1990 Fiscal Year Annual Research Report

生理活性物質の合成と作用発現構造

Research Project

Project/Area Number	02303017
Research Institution	Nagoya City University
Principal Investigator	塩入孝之名古屋市立大学, 薬学部, 教授 (20012627)
Co-Investigator(Kenkyū-buntansha)	濱田康正名古屋市立大学, 薬学部, 助教授 (90117846) 米光宰北海道大学, 薬学部, 教授 (60001038) 川添豊名古屋市立大学, 薬学部, 教授 (80106252) 池上四郎帝京大学, 薬学部, 教授 (10119555) 荒田洋治東京大学, 薬学部, 教授 (40011499)
Keywords	生理活性物質 / 効率的合成法 / 作用発現構造 / 生理活性ペプチド / 糖 / マクロリド / 薬物創製 / 物理化学的アプロ-チ
Research Abstract	本研究の目的は,生理活性物質の効率的合成法を開発すると同時に,生理活性物質の活性発現に必須の構造を究明し,それらを基盤として生物の営みを明らかにし,さらに進んで人間にとって有用な生理活性物質を創製せんとするものである。本年度は研究を1)生理活性ペプチドの効率的合成と作用発現構造の究明,2)糖,マクロリド,その他生理活性天然物の新規合成法の開拓と作用発現構造の究明,3)循環器,中枢そして癌を対象にした薬物の創製と作用発現構造の究明,4)物理化学的アプロ-チによる活性発現構造の究明の四つのプロジェクトにしぼり,16名の研究者が各プロジェクトにわかれて,相互に緊密な連絡,協力を行いながら,それぞれ独自の研究を強力に推進した。まずペプチドグル-プでは,抗腫瘍性ペプチドドラスタチン10の効率的合成法が開発され,また新規縮合剤BOIが開発され,心房性ナトリウム利尿ペプチドに関する医薬化学的検討が行われた。抗エイズウイルス活性を有する新規ペプチドが合成され,耐熱性エンテロトキシンの分子構造がX線結晶解析で明らかにされ,種々の神経ペプチドの活性と構造の関係が検討された。一方糖・マクロリドグル-プでは糖蛋白中のオリゴ糖の合成と,疑似糖の合成に成果をあげた。また種々の生理活性天然物のエナンチオ選択的合成法が開発され,一方ではコンホメ-ション制御を活用して,いくつかのマクロリド類の高効率の全合成が完了した。薬物創製グル-プでは,循環器疾患薬イソカルバサイクリンの改良合成法が達成され,MAO阻害活性天然物の種々の化学修飾が行われ,アルキル置換キノリン誘導体の代謝研究から発癌代謝機構が証明された。最後に物理化学グル-プは,多核NMRの方法により抗体の高次構造と機能の関連を解析し,一方抗腫瘍性環状ペプチドにつきその立体構造と活性の相関について検討された。

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] Y.Hamada: "Efficient stereoselective synthesis of dolastatin 10,an antineoplastic peptide from a sea hare" Tetrahedron Letters. 32. 931-934 (1991)
[Publications] Y.Kiso: "Solutionーphase synthesis of porcine brain natriuretic peptide(pBNP)using Sーtrimethylacetamido methylcysteine" Chem.Pharm.Bull.38. 1192-1199 (1990)
[Publications] K.Tomioka: "Stereoselective reactions XVIII.Synthesis and cytotoxiuty of the demethyl derivatines of steganes" Chem.Pharm.Bull.38. 1899-1901 (1990)
[Publications] K.Akaji: "Studies on peptides.CLXVIII.Syntheses of three peptides isolated from horsehoe crab hemocytes,tachyplesin I,tachyplesin II,and polyphemusin I" Chem.Pharm.Bull.37. 2661-2664 (1989)
[Publications] H.Ozaki: "Molecular structure of the toxic domain of heatーstable enterotoxin produced by a pathogenic strain of Escherichia coli:A putative binding site for a binding protein on rat intestinal epithelial cell membranes" J.Biol.Chem.271.
[Publications] H.Mukai: "Antagonism by GRP(18ー27)and substance P analogues on insulin release stimulated by GRP(18ー27)" Peptides. 11. 173-175 (1990)
[Publications] K.Fukase: "4ーNitrobenzyl group for protection of hydroxyl functions" Tetrahedron Letters. 31. 389-392 (1990)
[Publications] T.Takahashi: "A new synthetic approach to pseudoーsugars by Asymmetric DielsーAlder reaction.Synthesis of optically pure pseudoーβーDーmannopyranose,1ーaminoー1ーdeoxypseudoーαーDーmannopyranose and pseudoーαーLーmannopyranose derivatives" J.Chem.Soc.Perkin Trans 1. 3065-3072 (1990)
[Publications] S.Takano: "A convergent enantiocontrolled route to mevalonolactone and vitamin E from (S)ーOーbenzylglycidol" Tetrahedron Letters. 31. 3619-3622 (1990)
[Publications] M.Hikota: "Stereoselective synthesis of erythronolide A by extremely efficient lactonization based on conformational adjustment and high activation of secoーacid" Tetrahedron. 46. 4613-4628 (1990)
[Publications] S.Hashimoto: "A versatile and convenient method for the preparation of αー(Z)ー1ーalkenyl ketones from βーketo benzyl esters" J.Chem.Soc.,Chem.Commun.1100-1102 (1990)
[Publications] H.Sakagami: "Antiーinfluenza virus activity of synthetically polymerized phenylpropenoids" Biochem.Biophys.Res.Commun.172. 1267-1272 (1990)
[Publications] T.Igarashi: "Structure of a mouse immunoglobulin G that lacks the entire C_H1 domain:Protein sequencing and smallーangle Xーray scattering studies" Biochemistry. 29. 5727-5733 (1990)
[Publications] Y.Kamatani: "Molecular conformation of achatinーI,an endogenous neuropeptide containing Dーamino acid residue,Xーray erystal structure of its neutral form" FEBS Letters. 276. 95-97 (1990)
[Publications] 塩入孝之: "海洋生物由来の抗腫瘍活性環状ペプチドー合成,立体配座,生物活性" 化学同人, 31-46 (1990)

