JP5462494B2 - Cyclic depsipeptide - Google Patents
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Description
本発明は、生理活性物質としての新規な環状デプシペプチドに関するものである。 The present invention relates to a novel cyclic depsipeptide as a physiologically active substance.
近年，医薬品の素材として海洋生物の生産する生理活性物質が注目され、海洋生物由来の新規な環状デプシペプチドの単離が試みられている。また、環状デプシペプチドは、癌に対する薬理作用等の生理活性を有することが知られている（例えば、特許文献１〜３参照）。例えば、海洋軟体生物であるアメフラシ科のタツナミガイ（Dolabella auricularia）から単離された環状デプシペプチドの一つであるオーリライドは非常に強力な細胞毒性を示す（例えば、特許文献４参照）。 In recent years, bioactive substances produced by marine organisms have attracted attention as pharmaceutical materials, and attempts have been made to isolate novel cyclic depsipeptides derived from marine organisms. Moreover, it is known that cyclic depsipeptide has physiological activities, such as a pharmacological action with respect to cancer (for example, refer patent documents 1-3). For example, aurilide, which is one of cyclic depsipeptides isolated from the marine mollusc, Dolabella auricularia, exhibits very strong cytotoxicity (see, for example, Patent Document 4).
また、本発明者らは、制癌剤として有用である新規な環状デプシペプチドの創出につき鋭意検討する中で、頭楯目の海洋肉食性軟体動物であるPhilinopsis speciosaに着目し、Philinopsis speciosaの抽出物の分画を進めたところ、純粋な活性ペプチドの単離に成功し、これをkulokekahilide-2と命名してJ. Nat. Prod.（非特許文献１）に報告した。天然由来のkulokekahilide-2の生理活性について検証したところ、ガン細胞株であるＰ３８８、ＳＫ−ＯＶ−３、ＭＤＡ−ＭＢ−４３５、及びＡ−１０に対してＩＣ５０の値が、それぞれ、4.2、7.5、14.6、及び59.1nMという強い細胞毒性を示すことを発見した。 In addition, the present inventors, while intensively studying the creation of a novel cyclic depsipeptide useful as an anticancer drug, focused on Philinopsis speciosa, a marine carnivorous mollusc, and analyzed the extract of Philinopsis speciosa. As a result, the pure active peptide was successfully isolated and named kulokekahilide-2 and reported to J. Nat. Prod. (Non-patent Document 1). When the physiological activity of naturally derived kulokekahilide-2 was verified, the IC 50 value was 4.2 for cancer cell lines P388, SK-OV-3, MDA-MB-435, and A-10, respectively. It was found to exhibit strong cytotoxicity of 7.5, 14.6, and 59.1 nM.
さらに、この天然由来のkulokekahilide-2について高分解能質量分析および一次元および二次元ＮＭＲスペクトル（ＣＯＳＹ、ＨＭＱＣ、ＨＭＢＣ、ＮＯＥＳＹ）の解析に基づいて構造解析を行った結果、当該ペプチドがＣ４４Ｈ６７Ｎ５Ｏ１０の組成式を有し、alanine（Ａｌａ）、Isoleucine（Ｉｌｅ）、N-methylglycine（ＮＭｅＧｌｙ）、N-methylphenylalanine（ＮＭｅＰｈｅ）、およびalanineの５つのアミノ酸、ならびに、2-hydroxyisocaproic acid（leucic acid 、Ｈｉｃａ）および5,7-dihydroxy-2,6,8-trimethyl-2,8-decadienoic acid（５Ｓ，６Ｓ，７Ｓ-Ｄｔｄａ）の２つのヒドロキシ脂肪酸から構成されている新規な環状デプシペプチドであることを導出し、また、その構成アミノ酸の立体配置についても推定した。 Furthermore, as a result of structural analysis of this naturally-derived kulokekahilide-2 based on high-resolution mass spectrometry and analysis of one-dimensional and two-dimensional NMR spectra (COSY, HMQC, HMBC, NOESY), the peptide was C 44 H 67. N 5 O 10 having the composition formula, alanine (Ala), Isoleucine (Ile), N-methylglycine (NMeGly), N-methylphenylalanine (NMePhe), and alanine five amino acids, and 2-hydroxyisocaproic acid (leucic acid, Hica) and 5,7-dihydroxy-2,6,8-trimethyl-2,8-decadienoic acid (5S, 6S, 7S-Dtda) are novel cyclic depsipeptides composed of two hydroxy fatty acids In addition, the configuration of the constituent amino acids was also estimated.
本発明者らは上述の構造解析の結果に基づいて種々の立体異性体の合成を試みた。そして合成に成功した全ての立体異性体について生理活性を測定し、天然由来のkulokekahilide-2のスペクトルと全く同様なスペクトルを示す化合物（５）を合成異性体の中から見出し、この合成異性体は天然物と同等の細胞毒性を示した（非特許文献２）。 The present inventors tried to synthesize various stereoisomers based on the results of the above structural analysis. The bioactivity of all stereoisomers that were successfully synthesized was measured, and a compound (5) showing a spectrum exactly the same as the spectrum of natural kulokekahilide-2 was found from the synthetic isomers. It showed cytotoxicity equivalent to that of natural products (Non-patent Document 2).
しかし、この（５）に示す構造式で表される化合物は、細胞毒性が強いため、制癌剤等の医薬品に用いた場合に副作用を引き起こす虞がある。本発明者らは上述したkulokekahilide-2の立体異性体の合成を進めたところ、本発明に係る適度な生理活性を有する環状デプシペプチドを見出した。 However, since the compound represented by the structural formula shown in (5) is highly cytotoxic, it may cause side effects when used in pharmaceuticals such as anticancer drugs. The present inventors have proceeded with the synthesis of the above-described stereoisomer of kulokekahilide-2 and found a cyclic depsipeptide having an appropriate physiological activity according to the present invention.
本発明の目的は、医薬品として用いた場合に副作用を回避できる程度の適度な生理活性を有する新規な環状デプシペプチドを提供することである。 An object of the present invention is to provide a novel cyclic depsipeptide having an appropriate physiological activity that can avoid side effects when used as a pharmaceutical.
