JPH0977667A - Extinction promotor for nucleic acid base hydroxide - Google Patents
Extinction promotor for nucleic acid base hydroxideInfo
- Publication number
- JPH0977667A JPH0977667A JP25937795A JP25937795A JPH0977667A JP H0977667 A JPH0977667 A JP H0977667A JP 25937795 A JP25937795 A JP 25937795A JP 25937795 A JP25937795 A JP 25937795A JP H0977667 A JPH0977667 A JP H0977667A
- Authority
- JP
- Japan
- Prior art keywords
- hydroxide
- nucleobase
- compound
- nucleic acid
- extinction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明が属する技術分野】本発明は核酸塩基水酸化物消
去剤に関する。TECHNICAL FIELD The present invention relates to a nucleobase hydroxide eliminator.
【０００２】[0002]
【従来の技術】核酸又は核酸塩基、例えばグアニン又は
核酸中のグアニン部分が水酸化されて出来る８−ヒドロ
キシグアニンの様な核酸塩基水酸化物は、癌細胞、正常
細胞の区別無く、放射線障害や紫外線などの光障害の作
用機序と深く係わっていることが知られている。（フィ
ッシャー・ニールセンら「カルシノゲネシス」１４（１
１）、２４３１ー３、１９９３、別所ら「プロシーディ
ング・ナショナル・アカデミー・サイエンスＵＳＡ」９
０（１９）、８９０１−４、１９９３）これらの生成及
びその消失は前記文献によれば、発ガンの機構或いは癌
細胞の死滅機構と係わっていると言われている。発生し
た核酸塩基水酸化物はその消去過程に於いてＤＮＡ等の
核酸鎖の切断に関与するとの報告もある。この様な観点
から、放射線癌治療に於いて８−ヒドロキシグアニンに
代表される核酸塩基水酸化物類を消去することは放射線
治療等の癌治療を考える上で有意義なことと推測されて
いた。2. Description of the Related Art Nucleic acid or nucleobases, such as guanine or nucleobase hydroxide such as 8-hydroxyguanine formed by hydroxylation of guanine moiety in nucleic acid, can prevent radiation damage or radiation damage regardless of whether cancer cells or normal cells. It is known that it is deeply related to the mechanism of action of photodisorders such as ultraviolet rays. (Fischer Nielsen et al. "Carcinogenesis" 14 (1
1), 2431-3, 1993, Bessho et al. "Proceeding National Academy Science USA" 9
0 (19), 8901-4, 1993) It is said that the production and disappearance thereof are related to the mechanism of carcinogenesis or the mechanism of cancer cell death. It is also reported that the generated nucleobase hydroxide is involved in the cleavage of nucleic acid chains such as DNA in the elimination process. From such a viewpoint, it has been speculated that elimination of nucleobase hydroxides represented by 8-hydroxyguanine in radiation cancer treatment is significant in considering cancer treatment such as radiation treatment.
【０００３】かかる状況下、グアニン等の核酸塩基の水
酸化と消去のメカニズムを探る研究が為され、ベースグ
リコシダーゼやＮ−メチルプリン−ＤＮＡグリコシダー
ゼ等に水酸化グアニンを修復する作用があることが見い
だされたが、水酸化グアニン等核酸塩基の水酸化物の消
去を促進する物質は知られていなかった。Under such circumstances, studies have been conducted to investigate the mechanism of hydroxylation and elimination of nucleic acid bases such as guanine, and it has been found that base glycosidase, N-methylpurine-DNA glycosidase, etc. have an action of repairing hydroxylated guanine. However, a substance that promotes elimination of nucleobase hydroxide such as hydroxylated guanine was not known.
【０００４】一方、下記一般式（Ｉ）に表される化合物
は既に公知であり、これらが有する電子親和性に起因す
る腫瘍細胞中の低酸素細胞の放射線に対する感受性のみ
を増強する、いわゆる、低酸素細胞放射線増感作用を有
することは知られていたが、この化合物に核酸塩基の水
酸化物の消去を促進する作用があることは知られていな
かった。On the other hand, the compounds represented by the following general formula (I) are already known, and they enhance only the sensitivity of hypoxic cells in tumor cells to radiation due to their electron affinity. Although it is known to have an oxygen cell radiosensitizing effect, it has not been known that this compound has an effect of promoting elimination of nucleobase hydroxide.
