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1、hon p.1 100%127帝京大学薬学部薬化学教室（1990195津久井郡相模 湖町寸沢嵐10911） e-mail: hi-takaypharm.teikyo-u.ac.jp本総説，平成13年度日本薬学会学術貢献賞受賞 記念記述127YAKUGAKU ZASSHI 122(2) 127155 (2002)2002 The Pharmaceutical Society of JapanReviews機能性有機化合物創製応用 山 浩 明Creation of Functional Organic Compounds and Their ApplicationsHiroaki TAKAYAMA
2、 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, 10911 Suarashi, Sagamiko-machi, Thukui-gun, Kanagawa 1990195, Japan(Received October 29, 2001)Our studies on creation of functional organic compounds and their applications, have focused on three areas, n
3、amely,(A)organic chemical studies on VD(vitamin D)analogues,(B)studies on solitary wasp venoms, and(C)stud- ies on functional building blocks for organic synthesis. In the rst area, several novel and important vitamin D ana- logues were synthesized and biologically evaluated, and their high VDR(vita
4、min D receptor)binding anities were dis- cussed on the basis of conformational analysis and docking study by Molecular Mechanics Calculation to the LBD (ligand binding domain)of VDR: These compounds include 24,24-diuoro-1a,25-dihydroxy-VD3(2) (an anti- metabolism agent, the rst VD analogue having hi
5、gher potency than the natural hormone(1), 2a-methyl-1a,25-di- hydroxy-VD3(42b) (the rst A-ring-modied VD analogue exhibiting stronger VDR anity than 1)and its 20-epimer (43b) (a VD analogue having a highest HL-60 cell dierentiation inducing activity with a relatively low calcemic eect), and 2a-(v-hy
6、droxypropyl)-1a,25-dihydroxy-VD3(exceptionally high calcemic eect). In the second area, we isolated and determined the structure of pompilidotoxins(76, 77), novel peptide neurotoxins in solitary wasp venoms. In the third area, we created furan-fused 3-sulfolene, 4H, 6H-thieno3,4-c-furan 5,5-dioxide
7、and pyrrole-fused 3-sulfolene (96), 3,5-dihydro-1H-thieno3,4-cpyrrole 2,2-dioxide(125), and studied their inter- and intramolecular Diels-Alder reactions.Key wordsstructure-activity relationship; structural determination; vitamin D analogues; peptide neurotoxins in solitary wasp venoms; heteroaromat
8、ic-fused sulfolenes; Diels-Alder reaction帝京大学薬学部赴任以来研究，機能性有機化合物創製応用本総説主題3研究分野A, B, C分章，節設研究判次記述分野愛着，最近研究A-5, B，及C-3詳述A.D類縁体有機化学的研究（医薬化学）A-1.素置換D誘導体合成 抗 代 謝 24,24-diuoro-1a,25-dihydroxyvitamin D3合成活性評価A-2.D部化学修飾a) 一重項酸素反応酸素付加体合成活性，b) 二酸化反応付加体（3 誘導体）合成反応A-3.Calcidiol lactone合成立体配置決定A-4.種D3代謝産物構造決定，合成及
9、活性評価A-5.A環修飾活性型D誘導体合成活性評価B.独居性狩蜂毒嚢成分研究（天然物化学）C.機能性合成構築材研究（複素環化学）C-1.芳香環縮環含窒素複素環化合物合成反応C-2.3 化学修飾反応C-3.五員芳香族複素環縮環3 創製反応及縮環3hon p.2 100%128Fig. 1.Metabolism of Vitamin D3128Vol. 122 (2002)A-1.抗代謝24,24-diuoro-1a,25-di-hydroxyvitamin D3(2）合成1971年，DeLu-ca, KodicekD3（VD3）活性本体代謝物1a,25-dihydroxyvitamin D3(1
10、）構造決定我研究初1978年当時，更代謝研究活発行時，次代謝経路明 （Fig. 1） VD3肝臓25 位水酸化25-OH-D3循環型VD3血中最多量存在血中Ca濃度正常値，叉以下（VD欠乏状態），腎臓1a位水酸化活性型VD3(1）VD作用発現Ca濃度恒常性保他方，血中Ca濃度正常値高場合，側鎖24 位，26 位，23 位水酸化我1主代謝経路24位水酸化意義解明，位置素原子導入抗代謝活性型D3(2）合成当時VD合成，生合成経路変換法主，活性型D3合成基本Barton法金子法参照，lithocholic acidD導，全20行程合成，1a水酸基合成1)素導入a DAST効率良行（Fig. 2） L
11、ithocholic acid全収率20 合成24,24-diuoro-5b-cholestane-3a,25-diol(3） ，1)DDQ酸化（4），t-BuOKdecon-jugation行，還元5位化，次脱HBr，混合物中1,5,7-（6）得65,7-部4-phenyl-1,2,4-triazoline-3,5-dione保護7，m-CPBA酸化2種混合物（1：1）得a （8）LAH処理，開環脱保護進行D(9）得9常法従，光照射，熱異性化24,24-F2-1a,25-F2-(OH)2-D3(2）得2)生物活性研究DeLuca共同研究行3)Lithocholic acid20行程，全収率0
12、.07 極困難全合成，VDR結合能指標Ca代謝調節能，HL-60細胞分化誘導能，天然凌駕史上初VD創製時流，1990年代入，26,27-hexauoro-1a,25-dihydroxyvitamin D3医薬現実味帯，先24-uoro-1a,25-di-hydroxyvitamin D2合成4)行顕著活性示，幸2骨粗鬆症治療薬笠間努力日本油脂株開発我本化合物大量合成法開発効率標識化法開発行，入手容易1a-hydroxy-dehydro-epiandrosterone(10）改良法考案（Fig. 3） 5)10TBS保護体（11）Wittig反応，立体選択的Z （12）導，反応付立体特異的（13
13、）89 収率得次，接触水素化行位置及立体選択的望C-20, C-17立体配置有14得14順次NBS, n-Bu4NBr，及n-Bu4NF処理5,7-（15）41 得共役安定，保護次反応行常法従，C-20（16）変換（73), Reformatsky反応付，C-23混合物（17）与hon p.3 100%129Fig. 2.Synthesis of 24,24-F2-1a,25-(OH)2-D3(2) I a)DDQ in dioxane, reux, b)t-BuOK in DMSO, 15C, then H2O, c)Ca(BH4)2, EtOH-MeOH,10C, d)Ac2O, pyridine, e)NBS in hexane-benzene, re., f) collidine in xylene, re., g)4-phenyl-1,2,4,-triazoline-3,5-dione, h)NaOH in EtOH, i)m-CPBA in CHCl3, j)LAH in THF, re., k)hnin ether, l)EtOH, r. t.Fig. 3.Synthesis of 24,24-F2-1a,25-(OH)2-D3(2) II a)Ph3PCH2CH3Br, t-BuOK, b)HCHO