即ち、本発明に係る環状デプシペプチドによれば、
一般式（１）
General formula (1)
で表される化合物、又はその薬理上許容される塩若しくはエステル誘導体が提供される。（上記一般式（１）中、Ｒ１〜Ｒ１３は、水素原子、または炭素原子数１〜６個の分岐または直鎖のアルキル基を示す。）
また、本発明に係る環状デプシペプチドによれば、
一般式（２）
Moreover, according to the cyclic depsipeptide according to the present invention,
General formula (2)
で表される化合物、又はその薬理上許容される塩若しくはエステル誘導体が提供される。（上記一般式（２）中、Ｒ１〜Ｒ１３は、水素原子、または炭素原子数１〜６個の分岐または直鎖のアルキル基を示す。） Or a pharmacologically acceptable salt or ester derivative thereof. (In the general formula (2), R 1 to R 13 represent a hydrogen atom or a branched or straight chain alkyl group having 1 to 6 carbon atoms.)
本発明の環状デプシペプチドによれば、適度な生理活性を有し、制癌剤等の医薬品に用いた場合に副作用を回避できる。 The cyclic depsipeptide of the present invention has moderate physiological activity and can avoid side effects when used in medicines such as anticancer agents.
以下、本発明の実施の形態に係る環状デプシペプチドについて説明するが、本発明は、以下に述べる実施の形態に限定されるものではない。本実施の形態に係る環状デプシペプチドであるkulokekahilide-7Aの構造を下記式（３）に、kulokekahilide-7Bの構造式を下記式（４）にそれぞれ示す。なお、下記式（３）及び（４）は原子省略法によって記載され、省略された末端はすべてメチル基である。
本実施の形態に係るkulokekahilide-7A及びkulokekahilide-7Bは、Ｄ−アラニン（Ｄ−Ａｌａ）、Ｌ−イソロイシン（Ｌ−Ｉｌｅ）、Ｎ−メチルグリシン（ＮＭｅＧｌｙ）、Ｄ−メチルフェニルアラニン（Ｄ−ＭｅＰｈｅ）、及びＤ−アラニン（Ｄ−Ａｌａ）の５つのアミノ酸、ならびに、２−ヒドロキシイソカプロン酸（Ｄ−ｌｅｕｃｉｃ ａｃｉｄ、Ｈｉｃａ）および５，７−ジヒドロキシー２，６，８−トリメチルー２，８デカジエン酸（５Ｓ，６Ｓ，７Ｓ−Ｄｔｄａ）の２つのヒドロキシ脂肪酸から構成されている環状デプシペプチドである。 Kulokekahilide-7A and kulokekahilide-7B according to the present embodiment include D-alanine (D-Ala), L-isoleucine (L-Ile), N-methylglycine (NMeGly), and D-methylphenylalanine (D-MePhe). And five amino acids of D-alanine (D-Ala), and 2-hydroxyisocaproic acid (D-leucic acid, Hica) and 5,7-dihydroxy-2,6,8-trimethyl-2,8-decadienoic acid It is a cyclic depsipeptide composed of two hydroxy fatty acids (5S, 6S, 7S-Dtda).
また、本実施の形態に係るkulokekahilide-7A及びkulokekahilide-7Bは、Ｐ３８８マウス白血病細胞及びヒト子宮がん由来ＨａＬａ細胞に対して適度な細胞毒性を示す。 Further, kulokekahilide-7A and kulokekahilide-7B according to the present embodiment show moderate cytotoxicity against P388 mouse leukemia cells and human uterine cancer-derived HaLa cells.
本発明の化合物の構造及び生理活性について説明したが、次に本実施の形態に係る環状デプシペプチドの製造方法について説明する。本実施の形態に係るkulokekahilide-7A及びkulokekahilide-7Bは、以下に示す手順により合成される。 Having described the structure and physiological activity of the compound of the present invention, the method for producing the cyclic depsipeptide according to the present embodiment will be described next. Kulokekahilide-7A and kulokekahilide-7B according to the present embodiment are synthesized by the following procedure.
まず、Ｌ−イソロイシン（Ｌ−Ｉｌｅ）のカルボキシル基をトリクロロエチル基（Ｔｃｅ）で保護し、カルボシル基が保護されたＬ−イソロイシン（Ｌ−Ｉｌｅ−Ｔｃｅ）とする。そして、縮合剤を用い、Ｌ−Ｉｌｅ−Ｔｃｅとアミノ基がｔ−ブトキシカルボニル基（Ｂｏｃ）で保護されたＮ−メチルグリシン（Ｂｏｃ−Ｎ−ＭｅＧｌｙ）と反応させ、Ｂｏｃ−ジペプチド（Ｂｏｃ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）を得る。 First, the carboxyl group of L-isoleucine (L-Ile) is protected with a trichloroethyl group (Tce) to obtain L-isoleucine (L-Ile-Tce) in which the carbosyl group is protected. Then, using a condensing agent, L-Ile-Tce is reacted with N-methylglycine (Boc-N-MeGly) in which the amino group is protected with a t-butoxycarbonyl group (Boc), and Boc-dipeptide (Boc-N -MeGly-L-Ile-Tce).
次に、Ｄ−メチルフェニルアラニンのアミノ基をｔ−ブトキシカルボニル基（Ｂｏｃ）で保護したＤ−メチルフェニルアラニン（Ｂｏｃ−Ｄ−ＭｅＰｈｅ）と、Ｂｏｃ−ジペプチドのＮ末端側の保護基Ｂｏｃを除去したジペプチド（Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）とを縮合剤を用いて反応させ、Ｂｏｃ−トリペプチド（Ｂｏｃ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）を得る。 Next, D-methylphenylalanine (Boc-D-MePhe) obtained by protecting the amino group of D-methylphenylalanine with a t-butoxycarbonyl group (Boc), and a dipeptide obtained by removing the protecting group Boc on the N-terminal side of Boc-dipeptide (N-MeGly-L-Ile-Tce) is reacted with a condensing agent to obtain Boc-tripeptide (Boc-D-MePhe-N-MeGly-L-Ile-Tce).