【０００５】[0005]
【発明が解決しようとする課題】本発明はかかる状況に
鑑みて為された物であり、核酸塩基水酸化物消去促進剤
を提供することを課題とする。The present invention has been made in view of such circumstances, and an object of the present invention is to provide a nucleic acid base hydroxide elimination promoter.
【０００６】[0006]
【課題を解決するための手段】この様な状況を踏まえ
て、本発明者らは核酸塩基水酸化物消去促進作用を指標
に、各種化合物をスクリーニングした結果、下記一般式
（Ｉ）に表される化合物に優れた核酸塩基水酸化物消去
促進作用を見いだし発明を完成させた。以下、本発明に
ついて詳細に説明する。Under these circumstances, the present inventors screened various compounds using the action of promoting nucleobase hydroxide scavenging as an index, and as a result, they were represented by the following general formula (I). The inventors have found an excellent nucleobase hydroxide elimination-promoting action for a compound described above and completed the invention. Hereinafter, the present invention will be described in detail.
【０００７】[0007]
【化３】 （但し、Ｒは−ＣＨ2ＯＣＨ（ＣＨ2ＯＨ）ＣＨＯＨＣＨ
2ＯＨ、−ＣＨ2（ＣＯ）ＮＨＣＨ2ＣＨ2ＯＨ、−ＣＨ2
ＣＦ2（ＣＯ）ＮＨＣＨ2ＣＨ2ＯＨ又は−ＣＨ2ＣＨ（Ｏ
Ｈ）ＣＨ2ＮＨＣＨ2ＣＨ2Ｂｒを表す。）Embedded image (However, R is -CH 2 OCH (CH 2 OH) CHOHCH
2 OH, -CH 2 (CO) NHCH 2 CH 2 OH, -CH 2
CF 2 (CO) NHCH 2 CH 2 OH or -CH 2 CH (O
H) represents CH 2 NHCH 2 CH 2 Br. )
【０００８】（１）本発明の核酸塩基水酸化物消去促進
剤 本発明の核酸塩基水酸化物消去促進剤は上記一般式
（Ｉ）に表される化合物からなる。この様な化合物とし
ては、例えば、１−（２−ヒドロキシエチルアミノカル
ボニルメチル）−２−ニトロイミダゾール（化合物
１）、１ー（２，２−ジフルオロ−２−（２−ヒドロキ
シエチルアミノカルボニル）エチル）−２−ニトロイミ
ダゾール（化合物２）、１−（２，３−ジヒドロキシ−
１−ヒドロキシメチルプロピルオキシメチル）−２−ニ
トロイミダゾール（化合物３）、１−（２−ブロモエチ
ル）−３−（２−ニトロ−１−イミダゾリル）−２−プ
ロパノール（化合物４）等が挙げられるが、これらの内
最も好ましいものは化合物３である。これは、安全性に
優れるためである。これらの化合物は何れも公知であ
り、その製造方法も既に知られている。例えば、化合物
１、２は式１に示す様に、２−ニトロイミダゾールと対
応するハロゲノカルボン酸エステルをアルカリ存在下縮
合させ、次いでナトリウムメトキシド等を触媒に、対応
するアミンと反応させれば得られるし、又、化合物３は
式２に示すように、エリスリトールの３個の水酸基をア
シル化し、１個の水酸基をアセトキシメチル化したもの
と２−ニトロイミダゾールを酸触媒の存在下反応させ、
次いで脱アシル化すれば容易に得られる。又、化合物４
は式３に示す如く、２−ニトロイミダゾールとエピクロ
ルヒドリンをアルカリ存在下縮合させ、これとブロモエ
チルアミンを反応させれば容易に得られる。かくして得
られた一般式（Ｉ）に表される化合物は何れも、優れた
核酸塩基水酸化物消去促進作用を有する。又、これらの
化合物の急性毒性、即ち、ＬＤ５０値は何れも１ｇ／Ｋ
ｇであり、安全性上何の問題もない。(1) Nucleic Acid Base Hydroxide Elimination Promoter of the Present Invention The nucleic acid base hydroxide elimination promoter of the present invention comprises a compound represented by the above general formula (I). Examples of such a compound include 1- (2-hydroxyethylaminocarbonylmethyl) -2-nitroimidazole (Compound 1), 1- (2,2-difluoro-2- (2-hydroxyethylaminocarbonyl) ethyl ) -2-Nitroimidazole (Compound 2), 1- (2,3-dihydroxy-
1-hydroxymethylpropyloxymethyl) -2-nitroimidazole (compound 3), 1- (2-bromoethyl) -3- (2-nitro-1-imidazolyl) -2-propanol (compound 4) and the like can be mentioned. Compound 3 is the most preferred of these. This is because it is excellent in safety. All of these compounds are known, and their production methods are already known. For example, compounds 1 and 2 can be obtained by condensing 2-nitroimidazole and the corresponding halogenocarboxylic acid ester in the presence of an alkali as shown in Formula 1, and then reacting with the corresponding amine with sodium methoxide or the like as a catalyst. Further, as shown in Formula 2, Compound 3 is obtained by reacting erythritol with three hydroxyl groups acylated and one hydroxyl group acetoxymethylated to react 2-nitroimidazole in the presence of an acid catalyst,
