JP2012246243A - Novel resveratrol derivative - Google Patents
Novel resveratrol derivative Download PDFInfo
- Publication number
- JP2012246243A JP2012246243A JP2011118382A JP2011118382A JP2012246243A JP 2012246243 A JP2012246243 A JP 2012246243A JP 2011118382 A JP2011118382 A JP 2011118382A JP 2011118382 A JP2011118382 A JP 2011118382A JP 2012246243 A JP2012246243 A JP 2012246243A
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- JP
- Japan
- Prior art keywords
- resveratrol
- novel
- derivative
- resveratrol derivative
- sinapinic acid
- 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.)
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- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
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- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- OKKJLVBELUTLKV-FIBGUPNXSA-N trideuteriomethanol Chemical compound [2H]C([2H])([2H])O OKKJLVBELUTLKV-FIBGUPNXSA-N 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- DTAYOOZOCCYGJM-UTFSVEQESA-N vaticanol c Chemical compound C1=CC(O)=CC=C1[C@H]1[C@H](C=2C=C(O)C=C(O)C=2)C2=C3[C@H]([C@H](C=4C=CC(O)=CC=4)C=4C5=C6[C@H]([C@@H](OC6=CC=4O)C=4C=CC(O)=CC=4)C=4C=C(O)C=C(O)C=4)[C@@H](C=4C=CC(O)=CC=4)[C@H]5C3=C(O)C=C2O1 DTAYOOZOCCYGJM-UTFSVEQESA-N 0.000 description 1
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Abstract
Description
本発明は、新規レスベラトロール誘導体及び該新規レスベラトロール誘導体の製造方法、前記新規レスベラトロール誘導体を含有する抗癌剤、食品、医薬品及び医薬部外品に関するものである。 The present invention relates to a novel resveratrol derivative, a method for producing the novel resveratrol derivative, an anticancer agent, a food, a pharmaceutical and a quasi-drug containing the novel resveratrol derivative.
ブドウ果皮に含有されるスチルベン誘導体であるレスベラトロールについて、画期的な研究成果が明らかにされつつある。レスベラトロールは本来ブドウが病原菌から自己を守るファイトアレキシンとして存在する抗菌作用を有する化合物であり、赤系、白系を問わずブドウ果皮に含まれることが知られている。最近の研究で、レスベラトロールは哺乳動物に対しても有用な効果を有していることが明らかになりつつある。いわゆる「フレンチパラドックス」と言われる赤ワインの有用な生理効果は、レスベラトロールの抗酸化能を始めとして各種の生理活性機能が一因であるとされている。さらに、レスベラトロールは多くの疾病に効果があることが明らかにされつつあり（非特許文献１）、その一つにレスベラトロールは強い抗癌作用を有することが報告されている（非特許文献２）。
また、前記レスベラトロールの誘導体として、天然にはレスベラトロールの重合体、例えばε−ビニフェリン（二量体）、α−ビニフェリン（三量体）、バチカノールＣ（四量体）等が報告されている。非天然型のレスベラトロール誘導体についての報告もある（特許文献１）。
Breakthrough research results are being revealed for resveratrol, a stilbene derivative contained in grape skin. Resveratrol is a compound having an antibacterial action that originally exists as a phytoalexin that protects grapes from pathogenic bacteria and is known to be contained in grape skins regardless of whether they are red or white. Recent studies are revealing that resveratrol has a useful effect on mammals as well. The useful physiological effect of red wine called so-called “French paradox” is attributed to various physiologically active functions including the antioxidant ability of resveratrol. Furthermore, resveratrol is being clarified to be effective for many diseases (Non-Patent Document 1), and one of them is reported that resveratrol has a strong anticancer activity (Non-patent Document 1). Reference 2).
In addition, as a derivative of resveratrol, a resveratrol polymer such as ε-viniferin (dimer), α-viniferin (trimer), vaticanol C (tetramer) and the like have been reported in nature. ing. There is also a report about a non-natural type resveratrol derivative (patent document 1).
一方、シナピン酸は植物の二次代謝産物の一つであり、樹木の主成分であるリグニンやリグナンの前駆体として植物界に多く存在する成分である。例えばリンゴなどの果実や、小麦などの穀物などに含まれている。また、シナピン酸の前駆体がアブラナ科の植物に多く含まれている。 On the other hand, sinapinic acid is one of the secondary metabolites of plants, and is a component that is abundant in the plant world as a precursor of lignin and lignan, which are the main components of trees. For example, it is contained in fruits such as apples and grains such as wheat. Moreover, a lot of precursors of sinapinic acid are contained in cruciferous plants.
シナピン酸やシナピン酸誘導体の有用性の開示がある。例えば、シナピン酸を含有する抗菌剤（特許文献２）、シナピン酸におけるげっ歯類の脳保護効果および認知改善効果（非特許文献３）、シナピン酸誘導体を有効成分とする脳機能改善剤（特許文献３）、シナピン酸を有効成分とする抗酸化剤（特許文献４）、ジヒドロシナピン酸を有効成分とする抗酸化剤および発癌予防剤（特許文献５）が知られている。 There is a disclosure of the usefulness of sinapinic acid and sinapinic acid derivatives. For example, antibacterial agents containing sinapinic acid (Patent Document 2), rodent brain protective effect and cognitive improvement effect in sinapinic acid (Non-patent Document 3), brain function improving agent containing sinapinic acid derivative as an active ingredient (patent Document 3), an antioxidant containing sinapinic acid as an active ingredient (Patent Document 4), an antioxidant containing dihydrosinapinic acid as an active ingredient, and a carcinogenesis preventing agent (Patent Document 5) are known.
このように、レスベラトロールやシナピン酸は食経験の豊かな天然物質であり、生体調節機能に優れた安全な化合物である。よって多岐に渡る各々の誘導体についての取り組みも多い。 Thus, resveratrol and sinapinic acid are natural substances with rich food experience and are safe compounds with excellent bioregulatory functions. Therefore, there are many efforts for various derivatives.
シナピン酸、レスベラトロール、それらの誘導体は、優れた有用性を示すものが多いことから、原料やリード化合物としてのこれらを効率的に製造する技術開示もなされている。例えば、ヒドロキシけい皮酸誘導体の製造方法（特許文献６）、キノベオン製造方法（特許文献７）、フェノール酸糖エステルの製造法（特許文献８）、キノリノン配糖体の製造方法（特許文献９）、酵素法によるフェルラ酸エステル類化合物の製造方法（特許文献１０）、けい皮酸誘導体の酵素合成法（特許文献１１）等が知られている。また、レスベラトロールについては、食品中のレスベラトロール濃度を高める取り組みがされており、紫外線照射によりレスベラトロール濃度を高めた後にレスベラトロール含有抽出物を得て、その抽出物を添加した食品が提案されている（特許文献１２）。 Since many sinapinic acids, resveratrol, and derivatives thereof exhibit excellent utility, technical disclosures for efficiently producing these as raw materials and lead compounds have been made. For example, a method for producing a hydroxycinnamic acid derivative (Patent Literature 6), a method for producing quinoveon (Patent Literature 7), a method for producing a phenolic acid sugar ester (Patent Literature 8), and a method for producing a quinolinone glycoside (Patent Literature 9) A method for producing a ferulic acid ester compound by an enzymatic method (Patent Document 10), an enzyme synthesis method for a cinnamic acid derivative (Patent Document 11), and the like are known. In addition, with regard to resveratrol, efforts have been made to increase the resveratrol concentration in foods, and after increasing the resveratrol concentration by ultraviolet irradiation, a resveratrol-containing extract was obtained and the extract was added. Foods have been proposed (Patent Document 12).