そして、アミノ基をｔ−ブトキシカルボニル基（Ｂｏｃ）で保護したＤ−アラニン（Ｂｏｃ−Ｄ−Ａｌａ）と、Ｂｏｃ−トリペプチドのＮ末端側の保護基Ｂｏｃを除去したトリペプチド（Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）と縮合剤を用いて反応させ、Ｂｏｃ−テトラペプチド（Ｂｏｃ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）を得る。 Then, D-alanine (Boc-D-Ala) in which the amino group is protected with a t-butoxycarbonyl group (Boc) and a tripeptide (D-MePhe-) in which the protecting group Boc on the N-terminal side of the Boc-tripeptide has been removed. N-MeGly-L-Ile-Tce) is reacted with a condensing agent to obtain Boc-tetrapeptide (Boc-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce).
そして、後述する方法により合成されるＤ−２−ヒドロキシイソカプロン酸（Ｄ−Ｈｉｃａ）とＢｏｃ−テトラペプチドのＮ末端側の保護基Ｂｏｃを除去したテトラペプチド（Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）とを縮合剤を用いて反応させ、ペンタペプチド（Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）を得る。 Then, D-2-hydroxyisocaproic acid (D-Hica) synthesized by the method described later and tetrapeptide (D-Ala-D-MePhe-N) from which the protecting group Boc on the N-terminal side of Boc-tetrapeptide has been removed. -MeGly-L-Ile-Tce) is reacted with a condensing agent to obtain a pentapeptide (D-Hica-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce).
そして、後述する合成方法により得られる５，７−ジヒドロキシー２，６，８−トリメチルー２，８デカジエン酸（５Ｓ，６Ｓ，７Ｓ−Ｄｔｄａ）の５位をメチルチオメチル基（ＭＴＭ）、７位をｔ−ブチルジメチルシリル基（ＴＢＳ）で保護し、ペンタペプチドと縮合剤を用いて反応させ、デプシヘキサペプチド（５Ｓ，６Ｓ，７Ｓ，５−Ｏ−ＭＴＭ−７−Ｏ−ＴＢＳ−Ｄｔｄａ−Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）を得る。 The 5-position of 5,7-dihydroxy-2,6,8-trimethyl-2,8-decadienoic acid (5S, 6S, 7S-Dtda) obtained by the synthesis method described later is the methylthiomethyl group (MTM) and the 7-position is Protected with t-butyldimethylsilyl group (TBS), reacted with pentapeptide with a condensing agent, and depsihexapeptide (5S, 6S, 7S, 5-O-MTM-7-O-TBS-Dtda-D -Hica-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce).
最後に、Ｄ−アラニンのアミノ基を９−フルオレニルメトキシカルボニル基（Ｆｍｏｃ）で保護したＦｍｏｃ−Ｄ−アラニンと、ＴＢＳ基を除去したデプシヘキサペプチド（５Ｓ，６Ｓ，７Ｓ，５−Ｏ−ＭＴＭ−Ｄｔｄａ−Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）とを縮合剤を用いて反応させ、デプシヘプタペプチド（ Ｆｍｏｃ−Ｄ−Ａｌａ−（５Ｓ，６Ｓ，７Ｓ）−５−Ｏ−ＭＴＭ−Ｄｔｄａ−Ｄ−Ｈｉｃａ−Ｌ−Ａｌａ−Ｄ−Ｍｅ−Ｐｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）を得る。 Finally, Fmoc-D-alanine in which the amino group of D-alanine is protected with 9-fluorenylmethoxycarbonyl group (Fmoc), and depsihexapeptide (5S, 6S, 7S, 5-O from which the TBS group has been removed) -MTM-Dtda-D-Hica-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce) using a condensing agent to react with depsiheptapeptide (Fmoc-D-Ala- (5S , 6S, 7S) -5-O-MTM-Dtda-D-Hica-L-Ala-D-Me-Phe-N-MeGly-L-Ile-Tce).
そして、デプシヘプタペプチドのＦｍｏｃ基を除去し、縮合剤（ＥＤＣｌ・ＨＣｌ）を用いて環化させ、MTM基を除去後kulokakahalide-7A及び7Bを得る。 Then, the Fmoc group of the depsiheptapeptide is removed and cyclized using a condensing agent (EDCl · HCl), and kulokakahalide-7A and 7B are obtained after removing the MTM group.
上述の実施の形態において縮合剤として、１−エチルー３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣｌ・ＨＣｌ）、ヘキサフルオロリン酸２−（１Ｈ−ベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム（ＨＢＴＵ）、ベンゾトリアゾール−１−イルオキシ−トリスジメチルアミノホスホニウム塩（Ｂｏｐ）及びＢｏｐ誘導体のホスホニウム塩等を用いることができる。 In the above embodiment, as the condensing agent, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl · HCl), hexafluorophosphoric acid 2- (1H-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium (HBTU), benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (Bop), a phosphonium salt of a Bop derivative, and the like can be used.
また、上述の実施の形態において添加剤を用いることもでき、添加剤としてジメチルアミノピリジン（ＤＭＡＰ）、ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、１−ヒドロキシ−７−アザベンゾトリアゾール（ＨＯＡｔ）を用いることができる。 In the above-described embodiment, an additive can also be used, and dimethylaminopyridine (DMAP), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) can be used as the additive. .
また、上述の実施の形態において、縮合反応に用いる溶媒として、無水または含水のクロロホルム、ジクロロメタン、酢酸エチル、ピリジン、ジオキサン、ジメチルホルムアミド（ＤＭＦ）、テトラヒドロフラン（ＴＨＦ）、ジメトキシエタン、アセトニトリル等が挙げられ、そして必要に応じてこれらの溶媒の２種以上を混合して用いることができる。 In the above-described embodiment, examples of the solvent used in the condensation reaction include anhydrous or hydrous chloroform, dichloromethane, ethyl acetate, pyridine, dioxane, dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane, and acetonitrile. If necessary, two or more of these solvents can be mixed and used.
