JP6784645B2 - 真菌のオルタナティブオキシダーゼ阻害剤 - Google Patents
真菌のオルタナティブオキシダーゼ阻害剤 Download PDFInfo
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- JP6784645B2 JP6784645B2 JP2017111886A JP2017111886A JP6784645B2 JP 6784645 B2 JP6784645 B2 JP 6784645B2 JP 2017111886 A JP2017111886 A JP 2017111886A JP 2017111886 A JP2017111886 A JP 2017111886A JP 6784645 B2 JP6784645 B2 JP 6784645B2
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Classifications
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Description
R2は、水素またはヒドロキシ基または炭素原子数1〜3のアルコキシ基であり;
R3は、炭素数1〜4のアルキル基により1または多置換されてもよい、炭素原子数4〜20の直鎖のまたは分岐したアルキルまたはアルキレンであり;
R4は、水素またはヒドロキシ基または炭素原子数1〜3のアルコキシ基であり;
R5は、ハロゲン基であり;および、
R6は、水素または炭素数1〜4のアルキル基であり;
ただし、少なくともR2およびR4の1つはヒドロキシ基または炭素原子数1〜3のアルコキシ基である。
R1は、CHO;CH2OH;CN;CH3;C(O)NH2;C(O)NHCH3;C(O)CH3;CF2CH3;CH2CH3;CH2OAc;COOH;およびCOOCH3から選択され;並びに、
R2は、ヒドロキシル基であり;
R3は、炭素数1〜4のアルキル基により1または多置換されてもよい、炭素原子数4〜20の直鎖のまたは分岐したアルキルまたはアルキレンであり;
R4は、ヒドロキシル基であり;
R5は、塩素原子であり;および、
R6は、水素または炭素数1〜4のアルキル基である。
R1は、CHO;CH2OH;CN;CH3;C(O)NH2;C(O)NHCH3;C(O)CH3;CF2CH3;CH2CH3;CH2OAc;COOH;およびCOOCH3から選択され;並びに、
R2は、ヒドロキシル基であり;
R3は、炭素数1〜2のアルキル基により1または多置換されてもよい、炭素原子数6〜15の直鎖のまたは分岐したアルキルまたはアルキレンであり;
R4は、ヒドロキシル基であり;
R5は、塩素原子であり;および、
R6は、水素または炭素数1〜4のアルキル基である。
R1は、CHO;CH2OH;CN;CH3;C(O)NH2;C(O)NHCH3;C(O)CH3;CF2CH3;CH2CH3;CH2OAc;COOH;およびCOOCH3から選択され;並びに、
R2は、ヒドロキシル基であり;
R3は、炭素原子数8〜10のアルキレン鎖であり、少なくとも一つのメチル基、好ましくは二つのメチル基で置換されており;
R4は、ヒドロキシル基であり;
R5は、塩素原子であり;および、
R6は、メチル基である。
R2は、水素またはヒドロキシ基または炭素原子数1〜3のアルコキシ基であり;
R3は、炭素数1〜4のアルキル基により1または多置換されてもよい、炭素原子数4〜20の直鎖のまたは分岐したアルキルまたはアルキレンであり;
R4は、水素またはヒドロキシ基または炭素原子数1〜3のアルコキシ基であり;
R5は、ハロゲン基であり;および、
R6は、水素または炭素数1〜4のアルキル基であり;
ただし、少なくともR2およびR4のうち1つは、ヒドロキシ基または炭素原子数1〜3のアルコキシ基である。
R2は、水素またはヒドロキシ基または炭素原子数1〜3のアルコキシ基であり;
R3は、炭素数1〜4のアルキル基により1または多置換されてもよい、炭素原子数4〜20の直鎖のまたは分岐したアルキルまたはアルキレンであり;
R4は、水素またはヒドロキシ基または炭素原子数1〜3のアルコキシ基であり;
R5は、ハロゲン基であり;および、
R6は、水素または炭素数1〜4のアルキル基であり;
ただし、少なくともR2とR4のうち1つはヒドロキシ基または炭素原子数1〜3のアルコキシ基である。
TTTATATATCCGATGTTTGGTGACAGCATTCTTGGTGCATGAAAAGTTACTCCCGGCGGCGAGGAACCGGTGACTTGGGAGAAGGGAGCGTTTGTTAATTGAAGGACTGGTACATGGATACCTGCGTACTTCATGCGGTCCTTTCTCGTGGTGGTAGGCCTGCATTTAGGTTTCTTTGATGTTTGACGCCGCAGTTACACAGGCTGAGGCTGACTTGGATTTCGTGTGTCCCGATAAGACATCGTGAACGAGTTATTTCCATCCCTTCTTTTCTTGTTCTCTTTTAGTTTGCTTAGAAGACGTTGCCGGCTTTTTTTCTTGACTGAGGTTGCTCGGGCTTTTATTCATTCACCTCTTCTTAGAGTTACCCGTTGCTTGCCGTGTTTCTTTGCTAGTGGCAATTGAAATACAACACCTACCTACTGTACCTTCACACACCTACAAACCTTTTTCTTATTTCGTCAAAATAACAGGATTCTGATTGAGACCACTATGTATGTGGCAAGAGTATCCACGAGGGTACAGTTCTCCAAACAGACTGCTTCGCATCTTTCCAAGGTCGTAGCAGCCAACTTTTCACAATCATGTTCTGGCTCCCTCCATCGCGTTGGTCTTGGTGCGAGTCCAGTACTTCATACTTCACAATCTCATCGTGAGTTCTCTACGACGCCCCGAGCAGCGTTGAGAGATTTCTTCCCTCAGAAGGAAACGGAACTGATCCGGAAAACCAAACCAGCATGGGAACATCCCGACTTCAGCTACGAAGACATGAAAACCAAGGTCTTCTATGCCCACCGCGAACCAGCCGATTTCTCAGATCGTGTCGCATTATGGATGGTTCGCCTTTTAAGATGGGGAACCGACCTAGCAACGGGCTACAAACACGATGTAGAAGTGCCAAAGAAAATCGGTGATGCCAATGCCGTTGCAGAGACGAAGCCATATGGTATGAGTGAGCGAAAATGGTTGATTCGAATTATATTTTTGGAATCTGTTGCGGGTGTGCCAGGGATGGTTGCGGCTATGTTGAGGCATTTGCATTCGATGAGGAGGTTGAAGAGGGATAATGGATGGATTGAGACGCTTTTGGAGGAGAGTCAGAATGAGAGGATGCATCTCCTCACCTTCCTCAAAATGGCCGAACCAGGCTGGTTCATGAAATTCATGCTCCTGGGCGCCCAAGGCGTCTTCTTCAACAGCATGTTCATCTCCTACCTCATCTCCCCACGAACCTGCCACCGCTTCGTCGGCTACCTCGAAGAAGAAGCCGTCTTCACGTACACGCTCGCCATCCAAGACCTGGAAGCGGGCAAGCTGCCCCAATGGACGCACCCGGACTTCCGCGTCCCAGACATCGCCGTCGATTACTGGAAGATGCCCGAGGACAAACGCACCATGAGGGATCTCATGCTCTATGTGAGAGCGGATGAGGCGAAACATCGTGAGGTTAATCATACCCTGGGGAATCTGGATCAGGATGAGGATCCGAATCCGTTTGTTTCCGAGTATAAGGATGTGGGGAGGCCGCATCCTGGGAAGGGGATTGAGCATGTGCAGCCGATTGGGTGGGAGAGGAAGGATGTTATTTGAGAGTTGGAGCGAAGTCTTTTGCTCTTTTCTTGATCGCGATCGATGGCTCTCGACGACTAGATGAGGGACTTGAAGTCTTAAACTGCGACCAGGACTGCATAGAGATTACTACAGAGAGGCGTTTTGAGGTTTTTGGCGTTGGTTTATAGGTGTGCAAGATGGGTTCGGGCGTTTGTTCTGCTTTT [配列番号1]。
賦形剤はまた、封入材料であろう。粉末剤(powders)として、賦形剤は、本発明による微粉化した活性剤との混合物である微粉固体である。錠剤として、活性剤(例えば、モジュレーター)は、適切な割合で必要な圧縮特性を有する賦形剤と混合し、望ましい形および大きさに圧縮されるであろう。粉末剤(powders)および錠剤は、好ましくは、99%までの活性剤を含む。適切な固体の賦形剤は、例えば、リン酸カルシウム、ステアリン酸マグネシウム、タルク、糖、ラクトース、デキストリン、デンプン、ゼラチン、セルロース、ポリビニルピロリジン、低融点ワックスおよびイオン交換樹脂を含む。他の実施形態として、薬剤の賦形剤は、ゲルでもよく、組成物は、クリームまたは同種のものの形態でもよい。
材料と方法
オルタナティブオキシダーゼ(AOX)タンパク質は、Kido, Y. et al (2010) Biochim. Biophys. Acta 1797, 443−450、およびKido, Y. et al (2010) Acta. Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 66, 275−278にて概説された技術によって精製し、結晶化された。タンパク質の結晶構造は、上記論文にて概説された、蒸気ハンギングドロップ法(vapour hanging−drop technique)を用いて阻害剤の存在下および不在下の両方で得られた。阻害剤結合部位は、結晶構造から確認された。ポケットを囲む残基の分析は、図3で表すL177、E178、L267、A271およびY275がすべての真菌、植物およびトリパノソーマ類の種を横断して100%保存されていることを明らかにした。