Subsequent deacylation can be easily obtained. Also, compound 4
Can be easily obtained by condensing 2-nitroimidazole and epichlorohydrin in the presence of an alkali and reacting this with bromoethylamine as shown in Formula 3. All the compounds represented by the general formula (I) thus obtained have an excellent nucleobase hydroxide elimination accelerating action. In addition, the acute toxicity of these compounds, that is, LD50 values are all 1 g / K
g, and there is no problem in safety.
【０００９】[0009]
【化４】 Embedded image
【００１０】[0010]
【化５】 Embedded image
【００１１】[0011]
【化６】 [Chemical 6]
【００１２】[0012]
【化７】 [Chemical 7]
【００１３】[0013]
【化８】 Embedded image
【００１４】[0014]
【化９】 Embedded image
【００１５】[0015]
【化１０】 Embedded image
【００１６】（２）本発明の医薬組成物 本発明の医薬組成物は上記核酸塩基水酸化物消去促進剤
から選ばれる１種以上と製剤上の任意成分からなる。製
剤上の任意成分としては、通常医薬組成物で用いられて
いるものであれば特段の限定をされずに用いることが出
来る。この様な任意成分としては、賦形剤、増量剤、結
合剤、被覆剤、糖衣剤、安定剤、崩壊剤、着色剤、滑沢
剤、ｐＨ調製剤、可溶化剤、分散剤、増粘剤、等張剤等
が例示できる。更に本発明の医薬組成物は、癌治療に有
用な抗癌剤、制吐剤、麻薬、鎮痛剤、免疫抑制剤、ステ
ロイド剤、血管閉塞剤、放射線造影剤等を配合すること
もできる。これらの成分を常法により製剤化することに
より、本発明の医薬組成物は得られる。(2) Pharmaceutical composition of the present invention The pharmaceutical composition of the present invention comprises at least one selected from the above-mentioned nucleobase hydroxide scavenging accelerators and an optional component in the formulation. As an optional ingredient in the formulation, any one usually used in a pharmaceutical composition can be used without particular limitation. Such optional components include excipients, fillers, binders, coating agents, sugar coatings, stabilizers, disintegrants, colorants, lubricants, pH adjusters, solubilizers, dispersants, thickeners. Examples thereof include agents and isotonic agents. Furthermore, the pharmaceutical composition of the present invention may also contain an anticancer drug, an antiemetic drug, a narcotic drug, an analgesic drug, an immunosuppressive drug, a steroid drug, a vascular occlusion drug, a radiocontrast drug, etc. The pharmaceutical composition of the present invention can be obtained by formulating these components by a conventional method.
【００１７】本発明の医薬組成物の投与経路であるが、
通常用いられている経路であれば、特段の制限無く用い
ることが出来る。この様な投与経路としては、注射剤で
あれば、皮下投与、腹腔内投与、動脈投与、静脈投与等
が例示できる。更に本化合物は安定性に優れるため、経
口投与も可能である。又、投与量は、経口投与の場合１
日成人１人当たり５〜５００ｍｇを数回に分けて投与す
るのが適当である。注射剤として用いる場合は、１〜１
００ｍｇが適当である。The route of administration of the pharmaceutical composition of the present invention is
Any commonly used route can be used without particular limitation. Examples of such administration route include subcutaneous administration, intraperitoneal administration, arterial administration, and intravenous administration as long as they are injections. Furthermore, since this compound has excellent stability, it can be administered orally. Also, the dose is 1 for oral administration.