ここで、上述のkulokekahilide-7A及び7Bの合成に用いられるＤ−Ｈｉｃａ及び５Ｓ，６Ｓ，７Ｓ−Ｄｔｄａの合成方法について説明する。 Here, a method for synthesizing D-Hica and 5S, 6S, 7S-Dtda used for synthesizing the above-described kulokekahilide-7A and 7B will be described.
Ｄ−Ｈｉｃａは、市販のＬ−２−ヒドロキシイソカプロン酸（Ｌ−Ｈｉｃａ）のカルボキシル基をメチルエステル化し、安息香酸を用いた光延反応により水酸基が結合している炭素の立体配置を反転させ、アルカリを用いて加水分解を行うことにより得られる。 D-Hica methylates the carboxyl group of commercially available L-2-hydroxyisocaproic acid (L-Hica), reverses the configuration of the carbon to which the hydroxyl group is bonded by Mitsunobu reaction using benzoic acid, It is obtained by carrying out hydrolysis using an alkali.
次に、５Ｓ，６Ｓ，７Ｓ−Ｄｔｄａの合成方法について説明する。市販の（Ｓ）−（＋）−４−イソプロピルー３プロピオニル−２−オキサゾリジノンを出発物質に用いてアンチ選択的アルドール縮合を行い、Ｄｔｄａの６〜１０位に相当する炭素骨格を有する化合物が得られる。この化合物をアルデヒドに変換し、向山アルドール反応を行うと５位の水酸基の立体がＲ体である化合物が得られる。この５位の水酸基の立体をＳ体に反転させ、メチルチオメチル基で保護し、加水分解することにより５Ｓ，６Ｓ，７Ｓ−Ｄｔｄａが得られる。 Next, a method for synthesizing 5S, 6S, and 7S-Dtda will be described. Anti-selective aldol condensation is performed using commercially available (S)-(+)-4-isopropyl-3-propionyl-2-oxazolidinone as a starting material, and a compound having a carbon skeleton corresponding to positions 6 to 10 of Dtda is obtained. It is done. When this compound is converted into an aldehyde and subjected to the Mukaiyama aldol reaction, a compound in which the stereo of the hydroxyl group at the 5-position is an R form is obtained. The 5D hydroxyl group is inverted to the S form, protected with a methylthiomethyl group, and hydrolyzed to give 5S, 6S, 7S-Dtda.
なお、本実施の形態において、上記の式（３）または（４）に示した構造式によって表される化合物について説明したが、式（３）または（４）で表される化合物の他、当該化合物の薬理上許容される塩若しくはエステル誘導体であってもよい。薬理上許容される塩とは、常法に従って式（３）または（４）に示した構造式によって表される化合物を酸または塩基で処理することにより得られる塩であって、著しい毒性を有さず、医薬として使用され得る塩をいう。このような酸付加塩の例としては、塩酸、臭化水素酸、硫酸、リン酸等の無機酸、マレイン酸、フマル酸、酒石酸、クエン酸等の有機酸等による付加塩があげられ、塩基による塩としては、水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物、水酸化カルシウム、水酸化マグネシウム等のアルカリ土類金属水酸化物、グアニジン、トリエチルアミン、ジシクロヘキシルアミン等の有機塩基による塩が挙げられる。 Note that in this embodiment, the compound represented by the structural formula shown in the above formula (3) or (4) has been described. In addition to the compound represented by the formula (3) or (4), It may be a pharmacologically acceptable salt or ester derivative of the compound. A pharmacologically acceptable salt is a salt obtained by treating a compound represented by the structural formula represented by formula (3) or (4) with an acid or base according to a conventional method, and has extremely toxic properties. A salt that can be used as a medicine. Examples of such acid addition salts include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and organic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, and the like. Examples of salts based on alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and salts based on organic bases such as guanidine, triethylamine and dicyclohexylamine. Can be mentioned.
また、薬理上許容されるエステル誘導体とは、例えば上述の実施の形態において、式（３）または（４）に示した構造式によって表される化合物の水酸基が保護されたエステル誘導体をいう。本実施の形態においては、式（３）または（４）で示した化合物の水酸基中の水素原子をアシル基で置換することによってエステル誘導体を形成することができる。 In addition, the pharmacologically acceptable ester derivative refers to an ester derivative in which the hydroxyl group of the compound represented by the structural formula represented by formula (3) or (4) is protected in the above-described embodiment. In the present embodiment, an ester derivative can be formed by substituting a hydrogen atom in the hydroxyl group of the compound represented by formula (3) or (4) with an acyl group.
次に本実施の形態に係る環状デプシペプチドの実施の形態ついて、実施例を用いてより具体的に説明を行う。kulokekahilide-7A及び7Bは、以下の手順により得られる。 Next, the embodiment of the cyclic depsipeptide according to the present embodiment will be described more specifically using examples. kulokekahilide-7A and 7B are obtained by the following procedure.