また、厚生労働省の調べによると、平成２０年の日本人の死亡原因の３０％が悪性新生物つまり癌である。そのうち、医療技術や薬の発達により多くの癌の発生数が横這い又は減少しているのに対し、現在でも増加している癌の１つが口腔癌であり、癌発生の５％を占めている。また、２０１５年には現在の４倍の罹患数になると予想されている。現在の抗癌剤の研究では、日常的に摂取できる天然物由来の化合物としては、ルテオリンが知られている（非特許文献４）。
しかし、より抗癌活性が強く、日常的に摂取できる安全な癌、特に口腔癌の治療薬、予防薬の開発が望まれている。
According to a survey by the Ministry of Health, Labor and Welfare, 30% of Japanese deaths in 2008 are malignant neoplasms or cancer. Among them, the incidence of many cancers has leveled off or decreased due to the development of medical technology and drugs, while one of the increasing cancers is oral cancer, accounting for 5% of cancer occurrences. . In 2015, the number of affected cases is expected to be four times the current number. In the current research on anticancer agents, luteolin is known as a natural product-derived compound that can be ingested on a daily basis (Non-patent Document 4).
However, it is desired to develop a therapeutic or preventive agent for safe cancer, particularly oral cancer, which has stronger anticancer activity and can be taken on a daily basis.
本発明者らは、レスベラトロールやシナピン酸に関する前記の状況を鑑みて、新規な生理活性又は、強力な生理活性を有するレスベラトロール誘導体の探索と、その製造方法を確立すべく鋭意検討した結果、意外にもレスベラトロールとシナピン酸を金属塩存在下で加熱処理するという簡便且つ安全な方法により、レスベラトロール、シナピン酸、既知のレスベラトロール誘導体及びルテオリンに比べて優れた抗癌活性、特に口腔癌に対する抗癌活性を有する新規なレスベラトロール誘導体を製造することに成功し、本発明を完成するに至った。 In view of the above-described situation regarding resveratrol and sinapinic acid, the present inventors have intensively studied to search for a novel physiological activity or a resveratrol derivative having a strong physiological activity and to establish a production method thereof. As a result, unexpectedly superior anti-cancer compared to resveratrol, sinapinic acid, known resveratrol derivatives and luteolin by a simple and safe method of heat-treating resveratrol and sinapinic acid in the presence of metal salt The present invention has been completed by successfully producing a novel resveratrol derivative having activity, particularly anticancer activity against oral cancer.
したがって、本発明は、レスベラトロール、シナピン酸、既知のレスベラトロール誘導体及びルテオリンより強力な抗癌活性、特に口腔癌に対する活性を有する新規レスベラトロール誘導体を提供し、さらに該新規レスベラトロール誘導体を、効率よく、安全に生成する方法を提供することを目的とする。
また、本発明は、前記新規レスベラトロール誘導体を含有することを特徴とする抗癌剤、さらには、食品、医薬品、医薬部外品を提供することを目的とする。
Accordingly, the present invention provides a novel resveratrol derivative having resveratrol, sinapinic acid, a known resveratrol derivative and luteolin having a stronger anticancer activity, in particular, an activity against oral cancer, and the novel resveratrol It is an object to provide a method for efficiently and safely producing a derivative.
Another object of the present invention is to provide an anticancer agent characterized by containing the novel resveratrol derivative, and further a food, a pharmaceutical, and a quasi-drug.
本発明の要旨は、
〔１〕式（１）：
The gist of the present invention is as follows:
[1] Formula (1):
で示される新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテル、
〔２〕前記〔１〕記載の新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテルを含有する抗癌剤、
〔３〕前記〔１〕記載の新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテルを含有する口腔癌細胞に対する抗癌剤、
〔４〕前記〔１〕記載の新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテルを含有する食品、医薬品又は医薬部外品、
〔５〕レスベラトロールとシナピン酸を金属塩存在下で加熱処理することにより、目的の化合物を生成することを特徴とする前記〔１〕記載の新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテルの製造方法
に関する。
A novel resveratrol derivative represented by: or a pharmaceutically acceptable salt, ester or ether thereof,
[2] An anticancer agent comprising the novel resveratrol derivative according to [1], or a pharmaceutically acceptable salt, ester or ether thereof,
[3] An anticancer agent for oral cancer cells containing the novel resveratrol derivative according to [1], or a pharmaceutically acceptable salt, ester or ether thereof,
[4] A novel resveratrol derivative according to the above [1], or a food, pharmaceutical or quasi-drug containing a pharmaceutically acceptable salt, ester or ether thereof,
[5] The novel resveratrol derivative according to the above [1], or a pharmaceutically acceptable salt thereof, wherein the target compound is produced by heat-treating resveratrol and sinapinic acid in the presence of a metal salt. It relates to a process for the production of possible salts, esters or ethers.
本発明の新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテル（以下、新規レスベラトロール誘導体という）は、レスベラトロール、シナピン酸、既知のレスベラトロール誘導体及びルテオリンと比べて、抗癌活性、特に抗口腔癌活性に優れていることから、新規な抗癌剤として有用である。
また、本発明の新規レスベラトロール誘導体は、前記のような生理活性に優れることに加えて、安全性にも優れることから、食品、医薬品及び医薬部外品に配合することができる。
The novel resveratrol derivative of the present invention, or a pharmaceutically acceptable salt, ester or ether thereof (hereinafter referred to as a novel resveratrol derivative) includes resveratrol, sinapinic acid, known resveratrol derivatives and luteolin. Compared with the anticancer activity, particularly the anti-oral cancer activity, it is useful as a novel anticancer agent.
Moreover, since the novel resveratrol derivative of this invention is excellent also in safety | security in addition to being excellent in the above physiological activities, it can be mix | blended with a foodstuff, a pharmaceutical, and a quasi-drug.
以下、本発明について詳細に説明する。
本発明の新規レスベラトロール誘導体は、式（１）：
Hereinafter, the present invention will be described in detail.
The novel resveratrol derivative of the present invention has the formula (1):
で示される新規レスベラトロール誘導体、又はその薬学的に許容可能な塩、エステル若しくはエーテルである。 Or a pharmaceutically acceptable salt, ester or ether thereof.