1990 Fiscal Year Annual Research Report

生理活性物質の合成と作用発現構造

Principal Investigator

塩入 孝之 名古屋市立大学, 薬学部, 教授 (20012627)

Research Products

[Publications] Y.Hamada: "Efficient stereoselective synthesis of dolastatin 10,an antineoplastic peptide from a sea hare" Tetrahedron Letters. 32. 931-934 (1991)

[Publications] Y.Kiso: "Solutionーphase synthesis of porcine brain natriuretic peptide(pBNP)using Sーtrimethylacetamido methylcysteine" Chem.Pharm.Bull.38. 1192-1199 (1990)

[Publications] K.Tomioka: "Stereoselective reactions XVIII.Synthesis and cytotoxiuty of the demethyl derivatines of steganes" Chem.Pharm.Bull.38. 1899-1901 (1990)

[Publications] K.Akaji: "Studies on peptides.CLXVIII.Syntheses of three peptides isolated from horsehoe crab hemocytes,tachyplesin I,tachyplesin II,and polyphemusin I" Chem.Pharm.Bull.37. 2661-2664 (1989)

[Publications] H.Ozaki: "Molecular structure of the toxic domain of heatーstable enterotoxin produced by a pathogenic strain of Escherichia coli:A putative binding site for a binding protein on rat intestinal epithelial cell membranes" J.Biol.Chem.271.

[Publications] H.Mukai: "Antagonism by GRP(18ー27)and substance P analogues on insulin release stimulated by GRP(18ー27)" Peptides. 11. 173-175 (1990)

[Publications] K.Fukase: "4ーNitrobenzyl group for protection of hydroxyl functions" Tetrahedron Letters. 31. 389-392 (1990)

[Publications] S.Takano: "A convergent enantiocontrolled route to mevalonolactone and vitamin E from (S)ーOーbenzylglycidol" Tetrahedron Letters. 31. 3619-3622 (1990)

[Publications] M.Hikota: "Stereoselective synthesis of erythronolide A by extremely efficient lactonization based on conformational adjustment and high activation of secoーacid" Tetrahedron. 46. 4613-4628 (1990)

[Publications] S.Hashimoto: "A versatile and convenient method for the preparation of αー(Z)ー1ーalkenyl ketones from βーketo benzyl esters" J.Chem.Soc.,Chem.Commun.1100-1102 (1990)

[Publications] H.Sakagami: "Antiーinfluenza virus activity of synthetically polymerized phenylpropenoids" Biochem.Biophys.Res.Commun.172. 1267-1272 (1990)

[Publications] T.Igarashi: "Structure of a mouse immunoglobulin G that lacks the entire C_H1 domain:Protein sequencing and smallーangle Xーray scattering studies" Biochemistry. 29. 5727-5733 (1990)

[Publications] Y.Kamatani: "Molecular conformation of achatinーI,an endogenous neuropeptide containing Dーamino acid residue,Xーray erystal structure of its neutral form" FEBS Letters. 276. 95-97 (1990)

[Publications] 塩入 孝之: "海洋生物由来の抗腫瘍活性環状ペプチドー合成,立体配座,生物活性" 化学同人, 31-46 (1990)

塩入孝之名古屋市立大学, 薬学部, 教授 (20012627)

[Publications] 塩入孝之: "海洋生物由来の抗腫瘍活性環状ペプチドー合成,立体配座,生物活性" 化学同人, 31-46 (1990)