was found to be consistanted with reported data. In addition, we also design and synthesize two analogs of Largazole.
Largazole is a cyclic depsipeptide, isolated from a cyanobacterium of Floridian marine cyanobacterium Symploca sp.. This compound exhibited potent growth-inhibitory activety in several cancer cell lines. It possesses a dense combination of unusual structural features, including a substituted 4-methylthiazoline fused to a thiazole, L-valine and (3S,4E)-3-hydroxyl-7-thio-4-heptenoic acid. The thesis described less-protection synthesis of Largazole, in which the key steps included thiazoline-thiazole formation, the use of the Nagao thiazolidinethione auxiliary for a diastereoselective actetate aldol reaction, the amino-exchange reaction of the amino of thiazoline-thiazole derivative and active amide which was formed with Nagao thiazolidinethione and carbonyl, and macrolactamization. The molecular structure of the product was determined by ~1H-NMR, ~(13)C-NMR, ESI-MS and was found to be consistanted with reported data. In addition, we also design and synthesize two analogs of Largazole.
引文
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[29]Yanping Chen,Celine Gambs,et al.Total Synthesis of the Depsipeptide FR-901375[J].J.Org.Chem.2003,68:8902-8905
[30]Andre B.,Charette,Peter Chua.Mild Method for the Synthesis of Thiazolines from Secondary and Tertiary Amide[J].J.org.Chem.1998,63:908-909
[31]Dominique Delaunay,LoYc Toupet,Maurice Le Corre.Reactivity of β-Amino Alcohols with Carbon Disulfide.Study on the Synthesis of 2-Oxazolidinethiones and 2-Thiazolidinethiones[J].J.Org.Chem.1995,60:6604-6607
[32]Michael T.Crirnmins,Madam Shamszad,et al.Highly Selective Acetate Aldol Additions Using Mesityl-Substituted Chiral Auxiliaries[J].Org.Lett.2007,9(1):149-152
[33]Mukalyama T.[J].Angew.Chem.lnt.Ed.Engl.1979,18:707-721
[34]Isamu Shiina,Mad Kubota,et al.An Effective Use of Benzoic Anhydride and Its Derivatives for the Synthesis of Carboxylic Esters and Lactones:A Powerful and Conveninent Mixed Anhy -dride Method Promoted by Basic Cataylsts[J].J.org.Chem.2004,69:1882-1830
[35]田华硕士论文
[36]Ayman El-Faham,Fernando Albericio.[J].J.org.Chem.2008,73:2731-2737
[2]刘艾林,龙娟,王楠,杜冠华.抗肿瘤药物的新靶点:组蛋白去乙酰化酶抑制剂的研究进展[J].药学学报,2005,40(7):585-590
[3]Venter JC,Adam MD,Myers EW,et al.[J].Science,2001,291:5507
[4]Archer SY,Meng S,Shei A,et al.p2[WAF]is required for butyrate-mediated growth inhibition of human colon cancer cells[J].Proc Natl Acad Sci USA,1998,95(12):6791-6796
[5]Shi Y,Mello CA,et al.CBP/p300 homolog specificies multiple differentiation pathways in Caenorhabditis elegants[J].Genes Dev.1998,12(7):943-955
[6]Gu W,Roeder RG,et al.Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain[J].Cell.1997,90(4):595-606
[7]Sakaguchi K,Herren JE,et al.DNA damage activates p53 through a phosphorylation-acetylation cascade[3].Genes Dev.1998,12(18):2831-2841
[8]Juan LJ,Shai WJ,et al.Histone decaetylases specifically down-regulate p53-dependt gene activation[J].Biol Chem.2000,275(27):20436-20443
[9]Jonestone RW,et al.Histone-deacetylase inhibitiors:noved drugs for the treatpeutic target[J].Nature Rev Drug Discov.2002,1(4):287-299
[10]Kanchan Taori,Valerie J.Paul,Hendrik Luesch.Structure and Activity of Largazole,a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca sp.[J].J.Am.Chem.Soc.2008,130:1806-1807
[11]Yongcheng Ying,Kanchan Taori,Hendrik Luesch.Total Synthesis and Molecular Target of Largazole,a Historic Deacetylase Inhibitor[J].J.Am.Chem.Soc.2008,130:8455-8459
[12]Albert Bowers,Nathan West,et al.Total Synthesis and Biological Mode of Action of Largazole:A Potent Class Ⅰ Historic Deacetylase Inhibitor[J].J.Am.Chem.Soc.2008,130:11219-11222