（１）ジペプチド（Ｂｏｃ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）
Ｂｏｃ−Ｌ−Ｉｌｅ（１．３９ｇ、６．０ｍｍｏｌ）のＣＨ２Ｃｌ２（１６．０ｍＬ）に溶液に、トリクロロエタノール（ＴｃｅＯＨ、０．６９ｍＬ、７．２ｍｍｏｌ）、ＤＭＡＰ（７３ｍｇ、０．６ｍｍｏｌ）、縮合剤にＥＤＣＩ・ＨＣｌ（１．３８ｇ、７．２ｍｍｏｌ）を加え、Ｂｏｃ−Ｌ−Ｉｌｅ−ＯＴｃｅを得た。これに４Ｍ塩酸ジオキサン溶液（１２ｍＬ）で処理し、Ｌ−Ｉｌｅ−ＯＴｃｅ・ＨＣｌとした。この塩酸塩をＣＨ２Ｃｌ２−ジメチルホルムアミド（ＤＭＦ）（１：１、２４ｍＬ）に溶解し、トリエチルアミン（Ｅｔ３Ｎ、０．８４ｍＬ、６．０ｍｍｏｌ）、Ｂｏｃ−ＮＭｅＧｌｙ（１．３６ｇ、７．２ｍｍｏｌ)、ＨＯＢｔ（９７３ｍｇ、７．２ｍｍｏｌ）、そしてＥＤＣＩ・ＨＣｌ（１．３８ｇ、７．２．０ｍｍｏｌ）を加え、縮合し、Ｂｏｃ−ジペプチド（２．３６ｇ、５．４５ｍｍｏｌ、９１％）を得た。
(1) Dipeptide (Boc-N-MeGly-L-Ile-Tce)
To a solution of Boc-L-Ile (1.39 g, 6.0 mmol) in CH 2 Cl 2 (16.0 mL), trichloroethanol (TceOH, 0.69 mL, 7.2 mmol), DMAP (73 mg, 0.6 mmol). EDCI · HCl (1.38 g, 7.2 mmol) was added to the condensing agent to obtain Boc-L-Ile-OTce. This was treated with a 4M hydrochloric acid dioxane solution (12 mL) to give L-Ile-OTce · HCl. This hydrochloride salt was dissolved in CH 2 Cl 2 -dimethylformamide (DMF) (1: 1, 24 mL), triethylamine (Et 3 N, 0.84 mL, 6.0 mmol), Boc-NMeGly (1.36 g, 7. 2 mmol), HOBt (973 mg, 7.2 mmol), and EDCI.HCl (1.38 g, 7.2.0 mmol) were added and condensed to give Boc-dipeptide (2.36 g, 5.45 mmol, 91%). It was.
（２）トリペプチド（Ｂｏｃ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）
Ｂｏｃ−ジペプチド（３．７１ｇ、８．５６ｍｍｏｌ）を、４Ｍ塩酸−ジオキサン溶液（２０ｍＬ）で処理し、ジペプチド塩酸塩を得た。この塩酸塩（６４４ｍｇ、１．７４ｍｍｏｌ）のＣＨ２Ｃｌ２−ＤＭＦ（１：１、６ｍＬ）溶液に、ジイソプロピルエチルアミン（ｉＰｒ２Ｎｅｔ、０．９４ｍＬ、５．２２ｍｍｏｌ）及びＢｏｃ−Ｄ−ＮＭｅＰｈｅ（５４２ｍｇ、１．９４ｍｍｏｌ)を加え、ＨＢＴＵ（７９２ｍｇ、２．０９ｍｍｏｌ）を用いて縮合し、Ｂｏｃ−トリペプチド（８８２ｍｇ、１．４８ｍｍｏｌ、８５％）を得た。
(2) Tripeptide (Boc-D-MePhe-N-MeGly-L-Ile-Tce)
Boc-dipeptide (3.71 g, 8.56 mmol) was treated with 4M hydrochloric acid-dioxane solution (20 mL) to obtain dipeptide hydrochloride. To a solution of this hydrochloride (644 mg, 1.74 mmol) in CH 2 Cl 2 -DMF (1: 1, 6 mL) was added diisopropylethylamine (iPr 2 Net, 0.94 mL, 5.22 mmol) and Boc-D-NMePhe (542 mg). 1.94 mmol) was added and condensed with HBTU (792 mg, 2.09 mmol) to give Boc-tripeptide (882 mg, 1.48 mmol, 85%).
（３）テトラペプチド（Ｂｏｃ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）
Ｂｏｃ−トリペプチド（２．２３ｇ、２．７６ｍｍｏｌ）を、４Ｍ塩酸−ジオキサン溶液（７．０ｍＬ）で処理し、トリペプチド塩酸塩を得た。この塩酸塩（２．０２ｇ、３．７６ｍｍｏｌ）のＣＨ２Ｃｌ２−ＤＭＦ（１：１、１５．０ｍＬ）溶液に、Ｅｔ３Ｎ（０．５２ｍＬ、３．７６ｍｍｏｌ）、ｉＰｒ２ＮＥｔ（１．３３ｍＬ、７．５１ｍｍｏｌ）、Ｂｏｃ−Ｄ−Ａｌａ（８５３ｍｇ、４．５１ｍｍｏｌ）及びＰｙＢＯＰ（登録商標）（(Benzotriazol-1-yloxy）tripyrrolidinophosphonium hexafluorophospate 、２．３５ｇ、４．５１ｍｍｏｌ）を加え縮合し、Ｂｏｃ−テトラペプチド（１．４３ｇ、２．１０ｍｍｏｌ、５６％）を得た。
(3) Tetrapeptide (Boc-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce)
Boc-tripeptide (2.23 g, 2.76 mmol) was treated with 4M hydrochloric acid-dioxane solution (7.0 mL) to obtain tripeptide hydrochloride. To a solution of this hydrochloride (2.02 g, 3.76 mmol) in CH 2 Cl 2 -DMF (1: 1, 15.0 mL), Et 3 N (0.52 mL, 3.76 mmol), iPr 2 NEt (1. 33 mL, 7.51 mmol), Boc-D-Ala (853 mg, 4.51 mmol) and PyBOP (registered trademark) ((Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophospate, 2.35 g, 4.51 mmol) were added and condensed. -The tetrapeptide (1.43 g, 2.10 mmol, 56%) was obtained.