It is suitable to administer 5 to 500 mg per adult daily in several divided doses. When used as an injection, 1 to 1
00 mg is suitable.
【００１８】[0018]
【発明の実施の態様】以下に本発明の実施の態様につい
て説明する。本発明の実施の態様は、下記に示す製剤例
の様に作成した医薬組成物を、放射線治療或いは化学療
法を行っている癌患者に対して、経口投与の場合１日成
人１人当たり１０〜５００ｍｇを数回に分けて、注射剤
として用いる場合は、５〜１００ｍｇを数回に分けて投
与し、これらの放射線療法又は化学療法の効果を高める
ことである。投与のタイミングは放射線照射の前後のい
つでも、又抗癌剤の投与の前後のいつでも可能である。
好ましくは、抗癌剤の投与の極めて近傍の前後、或い
は、放射線照射の前後の極めて近傍が好ましい。又、照
射と同時或いは抗癌剤と同時に投与しても良く、予め抗
癌剤と共に製剤化して投与しても良い。尚、本発明が以
下に示す例にのみ限定されるものではないことは言うま
でもない。BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below. In the embodiment of the present invention, a pharmaceutical composition prepared as in the following formulation example is orally administered to a cancer patient who is undergoing radiotherapy or chemotherapy at a dose of 10 to 500 mg per adult per day. When it is used as an injection in several divided doses, 5 to 100 mg is divided into several divided doses to enhance the effects of these radiotherapy or chemotherapy. The timing of administration can be any time before or after irradiation, or any time before or after administration of the anticancer drug.
It is preferable that it is before and after administration of the anticancer agent, or before and after irradiation with radiation. Further, it may be administered at the same time as the irradiation or at the same time as the anticancer agent, or may be formulated in advance with the anticancer agent and administered. Needless to say, the present invention is not limited to the examples shown below.
【００１９】製剤例１ 下記の処方に基づいて、顆粒を作成した。即ち、処方成
分をグラッド造粒機に秤込み、５０重量部の５０％エタ
ノール水溶液を噴霧しながら混練りし造粒した。造粒物
を４０℃で４８時間送風乾燥し篩過して顆粒を得た。 化合物１ ２０重量部 乳糖 ２０重量部 結晶セルロース ２０重量部 ヒドロキシプロピルメチルセルロース １０重量部 デンプン ２９重量部 アルミニウムステアレート １重量部Formulation Example 1 Granules were prepared based on the following formulation. That is, the prescription ingredients were weighed in a Glad granulator, kneaded and granulated while spraying 50 parts by weight of a 50% ethanol aqueous solution. The granulated product was blow-dried at 40 ° C. for 48 hours and sieved to obtain granules. Compound 1 20 parts by weight Lactose 20 parts by weight Crystalline cellulose 20 parts by weight Hydroxypropyl methylcellulose 10 parts by weight Starch 29 parts by weight Aluminum stearate 1 part by weight
【００２０】製剤例２ 下記の処方に基づいて、顆粒を作成した。即ち、処方成
分をグラッド造粒機に秤込み、５０重量部の５０％エタ
ノール水溶液を噴霧しながら混練りし造粒した。造粒物
を４０℃で４８時間送風乾燥し篩過して顆粒を得た。 化合物２ ２０重量部 乳糖 ２０重量部 結晶セルロース ２０重量部 ヒドロキシプロピルメチルセルロース １０重量部 デンプン ２９重量部 アルミニウムステアレート １重量部Formulation Example 2 Granules were prepared based on the following formulation. That is, the prescription ingredients were weighed in a Glad granulator, kneaded and granulated while spraying 50 parts by weight of a 50% ethanol aqueous solution. The granulated product was blow-dried at 40 ° C. for 48 hours and sieved to obtain granules. Compound 2 20 parts by weight Lactose 20 parts by weight Crystalline cellulose 20 parts by weight Hydroxypropyl methylcellulose 10 parts by weight Starch 29 parts by weight Aluminum stearate 1 part by weight
【００２１】製剤例３ 下記の処方に基づいて、顆粒を作成した。即ち、処方成
分をグラッド造粒機に秤込み、５０重量部の５０％エタ
ノール水溶液を噴霧しながら混練りし造粒した。造粒物
