JP2022147840A - Phenyl furocoumarin derivative or salt thereof, agent for inhibiting functions of abc transporter, and pharmaceutical for enhancing antitumor effect of anticancer drug - Google Patents
Phenyl furocoumarin derivative or salt thereof, agent for inhibiting functions of abc transporter, and pharmaceutical for enhancing antitumor effect of anticancer drug Download PDFInfo
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Abstract
Description
特許法第30条第2項適用申請有り 発行日 2020年3月25日 刊行物 国立大学法人東北大学 博士学位論文Application for application of Article 30,
本発明は、フェニルフロクマリン誘導体又はその塩、ABCトランスポーターの機能抑制剤及び抗癌剤の抗腫瘍効果を増強するための医薬に関する。 TECHNICAL FIELD The present invention relates to a phenylfurocoumarin derivative or a salt thereof, a medicament for enhancing the antitumor effect of an ABC transporter function inhibitor, and an anticancer agent.
化学療法は癌の治療における選択肢のひとつであるが、癌細胞に抗癌剤耐性が生じることがあり、しばしば臨床の場面で問題となる。抗癌剤耐性のメカニズムのひとつに癌細胞におけるABC(ATP binding cassettes; ATP結合カセット)トランスポーターの過剰発現が挙げられる。ABCトランスポーターはATPをエネルギーとしで抗癌剤を細胞内から細胞外へ排出する膜輸送タンパクである(非特許文献1~3)。特にABCG2はABCBlやABCC1と同様に、抗癌測の多剤耐性に関し代表的なものである。ABCG2の排出機能を抑制できれば抗癌剤耐性の克服が可能となることが考えられるが、これまでに臨床応用可能な抑制剤は開発されていない(非特許文献4~7)。
Chemotherapy is one of the options for cancer treatment, but cancer cells may develop resistance to anticancer drugs, which often poses a problem in clinical settings. One of the mechanisms of anticancer drug resistance is overexpression of ABC (ATP binding cassettes) transporters in cancer cells. ABC transporters are membrane transport proteins that use ATP as energy to excrete anticancer drugs from the inside of cells to the outside of cells (Non-Patent
本発明は、新規のABCトランスポーターの機能抑制剤を提供することである。また、別の実施形態において、本発明は、抗癌剤の抗腫瘍効果を増強するための医薬を提供することである。 An object of the present invention is to provide a novel ABC transporter function inhibitor. Moreover, in another embodiment, the present invention provides a pharmaceutical for enhancing the antitumor effect of an anticancer agent.
かかる状況の下、本発明者らは多種多様な化合物について鋭意研究した結果、一般式(I)で表されるフェニルフロクマリン誘導体又はその塩がABCトランスポーターの機能抑制効果を奏することを見出した。また、本発明者らは、ABCトランスポーターの機能抑制効果を奏する上記フェニルフロクマリン誘導体又はその塩が抗癌剤の抗腫瘍効果を増強することを見出した。かかる本発明はかかる新たな知見に基づく。 Under such circumstances, the present inventors conducted intensive research on a wide variety of compounds and found that the phenylfurocoumarin derivative represented by the general formula (I) or a salt thereof exhibits an effect of inhibiting ABC transporter function. In addition, the present inventors have found that the phenylfurocoumarin derivative or a salt thereof, which exhibits an effect of suppressing ABC transporter function, enhances the antitumor effect of an anticancer agent. The present invention is based on such new findings.
従って、本発明は、以下の項を提供する:
項1.下記一般式(I)で表されるフェニルフロクマリン誘導体又はその塩を含む、ABCトランスポーターの機能抑制剤:
Accordingly, the present invention provides the following terms:
[式中、lは1~3の整数を示す。mは0~2の整数を示す。nは0~5の整数を示す。Rはアルキル基、アルコキシ基又はハロゲン原子を示す。nが2以上の場合、複数存在するRは同一でも異なってもよい。]。 [In the formula, l represents an integer of 1 to 3. m represents an integer of 0 to 2; n represents an integer of 0-5. R represents an alkyl group, an alkoxy group or a halogen atom. When n is 2 or more, multiple R may be the same or different. ].
項2.下記一般式(I)で表されるフェニルフロクマリン誘導体又はその塩を含む、抗癌剤の抗腫瘍効果を増強するための医薬:
[式中、lは1~3の整数を示す。mは0~2の整数を示す。nは0~5の整数を示す。Rはアルキル基、アルコキシ基又はハロゲン原子を示す。nが2以上の場合、複数存在するRは同一でも異なってもよい。]。 [In the formula, l represents an integer of 1 to 3. m represents an integer of 0 to 2; n represents an integer of 0-5. R represents an alkyl group, an alkoxy group or a halogen atom. When n is 2 or more, multiple R may be the same or different. ].
項3.下記一般式(I)で表されるフェニルフロクマリン誘導体又はその塩及び抗癌剤を含む、医薬:
[式中、lは1~3の整数を示す。mは0~2の整数を示す。nは0~5の整数を示す。Rはアルキル基、アルコキシ基又はハロゲン原子を示す。nが2以上の場合、複数存在するRは同一でも異なってもよい。]。 [In the formula, l represents an integer of 1 to 3. m represents an integer of 0 to 2; n represents an integer of 0-5. R represents an alkyl group, an alkoxy group or a halogen atom. When n is 2 or more, multiple R may be the same or different. ].
項4.基
[式中、n及びRは前記に同じ。]
が、基
[In the formula, n and R are the same as above. ]
but
[式中、n及びRは前記に同じ。]
である、項1に記載の機能抑制剤又は項2若しくは項3に記載の医薬。
[In the formula, n and R are the same as above. ]
項5.nが1~3の整数を示す、項1に記載の機能抑制剤、項2若しくは項3に記載の医薬、又は項4に記載の機能抑制剤若しくは医薬。
項6.下記一般式(I’)で表されるフェニルフロクマリン誘導体又はその塩:
[式中、l’は1~3の整数を示す。m’は0~2の整数を示す。n’は0~5の整数を示す。R’はアルキル基、アルコキシ基又はハロゲン原子を示す。n’が2以上の場合、複数存在するR’は同一でも異なってもよい。ただし、 [In the formula, l ' represents an integer of 1 to 3. m' represents an integer of 0-2. n' represents an integer of 0-5. R' represents an alkyl group, an alkoxy group or a halogen atom. When n' is 2 or more, a plurality of R' may be the same or different. however,
は除く。]。 except. ].
項7.基
[式中、n’及びR’は前記に同じ。]
が、基
[In the formula, n' and R' are the same as above. ]
but
[式中、n’及びR’は前記に同じ。]
である、項6に記載のフェニルフロクマリン誘導体又はその塩。
[In the formula, n' and R' are the same as above. ]
項8.n’が1~3の整数を示す、項6又は7に記載のフェニルフロクマリン誘導体又はその塩。
本発明によれば、一般式(I)で表されるフェニルフロクマリン誘導体又はその塩は、ABCトランスポーターの機能抑制効果を奏する。また、一般式(I)で表されるフェニルフロクマリン誘導体又はその塩は、抗癌剤の抗腫瘍効果を増強することができる。かかる抗腫瘍効果の増強作用は、抗癌剤を細胞内から細胞外へ排出するABCトランスポーターの機能抑制に起因するものと考えられる。 According to the present invention, the phenylfurocoumarin derivative represented by the general formula (I) or a salt thereof exerts an effect of inhibiting ABC transporter function. In addition, the phenylfurocoumarin derivative represented by general formula (I) or a salt thereof can enhance the antitumor effect of an anticancer drug. Such an antitumor effect-enhancing effect is considered to result from the suppression of the function of ABC transporters that excrete anticancer agents from the inside of cells to the outside of cells.
ABCトランスポーターの機能抑制剤
本発明は、下記一般式(I)で表されるフェニルフロクマリン誘導体又はその塩を含む、ABCトランスポーターの機能抑制剤を提供する:
ABC Transporter Function Inhibitor The present invention provides an ABC transporter function inhibitor containing a phenylfurocoumarin derivative represented by the following general formula (I) or a salt thereof:
[式中、lは1~3の整数を示す。mは0~2の整数を示す。nは0~5の整数を示す。Rはアルキル基、アルコキシ基又はハロゲン原子を示す。nが2以上の場合、複数存在するRは同一でも異なってもよい。]。 [In the formula, l represents an integer of 1 to 3. m represents an integer of 0 to 2; n represents an integer of 0-5. R represents an alkyl group, an alkoxy group or a halogen atom. When n is 2 or more, multiple R may be the same or different. ].
本発明において、一般式(I)で表されるフェニルフロクマリン誘導体を単に化合物(I)を示すこともある。 In the present invention, the phenylfurocoumarin derivative represented by general formula (I) may be simply referred to as compound (I).
本発明において、「アルキル基」とは、別途規定しない限り、直鎖状又は分枝鎖状の飽和炭化水素基を示し、例えば、炭素数1~6の直鎖状又は分枝鎖状の飽和炭化水素基等が挙げられる。具体的には、アルキル基には、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、t-ブチル基、n-ペンチル基、n-ヘキシル基等が含まれる。 In the present invention, unless otherwise specified, the term “alkyl group” refers to a linear or branched saturated hydrocarbon group, for example, a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. A hydrocarbon group etc. are mentioned. Specifically, the alkyl group includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group and the like. included.
本発明において、「アルコキシ基」とは、別途規定しない限り、アルキル部分が上記「アルキル基」であるアルコキシを示し、例えば、アルキル部分が炭素数1~6の直鎖状又は分枝鎖状の飽和炭化水素基であるアルコキシ基等が挙げられる。具体的には、アルコキシ基には、例えば、メチトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基、n-ブトキシ基、イソブトキシ基、t-ブトキシ基、n-ペンチルオキシ基、n-ヘキシルオキシ基等が含まれる。 In the present invention, unless otherwise specified, the term "alkoxy group" refers to alkoxy in which the alkyl moiety is the above "alkyl group", for example, the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms. An alkoxy group, which is a saturated hydrocarbon group, and the like are included. Specifically, alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, and n-hexyloxy. bases, etc. are included.