前記新規レスベラトロール誘導体において、炭素−炭素２重結合は、トランスまたはシスであってよく、新規レスベラトロール誘導体としてはシス体とトランス体との混合物を含む。 In the novel resveratrol derivative, the carbon-carbon double bond may be trans or cis, and the novel resveratrol derivative includes a mixture of cis isomer and trans isomer.
前記新規レスベラトロール誘導体の薬学的に許容可能な塩としては、例えば、リチウム塩、ナトリウム塩、カリウム塩等のアルカリ金属塩；マグネシウム塩、カルシウム塩、バリウム塩等のアルカリ土類金属塩；アルミニウム塩；アルミニウムヒドロキシド塩等の金属ヒドロキシド塩；アルキルアミン塩、ジアルキルアミン塩、トリアルキルアミン塩、アルキレンジアミン塩、シクロアルキルアミン塩、アリールアミン塩、アラルキルアミン塩、複素環式アミン塩等のアミン塩；α−アミノ酸塩、ω−アミノ酸塩等のアミノ酸塩；ペプチド塩又はそれらから誘導される第１級、第２級、第３級若しくは第４級アミン塩等が挙げられる。これらの薬理的に許容し得る塩は、単独で又は２種以上を混合して用いることができる。 Examples of the pharmaceutically acceptable salt of the novel resveratrol derivative include alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt, calcium salt and barium salt; aluminum Metal hydroxide salt such as aluminum hydroxide salt; alkylamine salt, dialkylamine salt, trialkylamine salt, alkylenediamine salt, cycloalkylamine salt, arylamine salt, aralkylamine salt, heterocyclic amine salt, etc. Amin salts; amino acid salts such as α-amino acid salts and ω-amino acid salts; peptide salts or primary, secondary, tertiary or quaternary amine salts derived therefrom. These pharmacologically acceptable salts can be used alone or in admixture of two or more.
前記新規レスベラトロール誘導体の薬学的に許容可能なエーテル又はエステルとは、ヒドロキシ基（−ＯＨ）の１個又は２個以上がエーテル化またはエステル化ヒドロキシ基であるものをいう。これらのエーテル化またはエステル化ヒドロキシ基は、非置換のまたは置換された１〜２６個の炭素原子を有する直鎖または分枝鎖アルキル基、または非置換のまたは置換された１〜２６個の炭素原子を有する直鎖または分枝鎖脂肪族、芳香脂肪族または芳香族カルボン酸に由来してもよい。エーテル化ヒドロキシ基はさらにグリコシド基であってもよく、エステル化ヒドロキシ基はさらにグルクロニドまたは硫酸基であってもよい。これらの薬理的に許容し得るエーテル又はエステルは、単独で又は２種以上を混合して用いることができる。 The pharmaceutically acceptable ether or ester of the novel resveratrol derivative refers to one in which one or more of the hydroxy groups (—OH) are etherified or esterified hydroxy groups. These etherified or esterified hydroxy groups are unsubstituted or substituted linear or branched alkyl groups having 1 to 26 carbon atoms, or unsubstituted or substituted 1 to 26 carbons. It may be derived from a linear or branched aliphatic, araliphatic or aromatic carboxylic acid having atoms. The etherified hydroxy group may further be a glycoside group, and the esterified hydroxy group may further be a glucuronide or sulfate group. These pharmacologically acceptable ethers or esters can be used alone or in admixture of two or more.
以上のような構造を有する本発明の新規レスベラトロール誘導体は、当該分野で周知の方法に従って化学合成することも可能ではあるが、反応工程が複雑であり、有害な試薬や工程を必要とする。また、化学合成では不純物を除去する煩雑さもあり、さらに安全性の観点から、新規レスベラトロール誘導体の精製を徹底する必要もあり、工業的には不向きな方法である。 The novel resveratrol derivative of the present invention having the structure as described above can be chemically synthesized according to a method well known in the art, but the reaction process is complicated and requires harmful reagents and processes. . In addition, chemical synthesis is complicated to remove impurities, and from the viewpoint of safety, it is necessary to thoroughly purify a novel resveratrol derivative, which is an industrially unsuitable method.
そこで、本発明者らは、鋭意検討した結果、レスベラトロールとシナピン酸を金属塩存在下で加熱処理することで、前記の化学合成法のように有害な試薬や工程を必要とせずに、新規レスベラトロール誘導体を効率的で安全に製造することができることを見出した。以下に、本発明の新規レスベラトロール誘導体の製造方法（以下、本発明の製造方法）について具体的に説明する。 Therefore, as a result of intensive studies, the present inventors conducted heat treatment of resveratrol and sinapinic acid in the presence of a metal salt, without requiring harmful reagents and steps as in the chemical synthesis method described above, It has been found that a novel resveratrol derivative can be produced efficiently and safely. Below, the manufacturing method (henceforth the manufacturing method of this invention) of the novel resveratrol derivative | guide_body of this invention is demonstrated concretely.
本発明の製造方法では、前駆体としてレスベラトロールを用いる。レスベラトロールにはトランス体とシス体の構造異性体が存在するが、加熱や紫外線によってトランス体とシス体の変換が一部生じる。したがって、レスベラトロールとしては、トランス体でもシス体でも、あるいはトランス体とシス体の混合物であってもよい。レスベラトロールは、ブドウ果皮から抽出・精製した天然由来のものであっても、化学合成された純度の高い化成品であっても良い。天然由来のレスベラトロールを用いる場合は、完全に精製されたものである必要はなく、後述のように所望の生成反応が進み最終的に本発明の新規レスベラトロール誘導体が得られるから、レスベラトロール以外の成分を含む混合物も使用できる。また、レスベラトロールには、塩、エーテル、エステル等の誘導体もあるが、本発明の製造方法では、これらの誘導体も原料として使用することができる。
ただし、新規レスベラトロール誘導体の回収率の観点からは、レスベラトロール換算で１重量％以上含有された混合物が原料として望ましい。
前記レスベラトロールとしては、ブドウ果皮、ピーナッツ等の原料からの抽出物、凍結乾燥品等を使用してもよい。
In the production method of the present invention, resveratrol is used as a precursor. Resveratrol has structural isomers of trans form and cis form, but some conversion of trans form and cis form occurs by heating or ultraviolet rays. Therefore, resveratrol may be a trans isomer, a cis isomer, or a mixture of a trans isomer and a cis isomer. Resveratrol may be a naturally derived product extracted and purified from grape skin, or a chemically synthesized chemical product synthesized with high purity. When natural resveratrol is used, it does not need to be completely purified, and the desired production reaction proceeds as described later, and finally the novel resveratrol derivative of the present invention is obtained. Mixtures containing ingredients other than veratrol can also be used. Resveratrol also includes derivatives such as salts, ethers and esters, but these derivatives can also be used as raw materials in the production method of the present invention.
However, from the viewpoint of the recovery rate of the novel resveratrol derivative, a mixture containing 1% by weight or more in terms of resveratrol is desirable as a raw material.