本研究の重要な新発見は、図2で示したように、化学量論的阻害剤の存在下および不在下の両方でオルタナティブオキシダーゼ(AOX)タンパク質の初めての結晶構造の決定である。本発明者らは、ポケットが変化しないこと、すなわち阻害剤の存在下または不在下で実質的に同じものであることを発見した。阻害剤の存在下でのAOXの結晶構造の知識は、本発明者らをいくつかの合理的な殺真菌性の分子設計に着手するための非常に強い立場に置き、このことは、下記で議論するように、AOXを特異的に標的とする植物病原性殺真菌剤として振る舞う性質を有するAOX阻害剤化合物のライブラリの作成という結果になっている。
本発明者らは、化合物、図5に示す化学構造である、アスコフラノンを基に、多くのAOX阻害剤を設計しおよび合成している。アスコフラノンは、複雑な合成経路を有しており、反応性の高いアルデヒド基(−CHO)を有する。いくつかのアスコフラノン誘導体は、合成され、すなわちコレトクロリンB(RがCHOである、図5で構造“2”とラベルされたもの)、RがCH2OHである図5に表す化合物“3”、およびRが図5で表す4a−4hの化合物である。
コレトクロリンBの化学構造は、図6に表され、その合成に用いる方法は、図7に表される。
オルシノール(5g、40mmol)およびZn(CN)2(7.1g、60mmol)は、N2下で機械の撹拌機により三口フラスコに入れられる。50mlのエーテルが加えられ、反応は、HClガスで飽和される。2時間後、エーテルは、移され、50mlの水が反応混合物に加えられる。100℃に熱せられ、生成物が分離(crash)される。粗生成物は、ブフナー濾過によって集められ、76%収率でアルデヒド(4.6g)を精製するために水から再結晶される。
オルシノールアルデヒド(Orcinol Aldehyde)(527mg、3.5mmol)は、N2下に置かれ、氷浴上で無水エーテルに溶解される。SO2Cl2(1.35ml、4.7mmol)は、エーテル(15ml)で希釈され、15分かけて滴下される。反応は、夜通し撹拌され、水を加え冷まされる。エーテル層は、0.1M NaHCO3および水で洗浄され、MgSO4によって乾燥され、真空下で濃縮される。粗固体はそこで、75%収率で生成物(459mg)を得るためにフラッシュ・クロマトグラフィー(トルエン:酢酸エチル 2:1 −> 1:1)によって精製される。
3-クロロ-4,6-ジヒドロキシ-2-メチル-ベンズアルデヒド(150mg、0.8mmol)は、10%KOH(0.9ml、0.8mmol)に溶解され、深紅の水溶液を生成する。反応は、氷浴上に置かれ、ゲラニルブロミド(0.39ml、1.6mmol)が加えられる。反応は、夜通し勢いよく撹拌され、エーテルで抽出される。有機層は、真空下で濃縮される前、NaHCO3で洗浄され、塩水につけられる。結果としての油(resultant oil)は、20%収率で純コレトクロリンB(52mg)を得るためにフラッシュクロマトグラフィー(石油エーテル(petrol ether) 40−60:エーテル 10:1 −>3:1)によって精製される。
本発明者らは、阻害剤のベンゼン環のヒドロキシル基および塩素置換基およびメチル置換基が高い力価にとって重要であるとされるが、フラノン部分は、疎水性側鎖、例えばゲラニル基が、コレトクロリンB(2)と同様にして、保持される限り、冗長である。
本発明者らは、E123およびY220の突然変異を起こし、それらが酵素活性および阻害剤結合に重要であることを明らかにした。
pREP1−AOX、pREP1−E123AおよびpREP1−Y220F(分裂酵母(S.pombe)の野生型AOXならびにE123AおよびY220Fの変異を発現するために使用された)の作製は、以前に説明されている[M.S. Albury,C. Affourtit,P.G. Crichton,A.L. Moore, Structure of the plant alternative oxidase − Site−directed mutagenesis provides new information on the active site and membrane topology, J. Biol. Chem. 277 (2002) 1190−1194:M.S. Albury, P. Dudley, F.Z. Watts, A.L. Moore, Targeting the plant alternative oxidase protein to Schizosaccharomyces pombe mitochondria confers cyanide−insensitive respiration, J. Biol. Chem. 271 (1996) 17062−17066.]。AOXの突然変異誘発は、pSLM−AORプラスミド[M.S. Albury, C. Affourtit, P.G. Crichton, A.L. Moore, Structure of the plant alternative oxidase − Site−directed mutagenesis provides new information on the active site and membrane topology, J. Biol. Chem. 277 (2002) 1190−1194]により、製造者の説明に従いクイックチェンジ突然変異誘発キット(Quick Change mutagenesis kit)(ストラタジーン(Stratagene))を用いて実施された。各々の全長(full length)突然変異AOXは、BspHI−BamHIフラグメントから切除され、NcoIおよびBamHIで消化された酵母菌の発現ベクターpREP1/N (NdeI部位をNcoIに置き換えられた改変pREP1[K. Maundrell, Nmt1 of fission yeast − a highly transcribed gene completely repressed by thiamine, J. Biol. Chem. 265 (1990) 10857−10864.])に結合され、pREP1−E123AおよびpREP1−Y220Fを得た。