本発明において、「ハロゲン原子」としては、別途規定しない限り、フッ素、塩素、臭素、ヨウ素等が挙げられ、塩素が好ましい。 In the present invention, unless otherwise specified, the "halogen atom" includes fluorine, chlorine, bromine, iodine and the like, with chlorine being preferred.
一般式(I)中、アルコキシ基としては、アルキル部分が炭素数1~6の直鎖状又は分枝鎖状の飽和炭化水素基であるアルコキシ基が好ましく、アルキル部分が炭素数1~3の直鎖状又は分枝鎖状の飽和炭化水素基であるアルコキシ基がより好ましく、メトキシ基がさらに好ましい。 In general formula (I), the alkoxy group is preferably an alkoxy group in which the alkyl moiety is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and the alkyl moiety has 1 to 3 carbon atoms. An alkoxy group, which is a linear or branched saturated hydrocarbon group, is more preferred, and a methoxy group is even more preferred.
一般式(I)において、lは1~3であり、1~2が好ましく、1がより好ましい。 In general formula (I), l is 1 to 3, preferably 1 to 2, more preferably 1.
一般式(I)において、mは0~2であり、0~1が好ましく、0がより好ましい。 In general formula (I), m is 0 to 2, preferably 0 to 1, and more preferably 0.
一般式(I)において、nは0~5であり、0~3が好ましく、0~2がより好ましい。Rがアルコキシ基の場合、nは1~2が好ましく、2がより好ましい。 In general formula (I), n is 0 to 5, preferably 0 to 3, more preferably 0 to 2. When R is an alkoxy group, n is preferably 1 to 2, more preferably 2.
一般式(I)においてnが1~5の場合、フェニル基に対するRの位置は特に限定されないが、少なくともパラ位にRが存在することが好ましい。また、nが2以上の場合、少なくともパラ位及びオルト位にRが存在することが好ましい。 When n is 1 to 5 in general formula (I), the position of R relative to the phenyl group is not particularly limited, but R is preferably present at least at the para position. Moreover, when n is 2 or more, it is preferable that R exists at least at the para-position and the ortho-position.
化合物(I)のうち、 Among the compounds (I),
以外は新規化合物である。 Others are new compounds.
従って、別の実施形態において本発明は、下記一般式(I’)で表されるフェニルフロクマリン誘導体又はその塩を提供する: Accordingly, in another embodiment, the present invention provides a phenylfurocoumarin derivative represented by the following general formula (I') or a salt thereof:
[式中、l’は1~3の整数を示す。m’は0~2の整数を示す。n’は0~5の整数を示す。R’はアルキル基、アルコキシ基又はハロゲン原子を示す。n’が2以上の場合、複数存在するR’は同一でも異なってもよい。ただし、 [In the formula, l ' represents an integer of 1 to 3. m' represents an integer of 0-2. n' represents an integer of 0-5. R' represents an alkyl group, an alkoxy group or a halogen atom. When n' is 2 or more, a plurality of R' may be the same or different. however,
は除く。]。 except. ].
本発明において、一般式(I’)で表されるフェニルフロクマリン誘導体を単に化合物(I’)と示すこともある。 In the present invention, the phenylfurocoumarin derivative represented by general formula (I') may be simply referred to as compound (I').
一般式(I’)中、アルコキシ基としては、アルキル部分が炭素数1~6の直鎖状又は分枝鎖状の飽和炭化水素基であるアルコキシ基が好ましく、アルキル部分が炭素数1~3の直鎖状又は分枝鎖状の飽和炭化水素基であるアルコキシ基がより好ましく、メトキシ基がさらに好ましい。 In general formula (I′), the alkoxy group is preferably an alkoxy group in which the alkyl portion is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and the alkyl portion has 1 to 3 carbon atoms. is more preferably an alkoxy group which is a linear or branched saturated hydrocarbon group, and more preferably a methoxy group.
一般式(I’)において、l’は1~3であり、1~2が好ましく、1がより好ましい。 In general formula (I'), l' is 1 to 3, preferably 1 to 2, and more preferably 1.
一般式(I’)において、m’は0~2であり、0~1が好ましく、0がより好ましい。 In general formula (I'), m' is 0 to 2, preferably 0 to 1, and more preferably 0.
一般式(I’)において、n’は0~5であり、0~3が好ましく、0~2がより好ましい。典型的な実施形態において、一般式(I’)において、n’は1である。R’がアルコキシ基の場合、nは1~2が好ましい。 In general formula (I'), n' is 0 to 5, preferably 0 to 3, more preferably 0 to 2. In a typical embodiment, n' is 1 in general formula (I'). When R' is an alkoxy group, n is preferably 1-2.
一般式(I’)においてn’が1~5の場合、フェニル基に対するR’の位置は特に限定されないが、少なくともパラ位にR’が存在することが好ましい。また、n’が2以上の場合、少なくともパラ位及びオルト位にR’が存在することが好ましい。 When n' is 1 to 5 in general formula (I'), the position of R' with respect to the phenyl group is not particularly limited, but R' is preferably present at least at the para position. Moreover, when n' is 2 or more, it is preferable that R' exists at least at the para-position and the ortho-position.
化合物(I)は、例えば、下記の製造法又は実施例に示す方法等により製造することができる。ただし、本発明化合物(I)の製造法はこれら反応例に限定されるものではない。 Compound (I) can be produced, for example, by the following production methods or the methods shown in Examples. However, the method for producing the compound (I) of the present invention is not limited to these reaction examples.
[式中、l’、m’、n’、R’は前述の通り。]
上記反応式において、まず、化合物(i)とN-ブロモスクシンイミドとを反応させて、化合物(ii)を生成する。当該反応において、化合物(i)とN-ブロモスクシンイミドとの使用割合は特に限定されないが、例えば、モル比で、1:1~1:3、好ましくは1:1~1:1.5の範囲で適宜設定できる。反応温度も特に限定されないが、例えば、-80~50℃、好ましくは-20~30℃の範囲で適宜設定できる。反応時間も限定されないが、例えば、1~12時間、好ましくは2~5時間の範囲で適宜設定できる。反応溶媒としては、例えば、アセトニトリル、塩化メチレン、N,N-ジメチルホルムアミド等を用いることができる。これらの溶媒は、一種単独で又は複数種類を組み合わせて用いることができる。また、触媒として、酢酸、リン酸等を用いてもよい。これらの触媒を用いる場合、その濃度は、限定されないが、例えば、0.5~3M、好ましくは1~2Mの範囲で適宜設定できる。これらの触媒を用いる場合、一種単独で又は複数種類を組み合わせて用いることができる。
[In the formula, l', m', n' and R' are as described above. ]
In the above reaction scheme, compound (i) is first reacted with N-bromosuccinimide to produce compound (ii). In the reaction, the ratio of compound (i) and N-bromosuccinimide to be used is not particularly limited. can be set appropriately. The reaction temperature is also not particularly limited, but can be appropriately set, for example, in the range of -80 to 50°C, preferably -20 to 30°C. The reaction time is also not limited, but can be appropriately set in the range of, for example, 1 to 12 hours, preferably 2 to 5 hours. Examples of reaction solvents that can be used include acetonitrile, methylene chloride, N,N-dimethylformamide, and the like. These solvents can be used singly or in combination. Moreover, acetic acid, phosphoric acid, or the like may be used as a catalyst. When these catalysts are used, their concentration is not limited, but can be appropriately set in the range of, for example, 0.5 to 3M, preferably 1 to 2M. When these catalysts are used, they can be used singly or in combination.
次に、化合物(ii)と化合物(iii)とを反応させて、化合物(I’)を生成する。当該反応において、化合物(ii)と化合物(iii)との使用割合は特に限定されないが、例えば、モル比で、1:1~1:3、好ましくは1:1~1:1.5の範囲で適宜設定できる。反応温度も特に限定されないが、例えば、0~120℃、好ましくは50~100℃の範囲で適宜設定できる。反応時間も限定されないが、例えば、2~24時間、好ましくは6~12時間の範囲で適宜設定できる。反応溶媒としては、例えば、テトラヒドロフラン、1,4-ジオキサン、N,N-ジメチルホルムアミド等を用いることができる。これらの溶媒は、一種単独で又は複数種類を組み合わせて用いることができる。また、触媒として、テトラキス(トリフェニルホスフィン)パラジウム(0)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン複合体等を用いてもよい。これらの触媒を用いる場合、その濃度は、限定されないが、例えば、0.001~0.05M、好ましくは0.002~0.01Mの範囲で適宜設定できる。これらの触媒を用いる場合、一種単独で又は複数種類を組み合わせて用いることができる。 Compound (ii) and compound (iii) are then reacted to form compound (I'). In the reaction, the ratio of compound (ii) and compound (iii) to be used is not particularly limited. can be set appropriately. The reaction temperature is also not particularly limited, but can be set appropriately in the range of, for example, 0 to 120°C, preferably 50 to 100°C. The reaction time is also not limited, but can be appropriately set, for example, in the range of 2 to 24 hours, preferably 6 to 12 hours. Examples of reaction solvents that can be used include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like. These solvents can be used singly or in combination. As a catalyst, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)/dichloromethane complex, or the like may be used. When these catalysts are used, their concentration is not limited, but can be appropriately set in the range of, for example, 0.001 to 0.05M, preferably 0.002 to 0.01M. When these catalysts are used, they can be used singly or in combination.