As said resveratrol, you may use the extract from raw materials, such as grape peel and a peanut, a freeze-dried product, etc.
また、本発明の製造方法では、前駆体としてシナピン酸も必要である。シナピン酸は、天然由来のものであっても、化学合成された純度の高い化成品であっても良い。天然由来のシナピン酸を用いる場合は、完全に精製されたものである必要はなく、後述のように所望の生成反応が進み最終的に本発明の新規レスベラトロール誘導体が得られるのであれば、シナピン酸以外の成分を含む混合物も使用できる。
ただし、新規レスベラトロール誘導体の回収量の観点からは、シナピン酸換算で５重量％以上含有された混合物が原料として望ましい。このような原料としては、例えば、リンゴ果実、穀物等の原料からの抽出物、凍結乾燥品等を使用してもよい。
In the production method of the present invention, sinapinic acid is also required as a precursor. Sinapic acid may be naturally derived or may be a chemically synthesized chemical product with high purity. When using naturally derived sinapinic acid, it is not necessary to be completely purified, as long as the desired production reaction proceeds and finally the novel resveratrol derivative of the present invention is obtained as described below, Mixtures containing ingredients other than sinapinic acid can also be used.
However, from the viewpoint of the recovered amount of the novel resveratrol derivative, a mixture containing 5% by weight or more in terms of sinapinic acid is desirable as a raw material. As such raw materials, for example, extracts from raw materials such as apple fruits and grains, freeze-dried products, and the like may be used.
本発明の製造方法では、レスベラトロール、シナピン酸、またはレスベラトロールとシナピン酸との混合物を適切な溶媒に溶解させる。この際、溶媒が水のみであれば、レスベラトロールやシナピン酸の水への溶解度が著しく低いために、水と有機溶媒の混合液や、有機溶媒のみに溶解させればよい。水と有機溶媒の配合比や、有機溶媒の種類については特に制限はなく、レスベラトロールやシナピン酸が十分に溶解すれば良い。中でも、メタノールやエタノールのみの溶媒や、水とメタノール、水とエタノール等の混合液を使用することが、安全性やコスト面から好ましい。新規レスベラトロール誘導体を含む反応後組成物に対して最終的な精製を十分に適用せずにその組成物を食品に使用する場合には、安全性や法規面から溶媒としてエタノールや含水エタノールを使用することが望ましい。
得られるレスベラトロール、シナピン酸、またはレスベラトロールとシナピン酸との混合物を含有する溶液中のレスベラトロールおよびシナピン酸の濃度について特に制限はないが、それぞれの濃度が高いほど、溶媒使用量が少ない等のメリットもあるため、レスベラトロールおよびシナピン酸の濃度は各々の溶媒に対しレスベラトロールおよびシナピン酸がそれぞれ飽和する濃度近くが好ましい。
また、レスベラトロール、シナピン酸は前記溶液中において生成反応前に完全に溶解していなくともよい。例えば、レスベラトロール含有溶液とシナピン酸含有溶液とを混合する場合、それぞれの溶液中のレスベラトロール濃度、シナピン酸濃度がともに飽和濃度以上であっても、混合液とした場合には、飽和濃度近くになるように調整しておけばよい。
In the production method of the present invention, resveratrol, sinapinic acid, or a mixture of resveratrol and sinapinic acid is dissolved in a suitable solvent. At this time, if the solvent is only water, the solubility of resveratrol or sinapinic acid in water is extremely low, and therefore, the solvent may be dissolved only in a mixed solution of water and an organic solvent or only in an organic solvent. There is no restriction | limiting in particular about the compounding ratio of water and an organic solvent, and the kind of organic solvent, and resveratrol and sinapinic acid should just fully melt | dissolve. Among them, it is preferable from the viewpoint of safety and cost to use a solvent containing only methanol or ethanol, or a mixed solution of water and methanol, water and ethanol, or the like. When the final refining composition containing a new resveratrol derivative is not fully applied to the final product and used in food, ethanol or hydrous ethanol is used as a solvent for safety and legal purposes. It is desirable to use it.
There is no particular limitation on the concentration of resveratrol and sinapinic acid in the solution containing the resulting resveratrol, sinapinic acid, or a mixture of resveratrol and sinapinic acid, but the higher the respective concentration, the more the amount of solvent used Therefore, the concentration of resveratrol and sinapinic acid is preferably close to the concentration at which resveratrol and sinapinic acid are saturated with respect to each solvent.
Resveratrol and sinapinic acid may not be completely dissolved in the solution before the formation reaction. For example, when a resveratrol-containing solution and a sinapinic acid-containing solution are mixed, even if the resveratrol concentration and sinapinic acid concentration in each solution are both equal to or higher than the saturated concentration, Adjustment should be made so that the concentration is close.
次に、前記レスベラトロールおよびシナピン酸を含有する溶液（以下、レスベラトロール、シナピン酸含有溶液）のｐＨを８未満に調整することが好ましい。調整方法として、例えば、レスベラトロール、シナピン酸含有溶液を調製した後にｐＨ調整剤を添加してｐＨを調整しても良いし、前記溶液の調製時に前もって溶媒のｐＨを調整しておいても良い。レスベラトロール、シナピン酸含有溶液の反応開始時のｐＨは８．０以上であれば、他の反応や目的化合物の分解も一方で生じるために最終的な新規レスベラトロール誘導体の回収量が低下する。したがって、反応開始時のｐＨは３以上８未満が望ましい。 Next, it is preferable to adjust the pH of the solution containing resveratrol and sinapinic acid (hereinafter referred to as resveratrol and sinapinic acid-containing solution) to less than 8. As an adjustment method, for example, after preparing a solution containing resveratrol and sinapinic acid, the pH may be adjusted by adding a pH adjusting agent, or the pH of the solvent may be adjusted in advance when preparing the solution. good. If the pH of the resveratrol and sinapinic acid-containing solution at the start of the reaction is 8.0 or more, other reactions and decomposition of the target compound may occur on the other hand, resulting in a reduction in the final recovered amount of the resveratrol derivative To do. Therefore, the pH at the start of the reaction is desirably 3 or more and less than 8.
本発明の製造方法では、前記レスベラトロール、シナピン酸含有溶液中に金属塩を添加する。前記金属塩としては、酸性塩、塩基性塩、正塩のいずれでもよく、また、単塩、複塩、錯塩のいずれでもよい。さらに、金属塩は１種類であっても、複数種類の混合物であってもよい。金属塩の例としては、食品添加物として認可されているものが安全性の面で好ましい。例えば、食品に添加することが認められているマグネシウム塩、カルシウム塩、ナトリウム塩、カリウム塩、亜鉛塩、銅塩等が挙げられる。
また、前記金属塩の混合物としては、例えば、ミネラルプレミックス（田辺製薬株式会社、グルコン酸亜鉛、クエン酸鉄アンモニウム、乳酸カルシウム、グルコン酸銅、リン酸マグネシウムを主成分としたミネラル混合物）のように金属塩を数種類含む物質が挙げられる。また、複数の金属塩を含む混合物として、ミネラルウォーターも挙げることができる。
なお、前記金属塩の含有量としては、新規レスベラトロール誘導体を生成可能な量であればよく、特に限定はない。
In the production method of the present invention, a metal salt is added to the resveratrol and sinapinic acid-containing solution. The metal salt may be any of an acid salt, a basic salt, and a normal salt, and may be any of a single salt, a double salt, and a complex salt. Furthermore, the metal salt may be one kind or a mixture of plural kinds. As an example of the metal salt, those approved as food additives are preferable in terms of safety. For example, magnesium salt, calcium salt, sodium salt, potassium salt, zinc salt, copper salt and the like that are permitted to be added to foods can be mentioned.