（４）ペンタペプチド（Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ）
Ｂｏｃ−テトラペプチド（１．３３ｇ、１．９５ｍｍｏｌ）を、４Ｍ塩酸−ジオキサン溶液（４．０ｍＬ）で処理し、トリペプチド塩酸塩を得た。この塩酸塩（１．１８g、１．９５ｍｍｏｌ）のＣＨ２Ｃｌ２−ＤＭＦ（１：１、８．０ｍＬ）溶液に、Ｅｔ３Ｎ（０．２７ｍＬ、１．９５ｍｍｏｌ）、Ｄ−Ｈｉｃａ（３２３ｍｇ、２．３４ｍｍｏｌ)、ＨＯＢｔ（２７８ｍｇ、１．９５ｍｍｏｌ）、ＥＤＣＩ・ＨＣｌ（７８５ｍｇ、３．９０ｍｍｏｌ）を加え縮合し、ペンタペプチド（１．４３ｇ、２．１０ｍｍｏｌ、５６％）を得た。
(4) Pentapeptide (D-Hica-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce)
Boc-tetrapeptide (1.33 g, 1.95 mmol) was treated with 4M hydrochloric acid-dioxane solution (4.0 mL) to obtain tripeptide hydrochloride. To a solution of this hydrochloride (1.18 g, 1.95 mmol) in CH 2 Cl 2 -DMF (1: 1, 8.0 mL), Et 3 N (0.27 mL, 1.95 mmol), D-Hica (323 mg, 2.34 mmol), HOBt (278 mg, 1.95 mmol) and EDCI.HCl (785 mg, 3.90 mmol) were added and condensed to obtain a pentapeptide (1.43 g, 2.10 mmol, 56%).
（５）デプシヘキサペプチド（５Ｓ，６Ｓ，７Ｓ−５−Ｏ−ＭＴＭ−７−Ｏ−ＴＢＳ−Ｄｔｄａ−Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ)
ペンタペプチド（４６３ｍｇ、０．６８ｍｍｏｌ）のＣＨ２Ｃｌ２（３．０ｍＬ）溶液に、５位をメチルチオメチル基（ＭＴＭ）、７位をｔ−ブチルジメチルシリル基（ＴＢＳ）で保護したジヒドロキシ酸（５Ｓ，６Ｓ，７Ｓ−５−Ｏ−ＭＴＭ−７−Ｏ−ＴＢＳ−Ｄｔｄａ、２３６ｍｇ、０．５７ｍｍｏｌ）、ＤＭＡＰ（６９．３ｍｇ、０．５７ｍｍｏｌ)、ＥＤＣＩ・ＨＣｌ（２１７ｍｇ、１．１３ｍｍｏｌ）を加え縮合し、デプシヘキサペプチド（４５６ｍｇ、０．４２ｍｍｏｌ、７５％）を得た。
(5) Depsihexapeptide (5S, 6S, 7S-5-O-MTM-7-O-TBS-Dtda-D-Hica-D-Ala-D-MePhe-N-MeGly-L-Ile-Tce)
Dihydroxy acid in which pentapeptide (463 mg, 0.68 mmol) in CH 2 Cl 2 (3.0 mL) was protected with methylthiomethyl group (MTM) at position 5 and t-butyldimethylsilyl group (TBS) at position 7 5S, 6S, 7S-5-O-MTM-7-O-TBS-Dtda, 236 mg, 0.57 mmol), DMAP (69.3 mg, 0.57 mmol), EDCI.HCl (217 mg, 1.13 mmol) were added. Condensation gave depsihexapeptide (456 mg, 0.42 mmol, 75%).
（６）デプシヘプタペプチド［Ｆｍｏｃ−Ｄ−Ａｌａ−（５Ｓ，６Ｓ，７Ｓ）−５−Ｏ−ＭＴＭ−７−Ｏ−ＴＢＳ−Ｄｔｄａ−Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−Ｔｃｅ］
デプシヘキサペプチド（４３７ｍｇ、０．６８ｍｍｏｌ）をフッ化水素−ピリジン塩（１．５３ｇ）のピリジン−テトラヒドロフラン（ＴＨＦ）（１：４、７．８ｍＬ）混合溶液（９．０ｍＬ）に溶かし、５５℃で反応させ、７位のＴＢＳ基を除去した（３４６ｍｇ、０．３６ｍｍｏｌ、８８％）。このアルコール（３３１ｍｇ、０．３４ｍｍｏｌ）のＣＨ２Ｃｌ２（１．４ｍＬ）溶液に、Ｆｍｏｃ−Ｄ−Ａｌａ（２１４ｍｇ、０．６９ｍｍｏｌ）、ＤＭＡＰ（４１．９ｍｇ、０．３４ｍｍｏｌ）およびＥＤＣＩ・ＨＣｌ（２６４ｍｇ、１．３７ｍｍｏｌ）を加え、縮合し、デプシヘプタペプチド（４０５ｍｇ、０．３２ｍｍｏｌ、９４％）を得た。
(6) Depsiheptapeptide [Fmoc-D-Ala- (5S, 6S, 7S) -5-O-MTM-7-O-TBS-Dtda-D-Hica-D-Ala-D-MePhe-N- MeGly-L-Ile-Tce]
Depsihexapeptide (437 mg, 0.68 mmol) was dissolved in a mixed solution (9.0 mL) of hydrogen fluoride-pyridine salt (1.53 g) in pyridine-tetrahydrofuran (THF) (1: 4, 7.8 mL). The reaction was carried out at 0 ° C. to remove the 7-position TBS group (346 mg, 0.36 mmol, 88%). To a solution of this alcohol (331 mg, 0.34 mmol) in CH 2 Cl 2 (1.4 mL), Fmoc-D-Ala (214 mg, 0.69 mmol), DMAP (41.9 mg, 0.34 mmol) and EDCI · HCl ( 264 mg, 1.37 mmol) was added and condensed to give depsiheptapeptide (405 mg, 0.32 mmol, 94%).