本発明の有効成分である化合物(I)の塩は、酸付加塩と塩基との塩を包含する。酸付加塩の具体例として、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、過塩素酸塩、リン酸塩等の無機酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、トリフルオロ酢酸塩、酢酸塩、メタンスルホン酸塩、p-トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩等の有機酸塩、及びグルタミン酸塩、アスパラギン酸塩等の酸性アミノ酸塩が挙げられる。塩基との塩の具体例としては、ナトリウム塩、カリウム塩又はカルシウム塩のようなアルカリ金属又はアルカリ土類金属塩、ピリジン塩、トリエチルアミン塩のような有機塩基との塩、リジン、アルギニン等の塩基性アミノ酸との塩が挙げられる。 Salts of compound (I), which is the active ingredient of the present invention, include acid addition salts and base salts. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate, oxalate, malonate, and succinic acid. salt, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane Examples include organic acid salts such as sulfonates, and acidic amino acid salts such as glutamate and aspartate. Specific examples of salts with bases include alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts, salts with organic bases such as pyridine salts and triethylamine salts, and bases such as lysine and arginine. and salts with synthetic amino acids.
本発明の有効成分である化合物(I)及びその塩は、水和物又は溶媒和物の形で存在することもあるので、これらの水和物及び溶媒和物もまた本発明の有効成分である化合物に包含される。 Since compound (I) and its salts, which are active ingredients of the present invention, may exist in the form of hydrates or solvates, these hydrates and solvates are also active ingredients of the present invention. contained in a compound.
溶媒和物を形成する溶媒としては、エタノール、プロパノール等のアルコール、酢酸等の有機酸、酢酸エチル等のエステル類、テトラヒドロフラン、ジエチルエーテル等のエーテル類、アセトン等のケトン類、DMSO(ジメチルスフホキシド)等が例示される。 Solvents that form solvates include alcohols such as ethanol and propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone, DMSO (dimethylsulfoxide Sid) and the like are exemplified.
本発明の抑制剤が対象とするABCトランスポーターとしては、ABCG2、ABCBl、ABCC1、ABCC2、ABCC3、ABCC4、ABCC5、ABCC6等が挙げられ、典型的には、ABCG2である。 ABC transporters targeted by the inhibitor of the present invention include ABCG2, ABCBl, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6 and the like, typically ABCG2.
本発明においては、本発明の有効成分である化合物(I)又はその塩そのものをABCトランスポーターの機能抑制剤として用いても、薬学的に許容される各種担体(例えば、等張化剤、キレート剤、安定化剤、pH調節剤、防腐剤、抗酸化剤、溶解補助剤、粘稠化剤等)と組み合わせた組成物として用いてもよい。 In the present invention, even if the compound (I) or its salt itself, which is the active ingredient of the present invention, is used as an ABC transporter function inhibitor, various pharmaceutically acceptable carriers (e.g., tonicity agents, chelates, agents, stabilizers, pH adjusters, preservatives, antioxidants, solubilizers, thickening agents, etc.).
等張化剤としては、例えば、グルコース、トレハロース、ラクトース、フルクトース、マンニトール、キシリトール、ソルビトール等の糖類、グリセリン、ポリエチレングリコール、プロピレングリコール等の多価アルコール類、塩化ナトリウム、塩化カリウム、塩化カルシウム等の無機塩類等が挙げられる。 Examples of tonicity agents include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol and sorbitol; polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol; sodium chloride, potassium chloride and calcium chloride; Inorganic salts etc. are mentioned.
キレート剤としては、例えば、エデト酸二ナトリウム、エデト酸カルシウム二ナトリウム、エデト酸三ナトリウム、エデト酸四ナトリウム、エデト酸カルシウム等のエデト酸塩類、エチレンジアミン四酢酸塩、ニトリロ三酢酸又はその塩、ヘキサメタリン酸ソーダ、クエン酸等が挙げられる。 Examples of chelating agents include edetate salts such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or salts thereof, and hexamethalin. acid sodium, citric acid, and the like.
安定化剤としては、例えば、亜硫酸水素ナトリウム等が挙げられる。 pH調節剤としては、例えば、塩酸、炭酸、酢酸、クエン酸等の酸が挙げられ、さらに水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物、炭酸ナトリウム等のアルカリ金属炭酸塩又は炭酸水素塩、酢酸ナトリウム等のアルカリ金属酢酸塩、クエン酸ナトリウム等のアルカリ金属クエン酸塩、トロメタモール等の塩基等が挙げられる。 Stabilizers include, for example, sodium bisulfite and the like. Examples of pH adjusters include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, and hydrogen carbonate. salts, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol;
防腐剤としては、例えば、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等のパラオキシ安息香酸エステル、グルコン酸クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム等の第4級アンモニウム塩、アルキルポリアミノエチルグリシン、クロロブタノール、ポリクォード、ポリヘキサメチレンビグアニド、クロルヘキシジン等が挙げられる。 Examples of antiseptics include sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, paraoxybenzoate such as butyl parahydroxybenzoate, chlorhexidine gluconate, benzalkonium chloride, chloride quaternary ammonium salts such as benzethonium and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine and the like.
抗酸化剤としては、例えば、亜硫酸水素ナトリウム、乾燥亜硫酸ナトリウム、ピロ亜硫酸ナトリウム、濃縮混合トコフェロール等が挙げられる。 Antioxidants include, for example, sodium bisulfite, dried sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, and the like.
溶解補助剤としては、例えば、安息香酸ナトリウム、グリセリン、D-ソルビトール、ブドウ糖、プロピレングリコール、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、D-マンニトール等が挙げられる。 Examples of solubilizing agents include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol and the like.
粘稠化剤としては、例えば、ポリエチレングリコール、メチルセルロース、エチルセルロース、カルメロースナトリウム、キサンタンガム、コンドロイチン硫酸ナトリウム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール等が挙げられる。 Examples of thickening agents include polyethylene glycol, methylcellulose, ethylcellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
組成物の実施形態において、組成物中の化合物(I)又はその塩の含有量は特に限定されず、化合物(I)の含有量換算で、例えば、90質量%以上、70質量%以上、50質量%以上、30質量%以上、10質量%以上、5質量%以上、1質量%以上等の条件から適宜設定できる。 In the embodiment of the composition, the content of compound (I) or a salt thereof in the composition is not particularly limited, and in terms of the content of compound (I), for example, 90% by mass or more, 70% by mass or more, 50% by mass or more, It can be appropriately set from conditions such as mass % or more, 30 mass % or more, 10 mass % or more, 5 mass % or more, 1 mass % or more.
組成物の実施形態において、組成物中の化合物(I)又はその塩の含有量は特に限定されず、化合物(I)の含有量換算で、例えば、90質量%以上、70質量%以上、50質量%以上、30質量%以上、10質量%以上、5質量%以上、1質量%以上等の条件から適宜設定できる。 In the embodiment of the composition, the content of compound (I) or a salt thereof in the composition is not particularly limited, and in terms of the content of compound (I), for example, 90% by mass or more, 70% by mass or more, 50% by mass or more, It can be appropriately set from conditions such as mass % or more, 30 mass % or more, 10 mass % or more, 5 mass % or more, 1 mass % or more.
抗癌剤の抗腫瘍効果を増強するための医薬
別の実施形態において、本発明は、化合物(I)又はその塩を含む、抗癌剤の抗腫瘍効果を増強するための医薬を提供する。
Pharmaceuticals for enhancing the antitumor effect of anticancer agents In another embodiment, the present invention provides a pharmaceutical for enhancing the antitumor effect of anticancer agents, containing compound (I) or a salt thereof.
かかる実施形態における化合物(I)及びその塩の内容等についての詳細は前述の通りである。本実施形態においても、本発明の有効成分である化合物(I)又はその塩そのものを医薬として用いても、薬学的に許容される各種担体(例えば、等張化剤、キレート剤、安定化剤、pH調節剤、防腐剤、抗酸化剤、溶解補助剤、粘稠化剤等)と組み合わせた医薬組成物として用いてもよい。 The details of compound (I) and salts thereof in such embodiments are as described above. In this embodiment, even if compound (I) or a salt thereof, which is an active ingredient of the present invention, is used as a medicament, various pharmaceutically acceptable carriers (e.g., tonicity agents, chelating agents, stabilizing agents, , pH adjusters, preservatives, antioxidants, solubilizers, thickening agents, etc.).
医薬組成物の実施形態において、組成物中の化合物(I)又はその塩の含有量は特に限定されず、化合物(I)の含有量換算で、例えば、90質量%以上、70質量%以上、50質量%以上、30質量%以上、10質量%以上、5質量%以上、1質量%以上等の条件から適宜設定できる。 In the embodiment of the pharmaceutical composition, the content of compound (I) or a salt thereof in the composition is not particularly limited, and in terms of the content of compound (I), for example, 90% by mass or more, 70% by mass or more, It can be appropriately set from conditions such as 50% by mass or more, 30% by mass or more, 10% by mass or more, 5% by mass or more, and 1% by mass or more.
製剤形態は、特に限定されず、例えば錠剤、丸剤、カプセル剤、散剤、顆粒剤、シロップ剤等の経口投与剤;注射剤(静脈注射、筋肉注射、局所注射等)、含嗽剤、点滴剤、外用剤(軟膏、クリーム、貼付薬、吸入薬)、座剤等の非経口投与剤等の各種製剤形態を挙げることができる。上記製剤形態のうち、好ましいものとしては、例えば、経口投与剤(錠剤、丸剤、カプセル剤、散剤、顆粒剤、シロップ剤等)等が挙げられる。 Formulations are not particularly limited, and examples include tablets, pills, capsules, powders, granules, syrups and other oral administration agents; injections (intravenous injection, intramuscular injection, local injection, etc.), gargles, drops. , external preparations (ointments, creams, patches, inhalants), and parenteral preparations such as suppositories. Among the above dosage forms, preferred are, for example, oral administration agents (tablets, pills, capsules, powders, granules, syrups, etc.).