Moreover, as a mixture of the metal salts, for example, a mineral premix (Tanabe Seiyaku Co., Ltd., a mineral mixture mainly composed of zinc gluconate, ammonium iron citrate, calcium lactate, copper gluconate, and magnesium phosphate) In addition, substances containing several kinds of metal salts are listed. Moreover, mineral water can also be mentioned as a mixture containing a some metal salt.
In addition, as content of the said metal salt, what is necessary is just the quantity which can produce | generate a novel resveratrol derivative, and there is no limitation in particular.
次に、金属塩存在下で、レスベラトロール、シナピン酸含有溶液を加熱処理する。この加熱処理により、新規レスベラトロール誘導体の生成反応を行う。生成反応を効率的に進ませるために、レスベラトロール、シナピン酸含有溶液の加熱温度は１１０℃以上に調整することが好ましい。また、使用する溶媒の沸点から考え、加圧加温が望ましい。例えば、開放容器にレスベラトロール、シナピン酸含有溶液を入れ、溶媒の沸点を超える高温で前記容器を加温する、密閉容器にレスベラトロール、シナピン酸含有溶液を入れて前記容器を加温する、レトルト装置やオートクレーブを用いて加圧加温する等、少なくとも部分的に溶液温度が１１０℃以上に達するように加熱することが好ましい。回収効率面から、溶液温度が均一に１１０℃〜１５０℃になることが、さらに好ましい。加熱時間も加熱温度と同様に限られたものではなく、効率的に目的の反応が進行する時間条件とすればよい。特に、加熱時間は加熱温度との兼ね合いによるものであり、加熱温度に応じた加熱時間にすることが望ましい。例えば、１３０℃付近で加熱する場合は、５分〜１２０分の加熱時間が望ましい。また、加熱は、一度でも良いし、複数回に分けて繰り返し加熱しても良い。複数回に分けて加熱する場合、蒸発した溶媒を補うために溶媒を新たに追加して行うことが好ましい。 Next, the resveratrol and sinapinic acid-containing solution is heat-treated in the presence of a metal salt. By this heat treatment, a formation reaction of a novel resveratrol derivative is performed. In order to advance the production reaction efficiently, the heating temperature of the resveratrol and sinapinic acid-containing solution is preferably adjusted to 110 ° C. or higher. Further, considering the boiling point of the solvent to be used, pressure heating is desirable. For example, resveratrol and sinapinic acid-containing solution are placed in an open container and the container is heated at a high temperature exceeding the boiling point of the solvent. Resveratrol and sinapinic acid-containing solution is placed in a sealed container and the container is heated. It is preferable to heat the solution so that the solution temperature reaches 110 ° C. or higher, for example, by heating under pressure using a retort device or an autoclave. From the viewpoint of recovery efficiency, it is more preferable that the solution temperature be 110 ° C. to 150 ° C. uniformly. The heating time is not limited as in the case of the heating temperature, and may be a time condition in which the target reaction efficiently proceeds. In particular, the heating time depends on the heating temperature, and it is desirable to set the heating time according to the heating temperature. For example, when heating near 130 ° C., a heating time of 5 minutes to 120 minutes is desirable. Further, the heating may be performed once or may be repeated repeatedly in a plurality of times. In the case of heating in a plurality of times, it is preferable to add a new solvent to supplement the evaporated solvent.
前記加熱処理による新規レスベラトロール誘導体の生成反応の終了は、例えば、ＨＰＬＣによる成分分析により新規レスベラトロール誘導体の生成量を確認して判断すればよい。 The completion of the production reaction of the novel resveratrol derivative by the heat treatment may be judged by confirming the production amount of the novel resveratrol derivative by component analysis by HPLC, for example.
得られる反応液中には、本発明の新規レスベラトロール誘導体が含有されている。
また、安全な原料のみを用いた工程で新規レスベラトロール誘導体を製造した場合には、前記新規レスベラトロール誘導体を含む混合物の状態で食品、医薬品または医薬部外品に使用することが可能である。例えば、天然由来のレスベラトロール、シナピン酸を含水エタノール溶媒に溶解し、ミネラルウォーターやミネラルプレミックスを添加して加熱処理した場合には、得られる反応液を食品原料の一つとして使用することが可能である。
The resulting reaction solution contains the novel resveratrol derivative of the present invention.
In addition, when a new resveratrol derivative is produced by a process using only safe raw materials, it can be used in foods, pharmaceuticals or quasi drugs in the state of a mixture containing the new resveratrol derivative. is there. For example, when natural resveratrol and sinapinic acid are dissolved in a water-containing ethanol solvent and heated by adding mineral water or mineral premix, use the resulting reaction solution as one of the food ingredients. Is possible.
また、風味面での改良やさらなる高機能化を望む場合は、前記反応液を濃縮して新規レスベラトロール誘導体の濃度を高める、あるいは前記反応液を精製し新規レスベラトロール誘導体の純品を得ることができる。濃縮、精製は、公知の方法で実施可能である。例えば、クロロホルム、酢酸エチル、エタノール、メタノール等を用いた溶媒抽出法や炭酸ガスによる超臨界抽出法等で抽出して新規レスベラトロール誘導体を濃縮できる。また、カラムクロマトグラフィーを利用して濃縮や精製を施すことも可能である。再結晶法や限外ろ過膜等の膜処理法も適用可能である。 Also, if you want to improve the flavor and further enhance the functionality, concentrate the reaction solution to increase the concentration of the new resveratrol derivative, or purify the reaction solution to obtain a pure product of the new resveratrol derivative. Can be obtained. Concentration and purification can be performed by a known method. For example, the novel resveratrol derivative can be concentrated by extraction with a solvent extraction method using chloroform, ethyl acetate, ethanol, methanol or the like, a supercritical extraction method with carbon dioxide gas, or the like. It is also possible to perform concentration and purification using column chromatography. A membrane treatment method such as a recrystallization method or an ultrafiltration membrane can also be applied.
また、前記反応液から式（１）で表される新規レスベラトロール誘導体を分離して回収する場合には、カラムクロマトグラフィー、ＨＰＬＣ等を用いてもよい。 In addition, when the novel resveratrol derivative represented by the formula (1) is separated and recovered from the reaction solution, column chromatography, HPLC, or the like may be used.