を４０℃で４８時間送風乾燥し篩過して顆粒を得た。 化合物３ ２０重量部 乳糖 ２０重量部 結晶セルロース ２０重量部 ヒドロキシプロピルメチルセルロース １０重量部 デンプン ２９重量部 アルミニウムステアレート １重量部Formulation Example 3 Granules were prepared according to the following formulation. That is, the prescription ingredients were weighed in a Glad granulator, kneaded and granulated while spraying 50 parts by weight of a 50% ethanol aqueous solution. The granulated product was blow-dried at 40 ° C. for 48 hours and sieved to obtain granules. Compound 3 20 parts by weight Lactose 20 parts by weight Crystalline cellulose 20 parts by weight Hydroxypropyl methylcellulose 10 parts by weight Starch 29 parts by weight Aluminum stearate 1 part by weight
【００２２】製造例４ 以下の処方に従って、注射剤を作成した。即ち、処方成
分を加熱可溶化し滅菌濾過し無菌充填封入し注射剤を得
た。 化合物１ １０ 重量部 精製水 ８０．２重量部 塩化ナトリウム ０．８重量部Production Example 4 An injection was prepared according to the following formulation. That is, the prescription components were solubilized by heating, sterile filtered, and aseptically filled and sealed to obtain an injection. Compound 1 10 parts by weight Purified water 80.2 parts by weight Sodium chloride 0.8 parts by weight
【００２３】製造例５ 以下の処方に従って、注射剤を作成した。即ち、処方成
分を加熱可溶化し滅菌濾過し無菌充填封入し注射剤を得
た。 化合物２ １０ 重量部 精製水 ８０．２重量部 塩化ナトリウム ０．８重量部Production Example 5 An injection was prepared according to the following formulation. That is, the prescription components were solubilized by heating, sterile filtered, and aseptically filled and sealed to obtain an injection. Compound 2 10 parts by weight Purified water 80.2 parts by weight Sodium chloride 0.8 parts by weight
【００２４】製造例６ 以下の処方に従って、注射剤を作成した。即ち、処方成
分を加熱可溶化し滅菌濾過し無菌充填封入し注射剤を得
た。 化合物４ １０ 重量部 精製水 ８０．２重量部 塩化ナトリウム ０．８重量部Production Example 6 An injection was prepared according to the following formulation. That is, the prescription components were solubilized by heating, sterile filtered, and aseptically filled and sealed to obtain an injection. Compound 4 10 parts by weight Purified water 80.2 parts by weight Sodium chloride 0.8 parts by weight
【００２５】[0025]
実施例１ Ｘ線照射による８−ヒドロキシグアノシン（８−ＯＨｄ
Ｇ）生成に対する本発明の核酸塩基水酸化物消去促進剤
の影響を下記の試験方法に従って検討した。核酸塩基水
酸化物消去促進剤としては、化合物３を用いた。即ち、
（１）１ｍＭ２’−デオキシグアノシン水溶液、及び
（２）１ｍＭ ２’−デオキシグアノシン， １ｍＭの
化合物３の水溶液を調製し、それぞれ １．５ｍｌ ｔ
ｕｂｅに３００μｌづつ分注した。各サンプルを２分間
笑気ガス にてバブリング（ガス流量 １００ｍｌ／
ｍｉｎ）し、水溶液を笑気ガス飽和させた後、Ｘ線照射
を施した。Ｘ線照射量は（１）が０、２０、６０、１０
０Ｇｙ、（２）が０、４０、８０、１２０、１６０Ｇｙ
である（各３サンプル照射）。Ｘ線照射後、８−ヒドロ
キシグアノシン量を高速液体クロマトグラフィーにて分
析した。（カラム：ＯＤＳ２５ｃｍ×４．６ｍｍ、移動
相：５％メタノールｉｎ５０ｍＭ燐酸バッファー（ｐＨ
６．０）、カラム温度：４０℃、流速：１ｍｌ／ｍｉ
ｎ、検知：電気化学検出器（＋６００ｍＶ））結果を図
１に示す。これより（２）の本発明の核酸塩基水酸化物
消去促進剤を添加したもの（●−●）の方が（１）のコ
ントロール（○−○）よりも水酸化物の量が少ないこと
が判る。更に、本発明の核酸塩基水酸化物消去促進剤が
水酸化物の生成に関与するＯＨラジカルそのものの生成
を抑制している可能性を排除するために、実際に２’−
デオキシグアノシンと反応したＯＨラジカル量をＯＨラ
ジカルと２’−デオキシグアノシン、化合物３との反応
速度定数を利用して算出し、横軸を補正し図２を得た。
図１と図２を比較するとパターンに差がないことが判
る。即ち、放射線によって生じるＯＨラジカル量は、本
発明の核酸塩基水酸化物消去剤である化合物３の有無に
変わり無く一定であり、化合物３が放射線照射によって
生じた核酸塩基の水酸化物の消去を促進していることが
判る。Example 1 8-Hydroxyguanosine (8-OHd by X-ray irradiation
G) The influence of the nucleobase hydroxide elimination promoter of the present invention on production was examined according to the following test method. Compound 3 was used as the nucleobase hydroxide elimination promoter. That is,
(1) 1 mM 2'-deoxyguanosine aqueous solution and (2) 1 mM 2'-deoxyguanosine, 1 mM aqueous solution of compound 3 were prepared, and each of them was 1.5 ml t.