本発明において、化合物(I)又はその塩の投与量は、投与経路、患者の年齢、体重、症状等によって異なり一概に規定できないが、化合物(I)の投与量として、成人に対する1日投与量が通常、約5000mg以下、好ましくは約1000mg以下になる量とすればよい。また、本発明によれば、化合物(I)は低用量でも効果を奏するため、化合物(I)の投与量として、成人に対する1日投与量が、約100mg以下、約10mg以下、約8mg以下、約5mg以下等であってもよい。化合物(I)又はその塩の投与量の下限も特に限定されず、例えば、化合物(I)の投与量として、成人に対する1日投与量が通常、0.1mg以上、好ましくは0.5mg以上の範囲で適宜設定できる。1日1回投与する場合は、1製剤中にこの量が含まれていればよく、1日3回投与する場合は、1製剤中にこの3分の1量が含まれていればよい。 In the present invention, the dose of compound (I) or a salt thereof varies depending on the route of administration, the patient's age, body weight, symptoms, etc., and cannot be categorically defined. is usually about 5000 mg or less, preferably about 1000 mg or less. In addition, according to the present invention, compound (I) is effective even at low doses. It may be about 5 mg or less, or the like. The lower limit of the dose of compound (I) or a salt thereof is not particularly limited. It can be set appropriately within the range. In the case of administration once a day, this amount should be contained in one formulation, and in the case of administration three times a day, one third of this amount may be contained in one formulation.
本発明の抗癌剤の抗腫瘍効果を増強するための医薬は、哺乳動物等の患者に投与される。哺乳動物としては、ヒト、サル、マウス、ラット、ウサギ、ネコ、イヌ、ブタ、ウシ、ウマ、ヒツジ等が挙げられ、好ましくはヒトである。 A medicament for enhancing the antitumor effect of the anticancer agent of the present invention is administered to a patient such as a mammal. Mammals include humans, monkeys, mice, rats, rabbits, cats, dogs, pigs, cows, horses, sheep and the like, preferably humans.
抗腫瘍効果を増強するための当該実施形態において、化合物(I)又はその塩と組み合わせる抗癌剤としては、特に限定されないが、典型的には、ABCトランスポーターにより細胞外に排出されるものが挙げられる。ABCトランスポーターにより細胞外に排出され得るものが好ましい。ABCトランスポーターを介した細胞外への排出されやすさの観点から、抗腫瘍剤としては、分子量が300~2000daのものが好ましく、400da以上のものがより好ましい。また、ABCトランスポーターを介した細胞外への排出されやすさの観点から、抗腫瘍剤としては、脂溶性が比較的高いものが好ましい。例えば、log P valueが2.9以上のものが好ましく、5以上のものがより好ましい(非特許文献8、9)。抗癌剤の具体例としては、イリノテカン、SN-38、ドキソルビシン、ダウノルビシン、エトポシド、ミトキサントロン、トポテカン、等の化学療法用抗癌剤;イマチニブ、ニロチニブ、ダサチニブ、ゲフィチニブ等の分子標的薬等が挙げられる。
In this embodiment for enhancing the antitumor effect, the anticancer agent to be combined with compound (I) or a salt thereof is not particularly limited, but typically includes those that are excreted extracellularly by ABC transporters. . Those that can be excreted out of the cell by ABC transporters are preferred. From the viewpoint of ease of extracellular excretion via ABC transporters, the antitumor agent preferably has a molecular weight of 300 to 2000 da, more preferably 400 da or more. In addition, from the viewpoint of ease of excretion to the outside of cells via ABC transporters, the antitumor agent preferably has relatively high lipid solubility. For example, the log P value is preferably 2.9 or more, more preferably 5 or more (
当該実施形態において、治療対象となる癌としては、乳癌、大腸癌、副腎癌、肝臓癌、肺癌等の固形癌;白血病、リンパ腫等の血液癌等が挙げられる。 In this embodiment, cancers to be treated include solid cancers such as breast cancer, colon cancer, adrenal cancer, liver cancer, and lung cancer; blood cancers such as leukemia and lymphoma;
当該実施形態において化合物(I)又はその塩と抗癌剤との使用割合は、限定されないが、例えば、前者1質量部に対し0.0001~10000質量部、好ましくは0.001~1000質量部、より好ましくは0.01~100質量部、さらに好ましくは0.1~10質量部の範囲で適宜設定できる。 In the embodiment, the ratio of compound (I) or a salt thereof to the anticancer agent is not limited, but is, for example, 0.0001 to 10000 parts by weight, preferably 0.001 to 1000 parts by weight per 1 part by weight of the former. It can be appropriately set in the range of preferably 0.01 to 100 parts by mass, more preferably 0.1 to 10 parts by mass.
抗癌剤を含む、医薬
別の実施形態において、化合物(I)又はその塩及び抗癌剤を含む、医薬を提供する。本発明において、「化合物(I)又はその塩及び抗癌剤を含む、医薬」とは、化合物(I)又はその塩及び抗癌剤が1つの製剤に含まれる実施形態だけでなく、化合物(I)もしくはその塩と抗癌剤とが別々の製剤に含まれている実施形態も包含される。本実施形態において、化合物(I)又はその塩及び抗癌剤を含む、医薬は、癌の予防又は治療のために用いることができる。
Pharmaceuticals Comprising Anti-Cancer Agents In another embodiment, pharmaceuticals comprising compound (I) or a salt thereof and an anti-cancer agent are provided. In the present invention, the term "pharmaceutical containing compound (I) or a salt thereof and an anticancer agent" refers not only to an embodiment in which compound (I) or a salt thereof and an anticancer agent are contained in one formulation, but also to compounds (I) or Also included are embodiments in which the salt and the anticancer agent are in separate formulations. In this embodiment, a medicament containing compound (I) or a salt thereof and an anticancer agent can be used for prevention or treatment of cancer.
かかる実施形態における化合物(I)及びその塩の内容、使用方法等についての詳細は前述の通りである。 The details of compound (I) and its salt in this embodiment, the method of use, etc. are as described above.
実施例1
8-(3,4-ジメトキシフェニル)オキシポイセダニン(化合物14)
Example 1
8-(3,4-dimethoxyphenyl)oxypoisedanin (compound 14)
オキシポイセダニン(910 mg, 3.18 mmol)をアセトニトリル(1.0 mL)および酢酸(0.1 mL)に溶解し,0℃に冷却して攪拌した.続けてN-ブロモスクシンイミド(700 mg, 3.93 mmol)を加え4時間攪拌した.反応液に水(10 mL)を加え,酢酸エチル(15 mL)で3回抽出した.得られた酢酸エチル層を合わせ,水(25 mL),飽和食塩水(25 mL)で洗浄し,無水硫酸ナトリウムで乾燥し,溶媒を減圧留去した.残渣をシリカゲルカラムクロマトグラフィ(ヘキサン-酢酸エチル(3:2)で溶出)で精製し,8-ブロモオキシポイセダニン(501 mg, 1.37 mmol,収率43%)を得た.
アルゴン雰囲気下で,8-ブロモオキシポイセダニン(52.0 mg, 0.143 mmol),3,4-ジメトキシフェニルボロン酸(30.5 mg, 0.167 mmol),炭酸カリウム(56.4 mg, 0.408 mmol)及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン複合体(8.9 mg, 0.011 mmol)にテトラヒドロフラン(2.0 mL)を加えた.12時間加熱還流した後,室温まで冷却し酢酸エチル(5.0 mL)を加えた.反応液をセライト濾過し,その濾液を減圧留去した.残渣をシリカゲルカラムクロマトグラフィ(ヘキサン-酢酸エチル(1:1)で溶出)で精製し,8-(3,4-ジメトキシフェニル)オキシポイセダニン(37.3 mg, 0.088 mmol,収率62%)を得た.
生成物は,EIMS(電子衝撃質量スペクトル)法による質量分析,ならびにNMRによって解析した.EIMSおよびNMRの結果を以下に示す.
EIMS m/z (rel. int.)422 [M]+ (100), 337(94), 306(45)
HREIMS m/z 422.1354 [M]+ (C24H22O7の計算値422.1364).
1H NMR (CDCl3, 400 MHz) δ 8.25 (1H, d, J = 9.8 Hz), 7.61 (1H, d, J = 2.3 Hz), 7.25 (1H, dd, J = 8.4, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.98 (1H, d, J = 2.3 Hz), 6.33 (1H, d, J= 9.8 Hz), 4.60 (1H, dd, J = 11.0, 4.3 Hz), 4.43 (1H, dd, J = 11.0, 6.6 Hz), 3.93 (3H, s), 3.90 (3H, s), 3.24 (1H, dd, J = 6.6, 4.3 Hz), 1.40 (3H, s), 1.33 (3H, s)。
Oxypoisedanin (910 mg, 3.18 mmol) was dissolved in acetonitrile (1.0 mL) and acetic acid (0.1 mL), cooled to 0°C and stirred. Subsequently, N-bromosuccinimide (700 mg, 3.93 mmol) was added and stirred for 4 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL) three times. The ethyl acetate layers obtained were combined, washed with water (25 mL) and saturated brine (25 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate (3:2)) to give 8-bromooxypoisedanin (501 mg, 1.37 mmol, yield 43%).
8-bromooxypoisedanine (52.0 mg, 0.143 mmol), 3,4-dimethoxyphenylboronic acid (30.5 mg, 0.167 mmol), potassium carbonate (56.4 mg, 0.408 mmol) and [1,1 Tetrahydrofuran (2.0 mL) was added to '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)/dichloromethane complex (8.9 mg, 0.011 mmol). After heating under reflux for 12 hours, the mixture was cooled to room temperature and ethyl acetate (5.0 mL) was added. The reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate (1:1)) to give 8-(3,4-dimethoxyphenyl)oxypoisedanin (37.3 mg, 0.088 mmol, yield 62%). rice field.
The products were analyzed by mass spectrometry by EIMS (electron impact mass spectroscopy) and NMR. EIMS and NMR results are shown below.
EIMS m/z (rel. int.) 422 [M] + (100), 337(94), 306(45)
HREIMS m/z 422.1354 [M] + ( calcd 422.1364 for C24H22O7).