前記濃縮物や精製物を、必要に応じて、減圧乾燥や凍結乾燥して溶媒除去することで、粉末状の新規レスベラトロール誘導体を得ることができる。 A powdered novel resveratrol derivative can be obtained by removing the solvent from the concentrate or purified product by drying under reduced pressure or lyophilization, if necessary.
また、得られた新規レスベラトロール誘導体は、必要に応じて、当該分野で公知の方法により、新規レスベラトロール誘導体の塩としたり、新規レスベラトロール誘導体のヒドロキシ基をエーテル化またはエステル化してもよい。 Further, the obtained new resveratrol derivative can be converted into a salt of the new resveratrol derivative or the etherified or esterified hydroxy group of the new resveratrol derivative by a method known in the art, if necessary. Also good.
以上のようにして得られる本発明の新規レスベラトロール誘導体は、レスベラトロール、シナピン酸、既知のレスベラトロール誘導体及びルテリオンに比べて、極めて優れた抗癌活性を有する。したがって、新規レスベラトロール誘導体を有効成分として含有する抗癌剤を提供することができる。 The novel resveratrol derivative of the present invention obtained as described above has extremely excellent anticancer activity as compared with resveratrol, sinapinic acid, known resveratrol derivatives and luterion. Therefore, the anticancer agent which contains a novel resveratrol derivative as an active ingredient can be provided.
特に、本発明の新規レスベラトロール誘導体の生理活性分野を考慮すると、癌予防・治療等の健康増進、さらには疾病治癒分野において用いることが好ましい。 In particular, considering the physiologically active field of the novel resveratrol derivative of the present invention, it is preferably used in the field of health promotion such as cancer prevention and treatment, and further in the field of disease healing.
なお、本発明で得られた新規レスベラトロール誘導体が持つさらなる効果効能は、得られた生理活性データより類推できる範囲で使用できる。 In addition, the further effect efficacy which the novel resveratrol derivative | guide_body obtained by this invention has can be used in the range which can be estimated from the obtained physiological activity data.
原料であるレスベラトロールおよびシナピン酸の安全性が確認されていることから、本発明の新規レスベラトロール誘導体の安全性も同様に優れたものであると考えられる。 Since the safety of resveratrol and sinapinic acid as raw materials has been confirmed, it is considered that the safety of the novel resveratrol derivative of the present invention is also excellent.
また、本発明の新規レスベラトロール誘導体は、前記のような生理活性を奏することから、食品、医薬品、医薬部外品等に配合して使用することができる。 Moreover, since the novel resveratrol derivative of the present invention exhibits the physiological activity as described above, it can be used by blending it with foods, pharmaceuticals, quasi drugs and the like.
前記食品としては、例えば、飲料、アルコール飲料、ゼリー、菓子等、どのような形態でもよく、菓子類の中でも、その容量等から保存や携帯に優れた、ハードキャンディ、ソフトキャンディ、グミキャンディ、タブレット等が挙げられるが、特に限定はない。また、新規レスベラトロール誘導体をワインに添加することで、ワインの健康機能効果をさらに増強した新規なワインとすることもできる。この新規なワインのように、嗜好性と健康機能効果の双方を持ち合わせた飲食品は、社会ニーズの非常に高い分野の飲食品であり、このニーズに十分応えることが可能である。また、新規レスベラトロール誘導体は、後述のように、癌、中でも口腔癌に対する優れた抗癌活性を有することから、現在問題になっている口腔癌に対する予防を目的に、容易に摂取できるキャンディー、グミキャンディ、タブレット等にすることができる。なお、食品には、機能性食品、健康食品、健康志向食品等も含まれる。 The food may be in any form such as beverage, alcoholic beverage, jelly, confectionery, etc., and among confectionery, hard candy, soft candy, gummy candy, tablet that is excellent in storage and carrying due to its capacity etc. There are no particular limitations. Further, by adding a novel resveratrol derivative to wine, it is possible to obtain a new wine that further enhances the health function effect of the wine. Like this new wine, foods and drinks that have both taste and health function effects are foods and drinks in fields with very high social needs, and can fully meet these needs. In addition, as described below, the novel resveratrol derivative has excellent anticancer activity against cancer, especially oral cancer, and therefore can be easily ingested for the purpose of preventing oral cancer, which is currently a problem, It can be a gummy candy, a tablet or the like. The food includes functional food, health food, health-oriented food, and the like.
前記医薬品としては、散剤、錠剤、丸剤、カプセル剤、細粒剤、顆粒剤等の固形製剤、水剤、懸濁剤、乳剤等の液剤、ゲル剤等が挙げられる。錠剤、丸剤、顆粒剤、顆粒を含有するカプセル剤の顆粒は、必要により、ショ糖等の糖類、マルチトール等の糖アルコールで糖衣を施したり、ゼラチン、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等でコーティングを施してもよいし、胃溶性若しくは腸溶性物質のフィルムで被覆してもよい。また、製剤の溶解性を向上させるために、前記の製剤を公知の可溶化処理を施すこともできる。常法に基づいて、前記液剤を注射剤、点滴剤に配合して使用してもよい。 Examples of the pharmaceutical include solid preparations such as powders, tablets, pills, capsules, fine granules and granules, liquids such as liquids, suspensions and emulsions, gels and the like. If necessary, the granules of capsules containing tablets, pills, granules, granules can be sugar-coated with sugars such as sucrose, sugar alcohols such as maltitol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. A coating may be applied, or a film of gastric or enteric material may be coated. Moreover, in order to improve the solubility of a formulation, the said formulation can also be given a known solubilization process. Based on a conventional method, the solution may be used in an injection or a drip.
医薬部外品としては、口腔に用いられる医薬部外品、例えば、歯磨き、マウスウオッシュ、マウスリンス、ドリンク剤が挙げられる。 Examples of quasi drugs include quasi drugs used for the oral cavity, such as toothpaste, mouthwash, mouth rinse, and drink.
本発明の新規レスベラトロール誘導体を用いて食品、医薬品または医薬部外品を調製する場合、本発明の効果が損なわれない範囲内で食品、医薬品または医薬部外品に通常用いられる成分を適宜任意に配合することができる。
例えば、食品の場合には、水、アルコール、澱粉質、蛋白質、繊維質、糖質、脂質、ビタミン、ミネラル、着香料、着色料、甘味料、調味料、安定剤、防腐剤のような食品に通常配合される原料または素材と組み合わせることができる。
医薬部外品の場合には、主剤、基材、界面活性剤、起泡剤、湿潤剤、増粘剤、透明剤、着香料、着色料、安定剤、防腐剤、殺菌剤等に組み合わせ、常法に基づいて、液状、軟膏状あるいはスプレー噴射可能な最終形態等にすることができる。
When preparing foods, pharmaceuticals or quasi drugs using the novel resveratrol derivative of the present invention, the components usually used in foods, drugs or quasi drugs are appropriately selected within the range that does not impair the effects of the present invention. It can mix | blend arbitrarily.