300 μl was dispensed into each ube. Bubbling each sample with laughing gas for 2 minutes (gas flow rate 100 ml /
min), the aqueous solution was saturated with laughing gas, and then subjected to X-ray irradiation. The X-ray irradiation dose of (1) is 0, 20, 60, 10
0 Gy, (2) is 0, 40, 80, 120, 160 Gy
(Irradiation of 3 samples each). After X-ray irradiation, the amount of 8-hydroxyguanosine was analyzed by high performance liquid chromatography. (Column: ODS 25 cm x 4.6 mm, mobile phase: 5% methanol in 50 mM phosphate buffer (pH
6.0), column temperature: 40 ° C., flow rate: 1 ml / mi
n, detection: electrochemical detector (+600 mV)) The results are shown in FIG. From this, the amount of hydroxide in the case of adding the nucleic acid base hydroxide elimination promoter of the present invention (2) (●-●) is smaller than that of the control (○-○) of (1). I understand. Furthermore, in order to eliminate the possibility that the nucleobase hydroxide elimination promoter of the present invention suppresses the production of OH radicals themselves involved in the production of hydroxide, 2'-
The amount of OH radicals reacted with deoxyguanosine was calculated using the reaction rate constant of OH radicals with 2'-deoxyguanosine and compound 3, and the horizontal axis was corrected to obtain FIG.
It can be seen from the comparison between FIGS. 1 and 2 that there is no difference in the patterns. That is, the amount of OH radicals generated by radiation is constant regardless of the presence or absence of the compound 3 as a nucleobase hydroxide scavenger of the present invention, and the compound 3 eliminates the nucleobase hydroxide generated by irradiation. You can see that they are promoting.
【００２６】実施例２ 絶対温度７７度条件下におけるＤＮＡのγ線照射による
８−ヒドロキシグアノシン生成に対する、本発明の核酸
塩基水酸化物消去剤の影響を化合物３を例にとって、次
のように検討した。即ち、（１） １２ｍＭ ＤＮＡ水
溶液、及び（２）１２ｍＭのＤＮＡ， １２ｍＭの化合
物３の水溶液を調製し、それぞれグラスチューブに５０
０μｌづつ分注した。各サンプルを２分間アルゴンガス
にてバブリング（ガス流量 １００ｍｌ／ｍｉｎ）し、
水溶液をアルゴンガス飽和させた後直ちに液体窒素にて
冷凍した。各サンプルは液体窒素にて冷却した状態でγ
線照射を施した。γ線照射量は（１）、（２）共に０、
１５ｋ、３０ｋＧｙである（各３サンプル照射）。γ線
照射後、ＤＮＡをアルカリホスファターゼ及びジエステ
ラーゼによりヌクレオシドレベルにまで加水分解し、限
外ろ過（分子量 １００００）を施した。その後高速液
体クロマトグラフィーにて分析し（実施例１と同条
件）、２’−デオキシグアノシン及び８−ヒドロキシグ
アノシン量を測定した。結果を図３に示す。（２）の本
発明の核酸塩基水酸化物消去促進剤存在下の方（●−
●）が（１）のコントロール（○−○）よりも８−ヒド
ロキシグアノシンの残余量が少ないことが判る。これよ
り、本発明の核酸塩基水酸化物消去促進剤はＤＮＡの様
なオリゴヌクレオチドの形態に於ける核酸塩基の水酸化
物の消去作用にも優れることが判る。Example 2 The influence of the nucleobase hydroxide scavenger of the present invention on the production of 8-hydroxyguanosine by γ-irradiation of DNA under an absolute temperature of 77 ° C. was examined as follows by taking Compound 3 as an example. did. That is, (1) 12 mM DNA aqueous solution, and (2) 12 mM DNA, 12 mM aqueous solution of compound 3 were prepared, and 50 each was placed in a glass tube.