1 H NMR (CDCl 3 , 400 MHz) δ 8.25 (1H, d, J = 9.8 Hz), 7.61 (1H, d, J = 2.3 Hz), 7.25 (1H, dd, J = 8.4, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.98 (1H, d, J = 2.3 Hz), 6.33 (1H, d, J = 9.8 Hz), 4.60 (1H , dd, J = 11.0, 4.3 Hz), 4.43 (1H, dd, J = 11.0, 6.6 Hz), 3.93 (3H, s), 3.90 (3H, s), 3.24 (1H, dd, J = 6.6, 4.3 Hz), 1.40 (3H, s), 1.33 (3H, s).
実施例2
8-フェニルオキシポイセダニン(化合物A)
Example 2
8-Phenyloxypoisedanine (Compound A)
ジメトキシフェニルボロン酸の代わりにフェニルボロン酸を用いること以外は,実施例1と同様の製法にしたがって標記化合物を合成した。 The title compound was synthesized in the same manner as in Example 1, except that phenylboronic acid was used instead of dimethoxyphenylboronic acid.
EIMS m/z (rel. int.)362 [M]+ (78), 278(100), 249(29), 85(98)
HREIMS m/z 362.1177 [M]+ (C22H18O5の計算値362.1154).
1H NMR (CDCl3, 400 MHz) δ 8.26 (1H, d, J = 9.4 Hz), 7.67 (2H, d, J = 7.8 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.48-7.52 (2H, m), 7.43 (1H, d, J= 7.8 Hz), 6.98 (1H, d, J = 2.0 Hz), 6.33 (1H, d, J = 9.4 Hz), 4.64 (1H, dd, J = 11.2, 3.8 Hz), 4.43 (1H, dd, J = 11.2, 7.2 Hz), 3.26 (1H, dd, J = 7.2, 3.8 Hz), 1.43 (3H, s), 1.37 (3H, s).
EIMS m/z (rel. int.) 362 [M] + (78), 278(100), 249(29), 85(98)
HREIMS m/z 362.1177 [M] + ( calcd 362.1154 for C22H18O5).
1 H NMR (CDCl 3 , 400 MHz) δ 8.26 (1H, d, J = 9.4 Hz), 7.67 (2H, d, J = 7.8 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.48-7.52 (2H, m), 7.43 (1H, d, J = 7.8 Hz), 6.98 (1H, d, J = 2.0 Hz), 6.33 (1H, d, J = 9.4 Hz), 4.64 (1H, dd, J = 11.2, 3.8 Hz), 4.43 (1H, dd, J = 11.2, 7.2 Hz), 3.26 (1H, dd, J = 7.2, 3.8 Hz), 1.43 (3H, s), 1.37 (3H, s).
実施例3
8-(4-クロロフェニル)オキシポイセダニン(化合物B)
Example 3
8-(4-chlorophenyl)oxypoisedanin (compound B)
ジメトキシフェニルボロン酸の代わりに4-クロロフェニルボロン酸を用いること以外は,実施例1と同様の製法にしたがって標記化合物を合成した。 The title compound was synthesized in the same manner as in Example 1, except that 4-chlorophenylboronic acid was used instead of dimethoxyphenylboronic acid.
EIMS m/z (rel. int.)398 [M+2]+ (20), 396 [M]+(59), 312(84), 85(100)
HREIMS m/z 396.0754 [M]+ (C22H17O5Cl の計算値396.0765).
1H NMR (CDCl3, 400 MHz) δ 8.26 (1H, d, J = 9.1 Hz), 7.63 (2H, d, J = 7.4 Hz), 7.61 (1H, d, J = 1.9 Hz), 7.46 (2H, d, J = 7.4 Hz), 7.00 (1H, d, J = 1.9 Hz), 6.33 (1H, d, J = 9.1 Hz), 4.64 (1H, dd, J= 10.8, 4.0 Hz), 4.45 (1H, dd, J = 10.8, 6.6 Hz), 3.27 (1H, dd, J= 6.6, 4.0 Hz), 1.43 (3H, s), 1.37 (3H, s).
EIMS m/z (rel. int.) 398 [M+2] + (20), 396 [M] + (59), 312(84), 85(100)
HREIMS m/z 396.0754 [M] + ( calcd for C22H17O5Cl 396.0765).
1 H NMR (CDCl 3 , 400 MHz) δ 8.26 (1H, d, J = 9.1 Hz), 7.63 (2H, d, J = 7.4 Hz), 7.61 (1H, d, J = 1.9 Hz), 7.46 (2H , d, J = 7.4 Hz), 7.00 (1H, d, J = 1.9 Hz), 6.33 (1H, d, J = 9.1 Hz), 4.64 (1H, dd, J = 10.8, 4.0 Hz), 4.45 (1H , dd, J = 10.8, 6.6 Hz), 3.27 (1H, dd, J= 6.6, 4.0 Hz), 1.43 (3H, s), 1.37 (3H, s).
実施例4
8-(4-メチルフェニル)オキシポイセダニン(化合物C)
Example 4
8-(4-methylphenyl)oxypoisedanine (compound C)
ジメトキシフェニルボロン酸の代わりに4-メチルフェニルボロン酸を用いること以外は,実施例1と同様の製法にしたがって標記化合物を合成した。 The title compound was synthesized in the same manner as in Example 1, except that 4-methylphenylboronic acid was used instead of dimethoxyphenylboronic acid.
EIMS m/z (rel. int.)376 [M]+ (79), 292(100), 263(34), 85(60)
HREIMS m/z 376.1304 [M]+ (C23H20O5の計算値376.1311).
1H NMR (CDCl3, 400 MHz) δ 8.26 (1H, d, J = 8.9 Hz), 7.60 (1H, d, J = 2.4 Hz), 7.56 (2H, d, J = 7.5 Hz), 7.33 (2H, d, J = 7.5 Hz), 6.97 (1H, d, J = 2.4 Hz), 6.32 (1H, d, J = 8.9 Hz), 4.62 (1H, dd, J= 11.2, 4.0 Hz), 4.44 (1H, dd, J = 11.2, 7.0 Hz), 3.27 (1H, dd, J= 7.0, 4.0 Hz), 2.42 (3H, s), 1.44 (3H, s), 1.37 (3H, s).
EIMS m/z (rel. int.) 376 [M] + (79), 292(100), 263(34), 85(60)
HREIMS m/z 376.1304 [M] + ( calcd 376.1311 for C23H20O5).
1 H NMR (CDCl 3 , 400 MHz) δ 8.26 (1H, d, J = 8.9 Hz), 7.60 (1H, d, J = 2.4 Hz), 7.56 (2H, d, J = 7.5 Hz), 7.33 (2H , d, J = 7.5 Hz), 6.97 (1H, d, J = 2.4 Hz), 6.32 (1H, d, J = 8.9 Hz), 4.62 (1H, dd, J = 11.2, 4.0 Hz), 4.44 (1H , dd, J = 11.2, 7.0 Hz), 3.27 (1H, dd, J= 7.0, 4.0 Hz), 2.42 (3H, s), 1.44 (3H, s), 1.37 (3H, s).
実施例5
8-(4-メトキシフェニル)オキシポイセダニン(化合物D)
Example 5
8-(4-Methoxyphenyl)oxypoisedanine (Compound D)
化合物Dは,ジメトキシフェニルボロン酸の代わりに4-メトキシフェニルボロン酸を用いること以外は,実施例1と同様の製法にしたがって合成された.
EIMS m/z (rel. int.)392 [M]+ (86), 308(100), 279(44)
HREIMS m/z 392.1239 [M]+ (C23H20O6の計算値392.1260).
1H NMR (CDCl3, 400 MHz) δ 8.28 (1H, d, J = 9.2 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 7.02 (2H, d, J = 8.4 Hz), 6.98 (1H, d, J = 2.1 Hz), 6.33 (1H, d, J = 9.2 Hz), 4.63 (1H, dd, J= 11.0, 4.0 Hz), 4.43 (1H, dd, J = 11.0, 6.8 Hz), 3.87 (3H, s), 3.28 (1H, dd, J = 6.8, 4.0 Hz), 1.42 (3H, s), 1.35 (3H, s).
Compound D was synthesized in the same manner as in Example 1, except that 4-methoxyphenylboronic acid was used instead of dimethoxyphenylboronic acid.
EIMS m/z (rel. int.) 392 [M] + (86), 308(100), 279(44)
HREIMS m/z 392.1239 [M] + ( calcd 392.1260 for C23H20O6 ).
1 H NMR (CDCl 3 , 400 MHz) δ 8.28 (1H, d, J = 9.2 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 7.02 (2H , d, J = 8.4 Hz), 6.98 (1H, d, J = 2.1 Hz), 6.33 (1H, d, J = 9.2 Hz), 4.63 (1H, dd, J = 11.0, 4.0 Hz), 4.43 (1H , dd, J = 11.0, 6.8 Hz), 3.87 (3H, s), 3.28 (1H, dd, J = 6.8, 4.0 Hz), 1.42 (3H, s), 1.35 (3H, s).
試験例
試験方法
I.細胞培養
ヒト大腸癌細胞株のHCT-116およびHCT-116/BCRPを用いた。HCT-116/BCRP は、HCT-116にレトロウイルスを用いてABCG2を遺伝子導入し過剰発現させた耐性株である。HCT-116、HCT-116/BCRP細胞は慶応大学薬学部薬学研究科化学療法学の杉本芳一教授より提供を受けた。これらの細胞株はDMEM(Dulbecco’s Modified Eagle’s Medium, Sigma)培地にて37℃、5%二酸化炭素下で培養した。培地には10% FBS (fetal bovine serum; ウシ胎仔血清、Sigma) 、1% ペニシリン-ストレプトマイシン(Sigma) を添加した。
Test Examples Test Methods I. Cell Culture Human colon cancer cell lines HCT-116 and HCT-116/BCRP were used. HCT-116/BCRP is a resistant strain in which ABCG2 is transfected into HCT-116 using a retrovirus and overexpressed. HCT-116 and HCT-116/BCRP cells were provided by Professor Yoshikazu Sugimoto, Department of Chemotherapy, Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Keio University. These cell lines were cultured in DMEM (Dulbecco's Modified Eagle's Medium, Sigma) medium at 37°C under 5% carbon dioxide. 10% FBS (fetal bovine serum; Sigma) and 1% penicillin-streptomycin (Sigma) were added to the medium.
