Mei, Zhen-Wu

Okayama University Scientific Achievement Repository

氏 名梅振武授与した学位博士専攻分野の名称工学学位授与番号博甲第4638号学位授与の日付平成24年 9月27日学位授与の要件 自然科学研究科機能分子化学専攻(学位規則第5条第1項該当)学位論文の題目 Studies on Development of Benign Technologies for Some Organic Transformations with Organic Catalysts and Synthesis ofthe Substituted Neocryptolepines as Drug Candidates of Antimalarial Agents (有機触媒による分子変換のための環境技術および抗マラリア活性を持つ医薬候補としての置換ネオクリプトレピンの合成と活性評価に関する研究)論文審査委員准教授井口 勉 教授尾坂明義 教授妹尾昌治単位論文内容の要旨In this thesis， the author engaged with three research topics focusing on the environmentally friendly technologies for organic transformations with organic catalysts and design and synthesis of neocryptolepine derivatives for antimalarial drug. The author‘s contributions during these work were summarized as below: 1. High performance and seleciive oxidation method for secondary alcohols by use of organic catalyst. A high performance oxidation method of alcohols with organic catalyst TEMPO substituted with an electron-withdrawing group (EWG) at the C4 position， which is useful for oxidation of the electron-deficient secondary alcoho1s such as ArCH(OH)CFCh， has been developed by using町.1田町 asa co・oxidant.Reactivity of Py・HBr3was discussed in terms of efficiency and se1ectivity in comparison with simi1ar bromine compounds such as BU4NBr3，叩dthe method was easily extended to the polymer supported bromine reagents as a ∞ーoxidant.Inductive activation of TEMPO by the appendage of EWG at the C4 position was shown to faci1tate the reaction rate， which was rationalized by measuring the cyc1ic voltammetry ofthe 4・substitutedTE恥1POs.2. Green procedure for preparation of carboxylic acids by TEMPO oxidation of primary aIcohols. 百leauthor developed an efficient primary alcohol-carboxylic acid conversion by employing TEMPO oxidation. A biphasic system composed of e伽 realsolvent THP and aqueous layer instead of often used harmfu1 solvents like CHzCh-aqueous 1ayer was proposed. During the TEMPO oxidation of prim訂yalcohols， m叩 yeasily available oxidants， such as Py'HBr3， BU4NBr3 and elec甘ooxidation，were successfully applied as co・oxidants.And this method could easily be applied to various primary alcoho1s inc1uding aromatic， aliphatic， and carbohydrate derivatives， some of which are of significant synthetic value. 3. Synthesis and evaluation of novel neocryptolepine derivatives for developing antimalarial agents. In order to obtain a high antimalaria1 activity， modiかingand changing the side chains at th巴C1 position of the neocrypto1epine derivatives were executed. At the same time， varying the substituents of an electron-withdrawing or electron-donating nature at the C2 position was examined for a SAR sωdy. As the strategic scaffold of this study， improved synthesis of the 1・chloroneocηrtolepineswas developed in three steps using N・methylanilinesand indole-3・carboxylateas the counterpart. Installation of a1kylamino andω咽 ninoalkylaminogroups at the ClI position of the neocrytolepine core was achieved by the reaction of the 11-chloroneocrypto1epines and the appropriate amines. For further variation， the aminoa1kylamino subsituents were transformed into the coπesponding acyclic or cyc1ic carbamides or thiocarbamides. These side-chain modified neocrypto1epine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro. The evaluation also inc1uded cytotoxicity toward mammalian L6 cels. Al1 tested compounds showed potent antiplasmodia1 activities against CQR (Kl) and CQS (NF54) in vitro and some compounds showed much greater potency than CQ. 論文審査結果の要旨The development of efficient metal-free oxidation method is currently pursued in organic reaction processes from environmentally point of view. Meanwhile， how to explore new drugs to meet the demand for drug-resistant diseases is stil a hot topic in the medicinal chemistry. Especially， malaria remains the most devastating disease in the tropical and subtropical regions， led to 216 million infected cases and 0.7 million died in 2010. This is due tωo app問ea釘r叩 c印eoぱfchloroqu凶lin悶I悶e(CQ)-刊.i凶nthree research t旬op戸ic凶stoward the e叩nv吋iro刀nm悶lent此旬凶al防yti仕ri均en凶dl防ytechnologies for or，屯g加 i比ctransformations with organic catalysts and design and synthesis of neocryptolepine derivatives for antimalarial drug. 1) A high performance method for oxidation has been developed using organic catalyst TEMPO in combination with Py・HBr3as a co・oxidant.Oxidation power of TEMPO was increased by the appendages of electron-withdrawing group at the C・4position， and enhanced reactivity was rationalized by measuring the cyclic voltammetry. The oxidation system comprised by the EWG-substituted TEお伊oand Py.HBr3 was applied to the secondary alcohols ofthe electron-deficient structures. 2) The author developed an efficient primary alcohol-carboxylic acid conversion by employing TEMPO oxidation in a biph田icsystem composed of THP and aqueous layer instead of often used harmful solvents like a CH2Clraqueous layer system. And this method was applied to various primary alcohols including aromatic， aliphatic， and carbohydrate derivatives， some of which are of significant synthetic value. 3) The author developed antimalarial agents by designing and synthesizing neocryptolepine derivatives with various substituents at the C2 position and aminoalkylamino substituents at the Cll position. For白.rthervariation， the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamides or thiocarbamides. These side-chain modified neocryptolepine derivatives were tested for antimalarial activity against CQR (Kl) and CQS (NF54) of Plasmodiumfalc抑'rumin vitro and c戸otoxicitytoward mammalian L6 cels. All tested compounds showed potent antiplasmodial activities against CQR (Kl) and CQS (NF54) in vitro and some compounds showed much greater potency than chloroquine (CQ). Some derivatives with high antimalarial activities and selective index were tested in vivo and showed moderate biological activity. Based on the aforementioned results we concluded that the thesis contains new， scientifically valuable results and represents an original contribution to the field. Therefore， we strongly recommend for the award of PhD degree inthe present form. 

有機触媒による分子変換のための環境技術および抗マラリア活性を持つ医薬候補としての置換ネオクリプトレピンの合成と活性評価に関する研究

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