Aliquots of 0 μl were dispensed. Bubbling each sample with argon gas for 2 minutes (gas flow rate 100 ml / min),
The aqueous solution was saturated with argon gas and immediately frozen in liquid nitrogen. Each sample was cooled with liquid nitrogen
It was irradiated with rays. γ-ray dose is 0 for both (1) and (2),
15 k and 30 kGy (irradiation of 3 samples each). After γ-irradiation, the DNA was hydrolyzed to the nucleoside level with alkaline phosphatase and diesterase, and subjected to ultrafiltration (molecular weight 10,000). Then, it was analyzed by high performance liquid chromatography (the same conditions as in Example 1), and the amounts of 2'-deoxyguanosine and 8-hydroxyguanosine were measured. The results are shown in FIG. Those in the presence of the nucleobase hydroxide elimination promoter of (2) of the present invention (●-
It is understood that the residual amount of 8-hydroxyguanosine is smaller than the control (○-○) of (1) in (). From this, it is understood that the nucleobase hydroxide elimination promoter of the present invention is excellent in the action of eliminating nucleobase hydroxide in the form of an oligonucleotide such as DNA.
【００２７】[0027]
【発明の効果】本発明の核酸塩基水酸化物消去促進剤は
核酸塩基水酸化物の消去促進作用に優れるので放射線療
法、光治療、化学療法等の癌治療に大変有益である。INDUSTRIAL APPLICABILITY Since the nucleobase hydroxide elimination promoter of the present invention is excellent in the promotion action of nucleobase hydroxide elimination, it is very useful for cancer treatment such as radiotherapy, phototherapy and chemotherapy.
【図１】 照射量と水酸化物の濃度のプロットを示す図
である。FIG. 1 is a diagram showing a plot of irradiation dose and hydroxide concentration.
【図２】 ＯＨラジカルの生成量と水酸化物の濃度のプ
ロットを示す図である。FIG. 2 is a diagram showing a plot of the production amount of OH radicals and the concentration of hydroxide.
【図３】 ＤＮＡに於ける照射量と水酸化物の濃度を示
す図である。FIG. 3 is a diagram showing the irradiation dose and the concentration of hydroxide in DNA.
Claims (7)
鎖、分岐又は環状のアルキル基を側鎖とする、ニトロ基
を有する複素芳香族化合物からなる核酸塩基水酸化物消
去促進剤。1. A nucleobase hydroxide elimination accelerator comprising a heteroaromatic compound having a nitro group, which has a linear, branched or cyclic alkyl group which may have an oxygen atom or a nitrogen atom as a side chain.
る、請求項１記載の核酸塩基水酸化消去促進剤。2. The nucleobase hydroxylation elimination promoter according to claim 1, wherein the heteroaromatic compound is imidazole.
−ニトロイミダゾール誘導体である、請求項１又は２記
載の核酸塩基水酸化物消去促進剤。3. A heteroaromatic compound having a nitro group is 2
-The nucleobase hydroxide elimination promoter according to claim 1 or 2, which is a nitroimidazole derivative.