II.化合物
本試験例では、化合物1~14として、東北大学薬学研究科が管理する化合物ライブラリーに登録されているものを使用した。各化合物の構造は、後述する表1-1~1-2に記載する。いずれの化合物も2μMとなるようにDMSOで溶解され、384ウェルプレートに2 μLずつ分注されて提供された。
II. Compounds In this test example, compounds 1 to 14 registered in the compound library managed by the Graduate School of Pharmaceutical Sciences, Tohoku University were used. The structure of each compound is shown in Tables 1-1 and 1-2 below. All compounds were dissolved in DMSO to 2 μM and provided in 2 μL aliquots in 384-well plates.
III.フローサイトメトリーによるPhA排出試験
フローサイトメトリーにより、各化合物のABCG2機能への抑制効果の検討を行った。細胞株はHCT-116/BCRPを用いた。ABCG2の蛍光基質であるフェオフォルバイドa(pheopheorbide a; PhA)はHCT-116細胞では細胞内に取り込まれることにより、細胞内の蛍光強度が増強するが、ABCG2を過剰発現しているHCT-116/BCRP細胞ではトランスポーターによって細胞外に排出されるため、細胞内の蛍光強度は減少する。そこにABCG2機能の抑制剤を併用すると細胞外への薬物排出が抑制され、細胞内に蓄積するため蛍光強度は増強する。したがって、PhAの蛍光強度を測定することで、ABCG2機能の抑制を評価することが可能である(図1)。
III. PhA efflux test by flow cytometry The inhibitory effect of each compound on ABCG2 function was examined by flow cytometry. The cell line used was HCT-116/BCRP. PhA, a fluorescent substrate of ABCG2, is taken up into HCT-116 cells, resulting in increased intracellular fluorescence intensity. In /BCRP cells, the intracellular fluorescence intensity decreases because it is excreted by the transporter. If an inhibitor of ABCG2 function is used in combination, drug excretion to the outside of the cell is suppressed and the drug accumulates inside the cell, resulting in an increase in fluorescence intensity. Therefore, inhibition of ABCG2 function can be evaluated by measuring the fluorescence intensity of PhA (Fig. 1).
培養したHCT-116/BCRP細胞を3×105細胞/mlの細胞濃度でIMDM(Iscove's Modified Dulbecco's Medium, Thermo Fisher Scientific)で調整し、FACSチューブ (Becton, Dickinson and Company) に加えた。フェオフォルバイドaを10 μMとなるように培養液に加え、既知のABCG2トランスポーターの抑制剤であるKo143 (Tocris bioscience) 1 μMを加えたチューブをポジティブコントロールとして用い、その他のチューブに化合物1を1、5、10 μMの濃度となるようにそれぞれ加え、37℃恒温槽に遮光下で30分間培養した。培養後、1500 rpmで5分間遠心し、上清を除去し、それぞれ1 mLのIMDMで再懸濁した。その後、フェオフォルバイドaは投与せず、Ko143、各候補薬剤を先ほど同様にそれぞれ加え、37℃恒温槽に遮光下で1時間培養した。培養後、1500 rpmで5分間遠心し、上清を除去しPBS (-) 300 μl でペレットを再懸濁した。蛍光強度の測定はBD FACS Verse (Becton, Dickinson and Company) で行い、フィルターにはPerCP-Cy5.5(励起波長488 nm、最大蛍光波長690 nm)を用いた。化合物1の代わりに化合物2~14を用いる以外、上記と同様にして、各化合物のABCG2機能への抑制効果を測定した。
Cultured HCT-116/BCRP cells were adjusted with IMDM (Iscove's Modified Dulbecco's Medium, Thermo Fisher Scientific) at a cell concentration of 3×10 5 cells/ml and added to FACS tubes (Becton, Dickinson and Company). A tube containing 10 μM pheophorbide a and 1 μM Ko143 (Tocris bioscience), a known ABCG2 transporter inhibitor, was used as a positive control, and
IV. 細胞毒性試験
化合物1~14に対し、CellTiter 96 AQueous One Solution Reagent (Promega)による細胞毒性試験(MTS assay)を行った。まず、HCT-116/BCRP細胞を96ウェルプレートに播種した。その際、1ウェル(100 μL)あたりの細胞数が、1×104個となるように調整した。細胞播種後は、37℃、5%二酸化炭素の環境で24時間培養を行った。その後上清を除去し、段階的にSN-38(抗癌剤イリノテカンの活性代謝物)の濃度を振り分けた培地を各ウェルに加えた。さらに、ポジティブコントロールとしてKo143 を1 μM、又は化合物1を5又は10 μMとなるようにそれぞれPBS (-)で濃度調整し、各ウェルに添加した。1ウェルあたりの容量を100 μLとした。化合物を投与したプレートは上記と同様の設定で72時間培養した。そして72時間後、100 μLの培地に入れ替え、20 μLのMTS溶液を加えた。1時間の培養後、プレートリーダーのMultiskan FC(Thermo Fisher Scientific)を用いて吸光度(492 nm)の測定を行った。化合物1のIC50(inhibitory concentration 50; 50%抑制濃度)はJMP Pro 14.0 (SAS International INC.)を使用して算出した。この試験で同定された候補薬剤とKo143に関し、ABCG2を発現していない親株への作用を確認するため、HCT-116を用いて上記と同じ手法で細胞毒性試験を行った。さらに、化合物1の毒性評価のため、候補薬剤及びKo143の濃度を段階的に振り分けた培地を使用し、上記と同じ手法で細胞毒性試験を行った。
IV. Cytotoxicity Test Compounds 1-14 were subjected to a cytotoxicity test (MTS assay) using CellTiter 96 AQueous One Solution Reagent (Promega). First, HCT-116/BCRP cells were seeded in 96-well plates. At that time, the number of cells per well (100 μL) was adjusted to 1×10 4 cells. After seeding the cells, the cells were cultured in an environment of 37°C and 5% carbon dioxide for 24 hours. After that, the supernatant was removed, and a medium in which the concentration of SN-38 (the active metabolite of the anticancer drug irinotecan) was distributed stepwise was added to each well. Furthermore, as a positive control, the concentrations of Ko143 and
化合物1の代わりに化合物2~14を用いる以外、上記と同様にして、各化合物の細胞毒性試験を行った。
The cytotoxicity test of each compound was performed in the same manner as above, except that compounds 2 to 14 were used instead of
V. ATP加水分解試験
ABCG2の基質結合部位に基質が結合すると、ATPのエネルギーを用いてトランスポーターが稼働し基質が細胞外に排出される。その際にATPはADPと無機リン酸に加水分解される(非特許文献10)。この実験では、産生される無機リン酸を発色反応において計測することで対象薬剤がATP加水分解へ与える効果を判定することが可能となる(非特許文献10、11)。
V. ATP hydrolysis test
When a substrate binds to the substrate-binding site of ABCG2, the energy of ATP is used to activate the transporter and the substrate is excreted out of the cell. At that time, ATP is hydrolyzed into ADP and inorganic phosphate (Non-Patent Document 10). In this experiment, the effect of the target drug on ATP hydrolysis can be determined by measuring the amount of inorganic phosphate produced in the color development reaction (
本試験例では、ヒトABCG2のcDNAによって遺伝子組み換えされたバクロウイルスを昆虫細胞に感染させ、昆虫細胞より抽出した細胞膜タンパクを用いた(非特許文献12)。このタンパクは Suresh V. Ambudkar 博士より提供を受けた。ATPase assay用チューブに2×ATPase buffer、H2Oを加え、そこに細胞膜タンパクを6 μg加えた。そこに各濃度(最終濃度が0.15~5.0μMとなるよう調整)に調節した化合物14をそれぞれのチューブに加えた。濃度ごとにオルトバナジウム酸 (Vi) (Sigma) 0.3 mMを添加したものVi (+) 、していないものVi (-) の2種類のチューブを用意した。5 mM ATPを加えた後、37℃恒温槽で20分静置した。その後、5% SDS(sodium dodecyl sulfate)を加え反応を停止させた。ATP加水分解によって生じた無機リン酸の量を計測してATP反応の程度を調べるため、無機リン酸反応試薬、1%アスコルビン酸を加え、発色反応を行い、10分間室温で静置した。その後、吸光度リーダーUltrospec 3100 pro (Amersham Biosciences) を用いて880 nmで吸光度を測定した。ViによってABCG2によるATP反応は抑制されるため、Vi (-) のチューブの反応 (タンパク全体のATP反応) からのVi (+) のチューブの反応 (ABCG2以外のATP反応) の差を求めることによってABCG2によるATP加水分解を算出した。各反応のEC50 (half maximal effective concentration; 50%効果濃度) は JMP Pro 14.0 (SAS International INC.)を用いて算出した。 In this test example, insect cells were infected with a baculovirus genetically modified with human ABCG2 cDNA, and cell membrane proteins extracted from the insect cells were used (Non-Patent Document 12). This protein was provided by Dr. Suresh V. Ambudkar. 2×ATPase buffer and H 2 O were added to an ATPase assay tube, and 6 μg of cell membrane protein was added thereto. Compound 14 adjusted to each concentration (adjusted to a final concentration of 0.15 to 5.0 μM) was added to each tube. Two types of tubes, Vi (+) with and without 0.3 mM of orthovanadate (Vi) (Sigma), were prepared for each concentration. After adding 5 mM ATP, the mixture was allowed to stand in a 37°C constant temperature bath for 20 minutes. After that, 5% SDS (sodium dodecyl sulfate) was added to stop the reaction. In order to measure the amount of inorganic phosphate produced by ATP hydrolysis and examine the extent of the ATP reaction, an inorganic phosphate reaction reagent and 1% ascorbic acid were added for color development reaction, and the mixture was allowed to stand at room temperature for 10 minutes. Absorbance was then measured at 880 nm using the absorbance reader Ultrospec 3100 pro (Amersham Biosciences). Since the ATP reaction by ABCG2 is inhibited by Vi, by calculating the difference between the Vi (-) tube reaction (the ATP reaction of the whole protein) and the Vi (+) tube reaction (ATP reaction other than ABCG2), ATP hydrolysis by ABCG2 was calculated. The EC50 (half maximal effective concentration; 50 % effective concentration) of each reaction was calculated using JMP Pro 14.0 (SAS International INC.).