For example, in the case of food, food such as water, alcohol, starch, protein, fiber, carbohydrate, lipid, vitamin, mineral, flavoring, coloring, sweetener, seasoning, stabilizer, preservative Can be combined with raw materials or materials usually blended in
In the case of quasi-drugs, combined with the main agent, base material, surfactant, foaming agent, wetting agent, thickener, clearing agent, flavoring agent, coloring agent, stabilizer, preservative, bactericidal agent, etc. Based on a conventional method, it can be in a liquid form, an ointment form, a final form capable of being sprayed, or the like.
本発明の新規レスベラトロール誘導体を食品に添加する場合には、該食品中に対して、通常は０．００１〜２０重量％添加することが好ましい。 When the novel resveratrol derivative of the present invention is added to food, it is usually preferable to add 0.001 to 20% by weight based on the food.
本発明の新規レスベラトロール誘導体を医薬用途で使用する場合、例えば、その摂取量は、所望の改善、治療又は予防効果が得られるような量であれば特に制限されず、通常その態様、患者の年齢、性別、体質その他の条件、疾患の種類並びにその程度等に応じて適宜選択される。１日当たり約０．１ｍｇ〜１，０００ｍｇ程度とするのがよく、これを１日に１〜４回に分けて摂取することができる。 When the novel resveratrol derivative of the present invention is used for pharmaceutical purposes, for example, the amount of intake thereof is not particularly limited as long as the desired improvement, treatment or prevention effect is obtained. It is appropriately selected according to the age, sex, constitution and other conditions, the type and degree of disease. About 0.1 mg to about 1,000 mg per day is preferable, and this can be taken in 1 to 4 times a day.
本発明の新規レスベラトロール誘導体を医薬部外品に添加する場合には、該医薬部外品中に、通常０．００１〜３０重量％添加するのが好ましい。 When the novel resveratrol derivative of the present invention is added to a quasi drug, it is usually preferable to add 0.001 to 30% by weight in the quasi drug.
また、本発明の新規レスベラトロール誘導体は、安全性に優れたものであるので、ヒトに対してだけでなく、例えば、非ヒト動物、例えば、ラット、マウス、モルモット、ウサギ、ヒツジ、ブタ、ウシ、ウマ、ネコ、イヌ、サル、チンパンジー等の哺乳類、鳥類、両生類、爬虫類等の治療剤または飼料に配合してもよい。飼料としては、例えばヒツジ、ブタ、ウシ、ウマ、ニワトリ等に用いる家畜用飼料、ウサギ、ラット、マウス等に用いる小動物用飼料、ウナギ、タイ、ハマチ、エビ等に用いる魚介類用飼料、イヌ、ネコ、小鳥、リス等に用いるペットフードが挙げられる。 Further, since the novel resveratrol derivative of the present invention is excellent in safety, not only for humans, for example, non-human animals such as rats, mice, guinea pigs, rabbits, sheep, pigs, You may mix | blend with mammals, such as a cow, a horse, a cat, a dog, a monkey, a chimpanzee, birds, amphibians, a reptile, etc., or a feed. As feed, for example, livestock feed used for sheep, pigs, cattle, horses, chickens, etc., feed for small animals used for rabbits, rats, mice, etc., feed for seafood used for eel, Thailand, yellowtail, shrimp, etc., dogs, The pet food used for a cat, a small bird, a squirrel, etc. is mentioned.
次に、本発明を実施例に基づいて詳細に説明するが、本発明はかかる実施例にのみ限定されるものではない。 EXAMPLES Next, although this invention is demonstrated in detail based on an Example, this invention is not limited only to this Example.
（実施例１：新規レスベラトロール誘導体の生成方法検討）
トランス−レスベラトロール（東京化成工業（株）製）１００ｍｇ、シナピン酸（和光純薬工業（株）製）１００ｍｇをエタノール２ｍＬに溶解し、（１）ミネラルウォーター（商品名「ゲロルシュタイナー」サッポロ飲料（株）製）２ｍＬ、（２）ミネラルプレミックス１００ｍｇ、水２ｍＬ、（３）リン酸マグネシウム・３水和物（和光純薬工業（株）製、ミネラルプレミックスの主成分）１００ｍｇ、水２ｍＬをそれぞれ加えて、レスベラトロール、シナピン酸含有溶液（ｐＨ：（１）４．９、（２）５．２、（３）５．３）を３種類調製した。このレスベラトロール、シナピン酸含有溶液をオートクレーブ（三洋電機（株）製、「ＳＡＮＹＯ ＬＡＢＯ ＡＵＴＯＣＬＡＶＥ」）にて１３０℃、３０分間加熱した。得られた反応溶液からそれぞれ１ｍＬを取り出して、メタノールにて５０ｍＬにメスアップし、このうちの１０μＬをＨＰＬＣにより分析した。
(Example 1: Examination of production method of novel resveratrol derivative)
100 mg of trans-resveratrol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 100 mg of sinapinic acid (manufactured by Wako Pure Chemical Industries, Ltd.) are dissolved in 2 mL of ethanol, and (1) mineral water (trade name “Gerol Steiner” Sapporo Beverage ( Co., Ltd.) 2 mL, (2) mineral premix 100 mg, water 2 mL, (3) magnesium phosphate trihydrate (manufactured by Wako Pure Chemical Industries, Ltd., main component of mineral premix) 100 mg, water 2 mL In addition to the above, resveratrol and sinapinic acid-containing solutions (pH: (1) 4.9, (2) 5.2, (3) 5.3) were prepared. The resveratrol and sinapinic acid-containing solution was heated at 130 ° C. for 30 minutes in an autoclave (manufactured by Sanyo Electric Co., Ltd., “SANYO LABO AUTOCLAVE”). 1 mL was taken out from each of the obtained reaction solutions, made up to 50 mL with methanol, and 10 μL of this was analyzed by HPLC.
ＨＰＬＣ分析は以下条件にて行った。
カラム：逆相用カラム「Ｄｅｖｅｌｏｓｉｌ（登録商標）Ｃ−３０−ＵＧ−５」（４．６ｍｍｉ．ｄ．×２５０ｍｍ）
移動相：Ａ・・・Ｈ2Ｏ（０．１％トリフルオロ酢酸（ＴＦＡ））， Ｂ・・・アセトニトリル（０．１％ＴＦＡ）
流速：１ｍＬ／ｍｉｎ
注入：１０μＬ
検出：２５４ｎｍ
勾配（容量％）：８０％Ａ／２０％Ｂから２０％Ａ／８０％Ｂまで３０分間、２０％Ａ／８０％Ｂから１００％Ｂまで５分間、１００％Ｂで１０分間（全て直線）
HPLC analysis was performed under the following conditions.