鎖、分岐又は環状のアルキル基を側鎖とする、ニトロ基
を有する複素芳香族化合物が一般式（Ｉ）に表される化
合物である、請求項１〜３の何れか一項に記載の核酸塩
基水酸化物消去促進剤。 【化１】 （但し、Ｒは−ＣＨ2ＯＣＨ（ＣＨ2ＯＨ）ＣＨＯＨＣＨ
2ＯＨ、−ＣＨ2（ＣＯ）ＮＨＣＨ2ＣＨ2ＯＨ、−ＣＨ2
ＣＦ2（ＣＯ）ＮＨＣＨ2ＣＨ2ＯＨ又は−ＣＨ2ＣＨ（Ｏ
Ｈ）ＣＨ2ＮＨＣＨ2ＣＨ2Ｂｒを表す。）4. A compound represented by the general formula (I), which is a heteroaromatic compound having a nitro group, which has a linear, branched or cyclic alkyl group which may have an oxygen atom or a hydrogen atom as a side chain. The nucleobase hydroxide elimination promoter according to any one of claims 1 to 3, which is Embedded image (However, R is -CH 2 OCH (CH 2 OH) CHOHCH
2 OH, -CH 2 (CO) NHCH 2 CH 2 OH, -CH 2
CF 2 (CO) NHCH 2 CH 2 OH or -CH 2 CH (O
H) represents CH 2 NHCH 2 CH 2 Br. )
（２，３−ジヒドロキシ−１−ヒドロキシメチルプロピ
ルオキシメチル）−２−ニトロイミダゾールである、請
求項１〜４の何れか一項に記載の核酸塩基水酸化物消去
促進剤。 【化２】 5. The compound represented by the general formula (I) is 1-
The nucleobase hydroxide elimination promoter according to any one of claims 1 to 4, which is (2,3-dihydroxy-1-hydroxymethylpropyloxymethyl) -2-nitroimidazole. Embedded image
ニンである、請求項１〜５の何れか一項に記載の核酸塩
基水酸化物消去促進剤。6. The nucleobase hydroxide elimination promoter according to any one of claims 1 to 5, wherein the nucleobase hydroxide is 8-hydroxyguanine.
塩基水酸化物消去剤を含有する医薬組成物。7. A pharmaceutical composition comprising the nucleobase hydroxide eliminator according to any one of claims 1 to 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25937795A JPH0977667A (en) | 1995-09-12 | 1995-09-12 | Extinction promotor for nucleic acid base hydroxide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25937795A JPH0977667A (en) | 1995-09-12 | 1995-09-12 | Extinction promotor for nucleic acid base hydroxide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0977667A true JPH0977667A (en) | 1997-03-25 |
Family
ID=17333288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25937795A Pending JPH0977667A (en) | 1995-09-12 | 1995-09-12 | Extinction promotor for nucleic acid base hydroxide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0977667A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008090732A1 (en) | 2007-01-26 | 2008-07-31 | Pola Pharma Inc. | Pharmaceutical composition |
| WO2008152764A1 (en) | 2007-06-14 | 2008-12-18 | Pola Pharma Inc. | Pharmaceutical composition |
| WO2019069891A1 (en) | 2017-10-02 | 2019-04-11 | 学校法人慶應義塾 | Cancer stem cell inhibitor |
-
1995
- 1995-09-12 JP JP25937795A patent/JPH0977667A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008090732A1 (en) | 2007-01-26 | 2008-07-31 | Pola Pharma Inc. | Pharmaceutical composition |
| US8420687B2 (en) | 2007-01-26 | 2013-04-16 | Pola Pharma Inc. | Pharmaceutical composition |
| US8450356B2 (en) | 2007-01-26 | 2013-05-28 | Pola Pharma Inc. | Pharmaceutical composition |
| US8541459B2 (en) | 2007-01-26 | 2013-09-24 | Pola Pharma Inc. | Pharmaceutical composition |
| WO2008152764A1 (en) | 2007-06-14 | 2008-12-18 | Pola Pharma Inc. | Pharmaceutical composition |
| US8202898B1 (en) | 2007-06-14 | 2012-06-19 | Pola Pharma Inc. | Pharmaceutical composition |
| US8258165B2 (en) | 2007-06-14 | 2012-09-04 | Pola Pharma Inc. | Pharmaceutical composition |
| US8258166B2 (en) | 2007-06-14 | 2012-09-04 | Pola Pharma Inc. | Pharmaceutical composition |
| WO2019069891A1 (en) | 2017-10-02 | 2019-04-11 | 学校法人慶應義塾 | Cancer stem cell inhibitor |
| US11400076B2 (en) | 2017-10-02 | 2022-08-02 | Keio University | Cancer stem cell inhibitor |
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