結果
コレトクロリンBおよびその誘導体は、植物および真菌のオルタナティブオキシダーゼ(AOX)の特異的阻害剤として実施例1〜5にて明らかにされている。この研究に続いて、本発明者らは、これらの化合物がまた、シトクロムbc1複合体の呼吸活性にいかなる影響を与えるのかどうかの試験に着手した。二つのソース(ラットの肝臓およびジャガイモ)のミトコンドリアは、図9にまとめた典型的データに示されるように、コレトクロリンB(CB)で滴定された。ミトコンドリアのソースは共に、いかなるオルタナティブオキシダーゼ(AOX)を含まず、ゆえに測定された呼吸活性は、シトクロムbc1複合体からであったに違いない。
結果
オルタナティブオキシダーゼが不在であるミトコンドリアを使用する注意深い滴定は、驚くべきことに、化合物がAOXを阻害することに加えてシトクロムbc1複合体の特異的阻害剤であることを明らかにした。データは、化合物がシトクロムbc1複合体のQoおよびQi結合部位の両方でシトクロムbc1複合体を阻害し、したがってオルタナティブオキシダーゼの不在下でさえとても強力な呼吸の阻害剤となることを示唆している。かかる発見の意味は、この化合物の誘導体が、オルタナティブオキシダーゼ(AOX)を阻害するだけではなく、シトクロムbc1複合体もまた阻害することで、非常に特異的および強力な二重機能殺真菌剤となるであろうことを示唆している。
したがって、コレトクロリンBは、QoおよびQi結合部位の両方でシトクロムbc1複合体、およびAOXもまた阻害するので、この化合物およびその誘導体は、極めて強力および頑強な阻害剤の機能を果たすことができる。
Claims (5)
- 下記化学式I:
R2は、ヒドロキシ基、または炭素原子数1〜3のアルコキシ基であり;
R3は、少なくとも1つのメチル基で置換された炭素原子数6〜15の分岐したアルカジエニル基であり;
R4は、ヒドロキシ基であり;
R5は、塩素(chlorine group)、臭素(bromine group)、またはフッ素(fluorine group)であり;および、
R6は、メチル基である;
で表される化合物の真菌のオルタナティブオキシダーゼ(AOX)を阻害するための農薬としての使用。 - R2が、ヒドロキシ基である、請求項1に記載の使用。
- R1が、CHO;CN;C(O)NH2;C(O)NHCH3;C(O)CH3;COOH;およびCOOCH3から選択され;並びに
R2が、ヒドロキシ基であり;
R3が、少なくとも1つのメチル基で置換された炭素原子数6〜15の分岐したアルカジエニル基であり;
R4が、ヒドロキシ基であり;
R5が、塩素原子であり;および
R6が、メチル基である、請求項1または2に記載の使用。 - R1が、CHO基ではない、請求項1〜3のいずれかの1項に記載の使用。
- 前記化合物がカララ・フラクシネア(Chalara fraxinea);セプトリア・トリチキ(Septoria tritici);ゴイマノミセス・グラミニス 変種 ティティチ(Gaeumannomyces gramminis var titici);マグナポルテ・グリセア(Magnaporthe grisea);マグナプロテ・オリゼ(Magnaporthe oryzae);リゾクトニア・ソラニ(Rhizoctonia solani);ボトリティス・シネレア(Botrytis cinerea);フシクラジウム・エフサム(Fusicladium effusum)別名フシクラドスポリウム・エフサム(Fusicladosporium effusum);ポドスファエラ・フスカ(Podosphaera fusca);ミクロドキウム・ニヴァレ(Microdochium nivale);ミクロドキウム・マユス(Microdochium majus);セプトリア・ノドウム(Septoria nodoum);タペシア・アクフォルミス(Tapesia acuformis);およびメタリジウム・アニソプリエ(Metarhizium anisopliae)から成る生物の群から選択された生物における真菌のオルタナティブオキシダーゼを阻害する農薬として使用される、請求項1〜4のいずれか1項に記載の使用。
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GB2511470A (en) | 2014-09-10 |
PH12014502383B1 (en) | 2014-12-22 |
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