（７）環化前駆体［Ｈ２Ｎ−Ｄ−Ａｌａ−（５Ｓ，６Ｓ，７Ｓ）−５−Ｏ−ＭＴＭ−７−Ｏ−ＴＢＳ−Ｄｔｄａ−Ｄ−Ｈｉｃａ−Ｄ−Ａｌａ−Ｄ−ＭｅＰｈｅ−Ｎ−ＭｅＧｌｙ−Ｌ−Ｉｌｅ−ＣＯＯＨ］
デプシヘプタペプチド（３８０ｍｇ、０．３０ｍｍｏｌ）のＴＨＦ（１２．１ｍＬ）溶液に、１Ｍ酢酸アンモニウム（２．０ｍＬ）、および亜鉛粉末（１．３９ｍｇ、２１．２ｍｍｏｌ）を加え、Ｃ−末端側のＴｃｅ基を脱離し、遊離カルボン酸（３１４ｍｇ、０．２８ｍｍｏｌ、９２％）とし、このカルボン酸（２８４ｍｇ、０．２５ｍｍｏｌ）のアセトニトリル（１２．６ｍＬ）溶液に、ジエチルアミン（１．３ｍＬ）を加え、Ｎ−末端側のＦｍｏｃ基を除去し、環化前駆体（２０３ｍｇ、０．２１ｍｍｏｌ、８９％）を得た。
(7) the cyclization precursor [H 2 N-D-Ala- (5S, 6S, 7S) -5-O-MTM-7-O-TBS-Dtda-D-Hica-D-Ala-D-MePhe- N-MeGly-L-Ile-COOH]
To a solution of depsiheptapeptide (380 mg, 0.30 mmol) in THF (12.1 mL), 1M ammonium acetate (2.0 mL) and zinc powder (1.39 mg, 21.2 mmol) were added, and C-terminal side The Tce group was eliminated to give a free carboxylic acid (314 mg, 0.28 mmol, 92%), and diethylamine (1.3 mL) was added to a solution of this carboxylic acid (284 mg, 0.25 mmol) in acetonitrile (12.6 mL). The Fmoc group on the N-terminal side was removed to obtain a cyclization precursor (203 mg, 0.21 mmol, 89%).
（８）環状化合物
環化前駆体（１９０ｍｇ、０．２１ｍｍｏｌ）のＣＨ２Ｃｌ２−ＤＭＦ（１０：１、２０９ｍＬ）混合溶液に、１−ヒドロキシ−７−アザベンゾトリアゾール（ＨＯＡｔ、５７０ｍｇ、４．１９ｍｍｏｌ）、ＥＤＣＩ・ＨＣｌ（８０４ｍｇ、４．１９ｍｍｏｌ)を加え、マクロラクタム化させ、環状化合物（１５２ｍｇ、０．１７ｍｍｏｌ、８２％）を得た。この環状化合物（１２８ｍｇ、０．１４５ｍｍｏｌ）のＴＨＦ−水（４：１、５．０ｍＬ）混合溶液に、２，６−ルチジン（０．３３７ｍＬ、２．８９ｍｍｏｌ）および硝酸銀（９８２ｍｇ、５．７８ｍｍｏｌ）を加え、６５℃で反応させ、ジヒドロキシ酸のＭＴＭ保護基を除去し、kulokekahilide-7A及び7Bの混合物（１０９ｍｇ、０．１３１ｍｍｏｌ、９１％）を得た。
(8) To a mixed solution of a cyclic compound cyclization precursor (190 mg, 0.21 mmol) in CH 2 Cl 2 -DMF (10: 1, 209 mL), 1-hydroxy-7-azabenzotriazole (HOAt, 570 mg, 4. 19 mmol) and EDCI.HCl (804 mg, 4.19 mmol) were added to effect macrolactamization to obtain a cyclic compound (152 mg, 0.17 mmol, 82%). To a mixed solution of this cyclic compound (128 mg, 0.145 mmol) in THF-water (4: 1, 5.0 mL), 2,6-lutidine (0.337 mL, 2.89 mmol) and silver nitrate (982 mg, 5.78 mmol) were added. And reacted at 65 ° C. to remove the MTM protecting group of dihydroxy acid to obtain a mixture of kulokekahilide-7A and 7B (109 mg, 0.131 mmol, 91%).
（９）kulokekahilide-7A及び7Bの単離
ＨＰＬＣ（Cosmosil 5C18-MS, 250×10mm、溶媒：50%アセトニトリル水、flow rate：２．５ｍＬ／ｍｉｎ、検出波長：２２０ｎｍ）を用いてkulokekahilide-7A（保持時間９１分）及び7B (保持時間１３３分)を単離し、kulokekahilide7A及び7Bをおよそ３：１の割合で得た。
(9) kulokekahilide-7A and 7B were isolated using kulokekahilide-7A (Cosmosil 5C18-MS, 250 × 10 mm, solvent: 50% acetonitrile water, flow rate: 2.5 mL / min, detection wavelength: 220 nm). Retention time 91 minutes) and 7B (retention time 133 minutes) were isolated to obtain kulokekahilide 7A and 7B in a ratio of approximately 3: 1.
上述した手順で合成したkulokekahilide-7Aの物理化学的性質を下記の表１に、kulokekahilide-7Bの物理化学的性質を下記の表２にそれぞれ示す。
（生理活性測定）
上述した手順で合成したkulokekahilide-7A及び7Bについて下記に示す条件の下、生理活性測定を行った。あわせて、比較例として、kulokekahilide-2、抗癌作用を示す抗生物質として既知のアドリアマイシン（ＡＤＭ）についても同様の条件下で生理活性測定を行った。ガン細胞株として、ヒト子宮がん由来ＨｅＬａ細胞、およびＰ３８８マウス白血病細胞を選択し、これらの細胞株のそれぞれについて、上記化合物をサンプルとして下記の条件で細胞毒性（ＩＣ５０）を測定した。なお、ＩＣ５０値は、サンプルを加えていないコントロールの吸収値から各サンプル投与群の吸収値を差し引き、これをコントロールの吸収値で割り、１００をかけて細胞増殖阻害率（％）としたうえで、各濃度での細胞増殖阻害率（％）を片対数グラフにプロットし、５０％阻害を与える濃度を算出することにより求めた。
(Physiological activity measurement)
Bioactivity was measured under the conditions shown below for kulokekahilide-7A and 7B synthesized by the procedure described above. In addition, as a comparative example, physiological activity was measured under the same conditions for kulokekahilide-2 and adriamycin (ADM), which is known as an antibiotic having anticancer activity. Human uterine cancer-derived HeLa cells and P388 mouse leukemia cells were selected as cancer cell lines, and the cytotoxicity (IC 50 ) of each of these cell lines was measured under the following conditions using the above compound as a sample. The IC 50 value is obtained by subtracting the absorption value of each sample administration group from the absorption value of the control to which no sample was added, dividing this by the absorption value of the control, and multiplying by 100 to obtain the cell growth inhibition rate (%). Thus, the cell growth inhibition rate (%) at each concentration was plotted on a semi-logarithmic graph, and the concentration giving 50% inhibition was calculated.