[13]Qi Ren,Lu Dai,Hui Zhang,et al.Total Syhthesis of Largazole[J].Synlett.2008,15:2379-2383
[14]Yoshitaka Numajiri,Yakashi Takahashi,et al.Total Syhthesis of Largazole and Its Biological Evaluation[J].Synlett.2008,16:2483-2486
[15]Albert A.Bowers,Nathan West,et al.Synthesis and Historic Deacetylase Inhibitory Activity of Largazole Analogs:Alteration of the Zinc-Binding Domain and Macrocyclic Scaffold[J].Org.Lett.2009,11(6):1301-1304
[16]Arun K.Ghosh,Sarang Kulkami.Enantioselective Total Synthesis of(+)-Largazole,a Potent Inhibitor of Histone Deacetylase[J].Org.Lett.,2008,10(17):3907-3909
[17]Tobias Seiser,Faustin Kamena,Nicolai Cramer.Synthesis and Biological Activity of Largazole and Derivatives[J].Angew.Chem.Int.Ed.2008,47:6483 -6485
[18]Gerald C.Mulqueen,Gerald pattenden,et al.Synthesis of the Thiazoline-based Siderophore(S)-Desferrithiocin.[J].Tetrahedron.1993,49(24):5339-5364
[19]Marcello Di Giacomo,Valerio Vinci,Lino Colombo.New fast and practical method for the enantioselective synthesis of a-vinyl,a-alkyl quaternary a-amino acids[J].Tetrahedron Asym -metry.2008,19:247-257
[20]Nagaswamy Kumaragurubaran,Karsten Juhl,et al.Direct l-Proline-Catalyzed Asymmetric □-Amination of Ketones[J].J.Am.Chem.Soc.2002,124(22):6254-6255
[21]Henning Vogt,Sylvia Vanderheiden,Stefan Brase.Proline-catalysed asymmetric amination of α,α-disubstituted aldehydes:synthesis of configurationally stable enantioenriched α-amino -aldehydes[J].Chem.Commun.2003:2448-2449
[22]Naidu S.Chowdari,Carlos F.Barbas,et al.Total Synthesis of LFA-1 Antagonist BIRT-337 via Organocatalytic Asymmetric Construction of A Quaternary Stereocenter[J].Org.Lett.2005,7(5):867-870
[23]Christopher J.Moody,Mark.C.Bagley,et al.Total synthesis of(1)-nostocyclamide[J].J.Chem.Soc.Perkin Trans.1,1998:601-607
[24]Pharmaceutical Research Center,Meiji Seika Kaisha,et al.CP0569,A New Broad-Spectrum Injectable Carbapenem.Part Ⅰ:Synthesis and Structure - Activity Relationships[J].Bioorg.Med.Chem.2003,11:3475-3485
[25]Patrick L.DeRoy,Andre B.Charette.Total Synthesis of(+)-Cystothiazole A[J].Org.Lett. 2003,5(22),4163-4165
[26]Pietrusiewicz K.Michal,Monkiewicz,Jaroslaw.[J].Tetrahedron Letters.1986,27(6):739-742
[27]Manfred Braun,Slike Graf.(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate[J].Organic Syntheses.Coll.1998,9:507;1995,72:32
[28]Manfred Braun,Slike Graf.Stereoselective aldol reaction of doubly deprotonated(R)-(+)-2-hydroxyl-1,2,2-triphenylethyl acetate(hytra):(R)-3-hydroxy-4-methylpentanoicacid[J].Organic Syntheses.Coll.1998,9:497;1995,72:38
[29]Yanping Chen,Celine Gambs,et al.Total Synthesis of the Depsipeptide FR-901375[J].J.Org.Chem.2003,68:8902-8905
[30]Andre B.,Charette,Peter Chua.Mild Method for the Synthesis of Thiazolines from Secondary and Tertiary Amide[J].J.org.Chem.1998,63:908-909
[31]Dominique Delaunay,LoYc Toupet,Maurice Le Corre.Reactivity of β-Amino Alcohols with Carbon Disulfide.Study on the Synthesis of 2-Oxazolidinethiones and 2-Thiazolidinethiones[J].J.Org.Chem.1995,60:6604-6607
[32]Michael T.Crirnmins,Madam Shamszad,et al.Highly Selective Acetate Aldol Additions Using Mesityl-Substituted Chiral Auxiliaries[J].Org.Lett.2007,9(1):149-152
[33]Mukalyama T.[J].Angew.Chem.lnt.Ed.Engl.1979,18:707-721
[34]Isamu Shiina,Mad Kubota,et al.An Effective Use of Benzoic Anhydride and Its Derivatives for the Synthesis of Carboxylic Esters and Lactones:A Powerful and Conveninent Mixed Anhy -dride Method Promoted by Basic Cataylsts[J].J.org.Chem.2004,69:1882-1830
[35]田华硕士论文
[36]Ayman El-Faham,Fernando Albericio.[J].J.org.Chem.2008,73:2731-2737