VI. ABCG2の発現確認(RT-qPCR)
HCT-116/BCRP細胞株におけるABCG2のmRNA発現の程度および化合物14のABCG2発現に対する影響を確認するため、定量リアルタイムPCRを行った。HCT-116細胞、HCT-116/BCRP細胞、および化合物14(10 μM)存在下で3日間培養したHCT-116/BCRP細胞を使用した。細胞株よりRNeasy Mini Kit (QIAGEN) を用いてtotal RNAを抽出し、NanoDrop2000 (Thermo Scientific) にて十分な濃度があることを確認した。抽出したtotal RNAをPrimeScript RT reagent Kit (TakaraBIO) を用いて逆転写反応を行い cDNA (complementary DNA; 相補的DNA) を合成した。リアルタイムPCR反応にはStepOnePlus Real Time PCR System (Life Technologies) 及びSYBR Premix Ex Taq II (Tli RNaseH Plus), ROX plus(TAKARA BIO)を用いて行い、2-ΔΔCt法で算出した。反応条件は、95℃30秒、95℃5秒、60℃30秒を1サイクルとして、40サイクル行った。内在性コントロールにはGAPDH(glyceraldehyde 3-phosphate dehydrogenase:グリセルアルデヒド3-リン酸デヒドロゲナーゼ)を用いた。mRNA発現量はGAPDHとの比で相対定量し、コントロールとの割合で表した。測定したmRNA量はHCT-116細胞との相対量として表した。
VI. ABCG2 expression confirmation (RT-qPCR)
To confirm the extent of ABCG2 mRNA expression and the effect of compound 14 on ABCG2 expression in the HCT-116/BCRP cell line, quantitative real-time PCR was performed. HCT-116 cells, HCT-116/BCRP cells, and HCT-116/BCRP cells cultured for 3 days in the presence of compound 14 (10 μM) were used. Total RNA was extracted from cell lines using RNeasy Mini Kit (QIAGEN) and confirmed to have sufficient concentration using NanoDrop2000 (Thermo Scientific). The extracted total RNA was subjected to reverse transcription reaction using PrimeScript RT reagent Kit (TakaraBIO) to synthesize cDNA (complementary DNA). Real-time PCR reaction was performed using StepOnePlus Real Time PCR System (Life Technologies), SYBR Premix Ex Taq II (Tli RNaseH Plus), ROX plus (TAKARA BIO) and calculated by the 2-ΔΔCt method. The reaction conditions were 40 cycles of 95°C for 30 seconds, 95°C for 5 seconds, and 60°C for 30 seconds. GAPDH (glyceraldehyde 3-phosphate dehydrogenase) was used as an endogenous control. The amount of mRNA expression was determined relative to GAPDH and expressed as a ratio to the control. The amount of mRNA measured was expressed as a relative amount to that of HCT-116 cells.
記にRT-qPCRに使用したプライマーの配列情報を示す。
ABCG2 (forward):5’-GGTCAGAGTGTGGTTTCTGTAGCA-3’(配列番号1)
ABCG2 (reverse):5’-GTGAGAGATCGATGCCCTGCTTTA-3’ (配列番号2)
GAPDH (forward): 5’-GCACCGTCAAGGCTGAGAAC-3’ (配列番号3)
GAPDH (reverse):5’-TGGTGAAGACGCCAGTGGA-3(配列番号4)
The sequence information of the primers used for RT-qPCR is shown below.
ABCG2 (forward): 5'-GGTCAGAGTGTGGTTTCTGTAGCA-3' (SEQ ID NO: 1)
ABCG2 (reverse): 5'-GTGAGAGATCGATGCCCTGCTTTA-3' (SEQ ID NO: 2)
GAPDH (forward): 5'-GCACCGTCAAGGCTGAGAAC-3' (SEQ ID NO: 3)
GAPDH (reverse): 5'-TGGTGAAGACGCCAGTGGA-3 (SEQ ID NO: 4)
VII.動物実験モデル
8-10週齢、雌のBALB/c nu-nuマウスを用いた腫瘍の皮下移植モデルを作成し、化合物14が抗癌剤の感受性に与える影響を検証するために動物実験を行った。本研究では、東北大学動物実験センターにて承認された動物実験計画書を用い(承認番号:2019医動-164)、「国立大学法人東北大学における動物実験等に関する規定とその解説 第14版」を遵守した。
細胞株にはABCG2を過剰発現したHCT-116/BCRPを用い、2×107 cells/mLとなるようにPBS (-)で細胞の懸濁を行った。そして、この細胞懸濁液とマトリゲルマトリックス(Corning)を2:1となるように氷上で混和し、1 mLシリンジに200 μLずつ取り分けた。皮下移植は3種混合麻酔(塩酸メデトミジン+ミダゾラム+酒石酸ブトルファノール混合麻酔)下に、マウスの左右の背部に行った。皮下移植後は1-2日毎に腫瘍の生着状態を確認し、腫瘍径が長径で5-10 mmとなったところで薬剤の投与を行った。抗癌剤については、これまでの報告から30 mg/kgのイリノテカンを腹腔内投与で用いることとした(非特許文献13、14)。また、候補薬剤の濃度についてはこれまでの報告例がなく、in vitroの実験で陽性コントロールとして用いたKo143の既報を参考に、10 mg/kgの濃度で腹腔内投与を行うことにした(非特許文献15)。そして、以下のような4群(n=5)に分けて薬剤投与を行った。a)生理食塩水のみ400 μLを腹腔内投与、b)イリノテカン30 mg/kgを生理食塩水に希釈し400 μLを腹腔内投与、c)候補薬剤10 mg/kgとイリノテカン30 mg/kgを生理食塩水に希釈し400 μLを腹腔内投与、d)候補薬剤10 mg/kgを生理食塩水に希釈し400 μLを腹腔内投与とした。なお、薬剤の調整について、候補薬剤は5% w/vの濃度となるようにDMSOで溶解後生理食塩水に希釈、イリノテカンは溶液状態で入手したため、そのまま生理食塩水に希釈した。初回投与日をday 0として、3日毎のday 3、6、9、12、15、18に計7回投与を行った。薬剤投与日に体重と腫瘍径を測定し、0.5 × (長径) × (短径)2で腫瘍体積を計算した。そして、day 21に体重と腫瘍径を測定後、マウスを深麻酔と頸椎脱臼で犠死させた。皮下腫瘍を摘出し、重量を測定した。
VII. animal model
An 8- to 10-week-old female BALB/c nu-nu mouse was used to create a tumor subcutaneous implantation model, and an animal experiment was performed to verify the effect of compound 14 on anticancer drug sensitivity. In this study, we used the animal experiment protocol approved by the Tohoku University Animal Experiment Center (approval number: 2019 Ido-164), "Rules and explanations for animal experiments at National University Corporation Tohoku University, 14th edition" complied with.
ABCG2-overexpressing HCT-116/BCRP was used as the cell line, and the cells were suspended in PBS (-) to a concentration of 2×10 7 cells/mL. Then, this cell suspension and Matrigel matrix (Corning) were mixed at a ratio of 2:1 on ice, and 200 µL of each was dispensed into 1 mL syringes. Subcutaneous transplantation was performed on the left and right dorsal regions of mice under triple anesthesia (medetomidine hydrochloride + midazolam + butorphanol tartrate mixed anesthesia). After subcutaneous transplantation, the state of tumor engraftment was checked every 1-2 days, and the drug was administered when the tumor diameter reached 5-10 mm in major axis. As for the anticancer agent, 30 mg/kg of irinotecan was used by intraperitoneal administration based on previous reports (Non-Patent Documents 13 and 14). In addition, there was no report on the concentration of the candidate drug so far, and referring to the previous report of Ko143, which was used as a positive control in in vitro experiments, we decided to perform intraperitoneal administration at a concentration of 10 mg/kg (non Patent document 15). Then, they were divided into the following four groups (n=5) and administered drugs. a) 400 μL of saline alone, b) 400 μL of 30 mg/kg irinotecan diluted in saline, c) 10 mg/kg candidate drug plus 30 mg/kg irinotecan d) 10 mg/kg of the candidate drug was diluted in physiological saline and 400 μL was intraperitoneally administered. Regarding preparation of the drug, the candidate drug was dissolved in DMSO and then diluted in physiological saline to a concentration of 5% w/v. Starting from the first administration day as
VIII.統計解析
フローサイトメトリーによる蛍光剤排出試験は、スクリーニング化合物の容量が限られていたため、1回ずつ行った。その後の実験では、3回以上の独立した試験を行い、平均値、標準偏差、標準誤差を算出した。平均値の検定にはStudent’s t検定を用いた。統計学的解析にはJMP Pro 14.0 (SAS International INC.)を用い、P < 0.05を統計学的に有意であるとした。
VIII. Statistical Analysis Fluorescent efflux studies by flow cytometry were performed in batches due to the limited volume of screening compounds. In subsequent experiments, 3 or more independent tests were performed and the mean, standard deviation and standard error were calculated. Student's t-test was used to test mean values. JMP Pro 14.0 (SAS International INC.) was used for statistical analysis, and P < 0.05 was considered statistically significant.