（Ｈｅｌａ細胞）
ヒト子宮がん由来ＨｅＬａ細胞は、２μｇ／ｍＬのゲンタマイシン、１０％ウシ胎児血清、１０μｇ／ｍＬの抗生物質を添加し、１ＭＨＣｌでｐＨ７．０−７．４に調節したＭＥＭ培地（ＧｉｂｃｏＢＲＬ）中で、３７℃、５％の二酸化炭素存在下で培養を行った。９６穴マクロプレートの各ウェルに細胞を含む２００μＬ（１０００細胞／ｍＬ）の培地を加えて２４時間培養を行った後に、各濃度のサンプル溶液２μＬを添加して９６時間培養を行った。５０μＬの3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2Htetrazolium bromide（ＭＴＴ） 生理食塩水溶液（１ｍｇ／ｍＬ）を各ウェルに加え３時間培養を続けた。上清を除去後、生じた沈殿にジメチルスルホキシド（ＤＭＳＯ）を加えて溶解し５１０ｎｍの吸収を測定した。
(Hela cells)
Human uterine cancer-derived HeLa cells were added in 2 μg / mL gentamicin, 10% fetal bovine serum, 10 μg / mL antibiotics, and adjusted to pH 7.0-7.4 with 1M HCl (GibcoBRL). The culture was performed at 37 ° C. in the presence of 5% carbon dioxide. After adding 200 μL (1000 cells / mL) medium containing cells to each well of a 96-well macroplate and culturing for 24 hours, 2 μL of each concentration of the sample solution was added and culturing was performed for 96 hours. 50 μL of 3- (4,5-dimethyl-2-thiazoyl) -2,5-diphenyl-2Htetrazolium bromide (MTT) physiological saline solution (1 mg / mL) was added to each well and the culture was continued for 3 hours. After removing the supernatant, dimethyl sulfoxide (DMSO) was added to the resulting precipitate and dissolved, and the absorbance at 510 nm was measured.
（Ｐ−３８８細胞）
Ｐ３８８マウス白血病細胞（ＪＣＲＢ１７）は、１００μｇ／ｍＬのカナマイシン、１０％ウシ胎児血清、１０μＭの２−ヒドロキシエチルジスルフィドを添加したＲＰＭＩ１６４０培地（ニッスイ）中で、３７℃、５％の二酸化炭素存在下で培養を行った。９６穴マクロプレートの各ウェルに１００μＬの細胞懸濁液（１×１０４細胞／ｍＬ）と１００μＬのサンプルを含む培地を加え、９６時間培養を行った。５０μＬの3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2Htetrazolium bromide（ＭＴＴ）生理食塩水溶液（１ｍｇ／ｍＬ）を各ウェルに加え３時間培養を続けた。上清を除去後、生じた沈殿にＤＭＳＯを加えて溶解し５１０ｎｍの吸収を測定した。
(P-388 cells)
P388 mouse leukemia cells (JCRB17) were cultured in RPMI 1640 medium (Nissui) supplemented with 100 μg / mL kanamycin, 10% fetal calf serum, 10 μM 2-hydroxyethyl disulfide at 37 ° C. in the presence of 5% carbon dioxide. Culture was performed. A medium containing 100 μL of the cell suspension (1 × 10 4 cells / mL) and 100 μL of the sample was added to each well of the 96-well macroplate and cultured for 96 hours. 50 μL of 3- (4,5-dimethyl-2-thiazoyl) -2,5-diphenyl-2Htetrazolium bromide (MTT) physiological saline solution (1 mg / mL) was added to each well and the culture was continued for 3 hours. After removing the supernatant, DMSO was added to the resulting precipitate to dissolve it, and the absorbance at 510 nm was measured.
以上、説明した条件で行った生理活性測定の結果を下記表３に示す。なお、下記表３において、Ｋ−７Ａはkulokekahilide-7Aを、Ｋ−７Ｂはkulokekahilide-7Bを、Ｋ−２はkulokekahilide-2を、ＡＤＭはアドリアマイシンを示すものとする。
上述した結果より、本実施例に係るkulokekahilide-7A及び7Bは、Ｐ３８８マウス白血病細胞及びヒト子宮がん由来ＨａＬａ細胞に対して、kulokekahilide-2及びこれらの２細胞に対して抗癌作用を示すアドリアマイシンよりも細胞毒性としては弱いが、適度な細胞毒性を示すことがわかった。 From the results described above, kulokekahilide-7A and 7B according to the present Example show that adriamycin exhibits anticancer activity against kulokekahilide-2 and these two cells against P388 mouse leukemia cells and human uterine cancer-derived HaLa cells. However, it was found to show moderate cytotoxicity.
本発明に係る環状デプシペプチドによれば、適度な生理活性を有し、制癌剤等の医薬品として用いた場合に副作用を回避することができる。 The cyclic depsipeptide according to the present invention has an appropriate physiological activity and can avoid side effects when used as a pharmaceutical agent such as an anticancer drug.
Claims (2)
（上記一般式（１）中、Ｒ１〜Ｒ１３は、水素原子、または炭素原子数１〜６個の分岐または直鎖のアルキル基を示す。） General formula (1)
(In the general formula (1), R 1 to R 13 represent a hydrogen atom or a branched or straight chain alkyl group having 1 to 6 carbon atoms.)
（上記一般式（２）中、Ｒ１〜Ｒ１３は、水素原子、または炭素原子数１〜６個の分岐または直鎖のアルキル基を示す。） General formula (2)
(In the general formula (2), R 1 to R 13 represent a hydrogen atom or a branched or straight chain alkyl group having 1 to 6 carbon atoms.)
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