試験結果
I.フローサイトメトリーによるPhA排出試験
下記表1-1~1-2に示す化合物1~14に対し、フローサイトメトリーを行った。結果のヒストグラムを図2aの1-2に示した。程度の差はあるが、ほとんどの化合物で濃度依存的な蛍光強度の増強を認めた。10 μMにおける蛍光強度について、各化合物と陽性コントロールとの比を示したものが図2bである。フローサイトメトリーにおける蛍光強度の中央値を用いて算出した。10 μMにおいて陽性コントロールの30%未満の化合物が6種類あり、これらはABCG2の抑制効果は低いものと考えた。それらを除く16種類に対し、次の細胞毒性試験を行った。
Test results I. PhA Excretion Test by Flow Cytometry Flow cytometry was performed on
II. 細胞毒性試験
(1) 抗癌剤感受性への影響
フローサイトメトリーによる解析で有効な抑制効果をもたらした7種類の化合物を用いて、HCT-116/BCRPに対する細胞毒性試験(MTS assay)を行った。結果を表2に示した。
II. Cytotoxicity test
(1) Effect on Anticancer Agent Sensitivity Cytotoxicity test (MTS assay) against HCT-116/BCRP was carried out using 7 kinds of compounds that showed an effective inhibitory effect in flow cytometric analysis. Table 2 shows the results.
No.7とNo.11は化合物そのものの細胞毒性が強く、IC50の評価はできなかった。
No. 14がフェニルフロクマリン誘導体である。
※Ko143および候補化合物の入っていない状態(Medium)でのIC50を1.0とした場合の相対的な感受性増強率を示した。
Compounds themselves of No. 7 and No. 11 had strong cytotoxicity, and their IC 50 values could not be evaluated.
No. 14 is a phenyl furocoumarin derivative.
*The relative susceptibility enhancement rate when IC 50 in the state without Ko143 and candidate compound (Medium) is 1.0 is shown.
陽性コントロールKo143 1 μMのIC50が0.26 ± 0.027、化合物14は、5 μMでIC50が0.36 ± 0.11 μM、10 μMでIC50が0.19 ± 0.018 μMであった。相対的な感受性増強率(fold reversal: 候補薬剤及び陽性コントロールを添加していない条件でのIC50との比で算出)はKo143 1μMで10.1倍、No.22は5 μMで7.3倍、10 μMで13.8倍であり、化合物1410μMにおいて最もSN-38の感受性を増強させる結果であった。この化合物14(本試験例において、化合物14をフェニルフロクマリン誘導体、a phenylfurocoumarin derivative: PFCと示すことがある)が最も効果的なABCG2抑制剤である可能性が高いと考え、以降の実験に用いることとした。PFCの構造式を図3Aに、細胞毒性試験の結果を図4Aに示す。さらに、この化合物と類似の構造をもつオキシポイセダニン(図3B、点線が共通構造)に対して、同様に細胞毒性試験を行った。オキシポイセダニンのfold reversalは5 μMで2.35倍、10 μMで3.0倍であり、PFCやKo143に比べ、ABCG2抑制効果は弱いものと考えられた。
The positive control Ko143 had an IC 50 of 0.26 ± 0.027 at 1 μM and compound 14 had an IC 50 of 0.36 ± 0.11 μM at 5 μM and an IC 50 of 0.19 ± 0.018 μM at 10 μM. The relative susceptibility enhancement rate (fold reversal: calculated as a ratio of IC 50 in the condition where no candidate drug or positive control was added) was 10.1 times at
(2) HCT-116に対する細胞毒性の評価
PFCのHCT-116に対する細胞毒性を評価するため、同様のMTS assayを行った。結果を表3、図4Bに示す。
(2) Evaluation of cytotoxicity against HCT-116
A similar MTS assay was performed to assess the cytotoxicity of PFC to HCT-116. The results are shown in Table 3 and Figure 4B.
表3、図4Bに示すように、抗癌剤投与のみのIC50は0.11 ± 0.0037 μM、Ko143 1 μM存在下のIC50は0.11 ± 0.0036 μM、PFC 5 μM存在下のIC50は0.077 ± 0.022 μM、PFC 10 μM存在下のIC50は0.057 ± 0.013 μMであった。PFC投与でわずかにIC50の低下を認めるものの、HCT-116/BCRPでの結果ほど著明ではなかった。 As shown in Table 3 and FIG. 4B, the IC 50 for anticancer drug administration alone was 0.11 ± 0.0037 µM, the IC 50 in the presence of 1 µM Ko143 was 0.11 ± 0.0036 µM, and the IC 50 in the presence of 5 µM PFC was 0.077 ± 0.022 µM. The IC50 in the presence of 10 µM PFC was 0.057 ± 0.013 µM. Although PFC administration slightly decreased IC 50 , it was not as marked as the result with HCT-116/BCRP.
(3) 化合物の毒性評価
Ko143とPFCに関し、単剤でのHCT-116及びHCT-116/BCRPに対する毒性評価を行った。表4に結果を示した。
(3) Toxicity evaluation of compounds
Ko143 and PFC were evaluated for single-agent toxicity against HCT-116 and HCT-116/BCRP. Table 4 shows the results.
これまでの実験で用いてきたKo143 1 μM、PFC 10 μMは、これまでの実験結果に影響を及ぼすほどの毒性はないことが示唆された。
It was suggested that
III. ATP加水分解試験
PFCによるATP加水分解への影響を評価した。結果を図5に示す。図5に示すように、PFCは濃度依存的にATP加水分解を促進し、EC50は0.038 ± 0.0064 μMであった。このことから、PFCは、ABCG2においてATP加水分解を促進する、つまりABCG2の基質結合部位に作用する化合物であることが示唆された。
III. ATP hydrolysis test
The effect of PFC on ATP hydrolysis was evaluated. The results are shown in FIG. As shown in Figure 5, PFC promoted ATP hydrolysis in a concentration-dependent manner with an EC50 of 0.038 ± 0.0064 µM. This suggests that PFC is a compound that promotes ATP hydrolysis in ABCG2, that is, acts on the substrate-binding site of ABCG2.
IV. ABCG2の発現に対する影響
HCT-116/BCRPにおけるABCG2の発現、またPFCのABCG2発現に対する影響を評価するため、RT-qPCRを行った。親株HCT-116でのABCG2発現量に対するHCT-116/BCRPおよびPFC存在下でのHCT-116/BCRPのABCG2発現量を算出し、結果を図6に示した。両者に有意差はなく、PFCはABCG2発現に影響を与えないことが示唆された。
IV. Effects on the expression of ABCG2
RT-qPCR was performed to evaluate ABCG2 expression in HCT-116/BCRP and the effect of PFC on ABCG2 expression. The ABCG2 expression level of HCT-116/BCRP and HCT-116/BCRP in the presence of PFC relative to the ABCG2 expression level of the parent strain HCT-116 was calculated, and the results are shown in FIG. There was no significant difference between the two, suggesting that PFC does not affect ABCG2 expression.
V. マウス皮下腫瘍モデルを用いた動物実験
マウス皮下腫瘍モデルで、PFCがイリノテカンの感受性を増強させるかを検証した。そして、4群に分けて治療薬の腹腔内投与を行った。腫瘍体積の変化を図7Aに示す。投与開始日の体積を基準として、増加率を評価した。今回の検討ではPFCがイリノテカンの感受性をどの程度増強させるかに着目したため、b)イリノテカン投与群に対する、c)フェニルフロクマリン誘導体+イリノテカン投与群の2群で比較したところ、day 12から有意に腫瘍増加率が小さかった。また、マウスの体重は徐々に減少が見られたものの、全てのグループで減少率は20%未満に留まっていた(図7B)。腫瘍重量に関しては、b)イリノテカン投与群とc)フェニルフロクマリン誘導体+イリノテカン投与群の間に有意差は認めなかったものの、b)群は207.8 ± 70.4 mg、c)群は159.7 ± 37.9 mgであり、腫瘍は小さい傾向であった(図7C)。
V. Animal Experiments Using a Mouse Subcutaneous Tumor Model A mouse subcutaneous tumor model was used to verify whether PFC enhances irinotecan sensitivity. Then, the animals were divided into four groups and intraperitoneally administered with a therapeutic agent. Changes in tumor volume are shown in Figure 7A. The rate of increase was evaluated based on the volume on the day of administration start. In this study, we focused on how much PFC enhances the sensitivity of irinotecan, so when we compared the two groups of b) irinotecan administration group and c) phenylfurocoumarin derivative + irinotecan administration group, there was a significant tumor increase from
4.考察
上記試験に示すように、化合物14(PFC)は、フローサイトメトリーでは基質の排出抑制を示し、細胞毒性試験では抗癌剤感受性の増強を示した。また、ATPase assayとRT-qPCRの結果を考えると、PFCはABCG2の発現を変化させず、直接的にABCG2の基質結合部位に作用し、阻害効果を示していると考えられた。さらに、ヌードマウスの皮下腫瘍モデルにおいて、PFCは目立った副作用を呈することなく、イリノテカンの感受性を増強させることを示した。
4. Discussion As shown in the above test, compound 14 (PFC) showed inhibition of substrate excretion in flow cytometry and enhanced anticancer drug sensitivity in cytotoxicity test. In addition, considering the results of ATPase assay and RT-qPCR, it was considered that PFC directly acts on the substrate-binding site of ABCG2 without changing the expression of ABCG2, showing an inhibitory effect. Furthermore, in a subcutaneous tumor model in nude mice, PFC was shown to enhance irinotecan sensitivity without significant side effects.
Claims (8)
が、基
である、請求項1に記載の機能抑制剤又は請求項2若しくは請求項3に記載の医薬。 group
but
The function inhibitor according to claim 1 or the medicament according to claim 2 or 3, which is
が、基
である、請求項6に記載のフェニルフロクマリン誘導体又はその塩。 group
but
The phenylfurocoumarin derivative or a salt thereof according to claim 6, which is
The phenylfurocoumarin derivative or a salt thereof according to claim 6 or 7, wherein n' represents an integer of 1 to 3.
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