Column: Column for reverse phase “Develosil (registered trademark) C-30-UG-5” (4.6 mm.d. × 250 mm)
Mobile phase: A: H 2 O (0.1% trifluoroacetic acid (TFA)), B: Acetonitrile (0.1% TFA)
Flow rate: 1 mL / min
Injection: 10 μL
Detection: 254 nm
Gradient (% by volume): 30 minutes from 80% A / 20% B to 20% A / 80% B, 5 minutes from 20% A / 80% B to 100% B, 10 minutes at 100% B (all linear)
得られたクロマトグラムを図１に示す。上から、反応前、（１）、（２）、（３）の反応溶液のクロマトグラムをそれぞれ示している。反応後には、レスベラトロールやシナピン酸以外のピークが検出され、複数の化合物が生成されていることが確認された。
例えば、図中、Ｂのピークは、シナピン酸の分解物であり、それ以外のピークで、反応前後で生成量に顕著な差があったのが、後述する新規レスベラトロール誘導体であるＡのピークである。なお、（１）、（２）、（３）の反応溶液の間では、Ａのピーク成分の生成量の差は殆どなく、つまり、今回用いた金属塩の種類による新規レスベラトロール誘導体の生成量の差は小さかった。
The obtained chromatogram is shown in FIG. From the top, the chromatograms of the reaction solutions (1), (2), and (3) are shown before the reaction. After the reaction, peaks other than resveratrol and sinapinic acid were detected, confirming that a plurality of compounds were produced.
For example, in the figure, the peak of B is a decomposition product of sinapinic acid, and the other peaks have a remarkable difference in the amount of product before and after the reaction. It is a peak. In addition, there is almost no difference in the amount of peak component A generated between the reaction solutions (1), (2), and (3), that is, the production of a novel resveratrol derivative depending on the type of metal salt used this time. The difference in quantity was small.
（実施例２：新規レスベラトロール誘導体の大量生成）
トランス−レスベラトロール１ｇ、シナピン酸１ｇをエタノール２０ｍＬに溶解し、ミネラルウォーター２０ｍＬを加えて、レスベラトロール、シナピン酸含有溶液（ｐＨ＝４．９）を得た。このレスベラトロール、シナピン酸含有溶液をオートクレーブにて１３０℃、９０分間加熱した。得られた反応溶液のうち１ｍＬをメタノールにて５０ｍＬにメスアップし、実施例１と同様にＨＰＬＣにより分析したところ、実施例１と同様のクロマトグラムが確認できた。
(Example 2: Mass production of novel resveratrol derivative)
1 g of trans-resveratrol and 1 g of sinapinic acid were dissolved in 20 mL of ethanol, and 20 mL of mineral water was added to obtain a resveratrol and sinapinic acid-containing solution (pH = 4.9). This resveratrol and sinapinic acid-containing solution was heated in an autoclave at 130 ° C. for 90 minutes. When 1 mL of the obtained reaction solution was made up to 50 mL with methanol and analyzed by HPLC in the same manner as in Example 1, the same chromatogram as in Example 1 was confirmed.
（実施例３：新規レスベラトロール誘導体の単離・構造決定）
実施例２で得られた反応物のうち、図１のＡで示したピークに含まれる化合物を分取ＨＰＬＣにより単離し、常法により乾燥したところ、新規化合物（以下ＵＨＡ１０２８）を１２９ｍｇ得た。単離精製したＵＨＡ１０２８は、褐色粉末状の物質であった。
(Example 3: Isolation and structure determination of a novel resveratrol derivative)
Among the reactants obtained in Example 2, the compound contained in the peak shown by A in FIG. 1 was isolated by preparative HPLC and dried by a conventional method. As a result, 129 mg of a new compound (hereinafter referred to as UHA1028) was obtained. The isolated and purified UHA1028 was a brown powdery substance.
次いで、前記ＵＨＡ１０２８の分子量を高分解能電子イオン化質量分析法（Ｅｌｅｃｔｒｏｎ Ｉｏｎｉｚａｔｉｏｎ−Ｍａｓｓ Ｓｐｅｃｔｒｏｍｅｔｒｙ）にて測定したところ、測定値は４０８．４４３６であり、理論値との比較から、以下の分子式を得た。
理論値Ｃ２４Ｈ２４Ｏ６（Ｍ+）：４０８．４４３８
分子式Ｃ24Ｈ24Ｏ6
Subsequently, when the molecular weight of the UHA1028 was measured by high resolution electron ionization-mass spectrometry, the measured value was 408.4436, and the following molecular formula was obtained from comparison with the theoretical value.
Theoretical value C24H24O6 (M + ): 408.4438
Molecular formula C 24 H 24 O 6
次に、前記ＵＨＡ１０２８を核磁気共鳴（ＮＭＲ）測定に供し、１Ｈ−ＮＭＲ、１３Ｃ−ＮＭＲ及び各種２次元ＮＭＲデータの解析から、前記ＵＨＡ１０２８が式（１）で表される構造を有することを確認した。式（１）で表される新規レスベラトロール誘導体は本発明の方法で効率的に生成できることが示された。 Next, the UHA1028 is subjected to nuclear magnetic resonance (NMR) measurement, and it is confirmed from analysis of 1H-NMR, 13C-NMR and various two-dimensional NMR data that the UHA1028 has a structure represented by the formula (1). did. It was shown that the novel resveratrol derivative represented by the formula (1) can be efficiently produced by the method of the present invention.
ＮＭＲ測定値について、ＵＨＡ１０２８を For NMR measurements, UHA1028
として、その1Ｈ核磁気共鳴スペクトル、13Ｃ核磁気共鳴スペクトルを表１に示す。
値はδ、ｐｐｍで、溶媒はメタノール−ｄ3で測定した。
Table 1 shows the 1 H nuclear magnetic resonance spectrum and 13 C nuclear magnetic resonance spectrum.
The values were δ and ppm, and the solvent was measured with methanol-d 3 .
また、ＵＨＡ１０２８の物理化学的性状は、以下のようになった。
（性状）
褐色粉末
（溶解性）
水：難溶
メタノール：溶解
エタノール：溶解
ＤＭＳＯ：溶解
クロロホルム：溶解
酢酸エチル：溶解
The physicochemical properties of UHA1028 were as follows.
(Properties)
Brown powder (soluble)
Water: Slightly soluble methanol: Dissolved ethanol: Dissolved DMSO: Dissolved chloroform: Dissolved ethyl acetate: Dissolved
（実施例４：ＵＨＡ１０２８のヒト骨髄球性白血病細胞に対する抗癌作用）
次に癌細胞に対する各化合物の効果を見るため、ＨＬ−６０細胞（Ｈｕｍａｎ ｐｒｏｍｙｅｌｏｃｙｔｉｃ ｌｅｏｋｅｍｉａ ｃｅｌｌｓ：ヒト骨髄球性白血病細胞）を用いた癌細胞増殖抑制作用について試験した。
(Example 4: Anticancer effect of UHA1028 on human myeloid leukemia cells)
Next, in order to see the effect of each compound on cancer cells, the cancer cell proliferation inhibitory action using HL-60 cells (Human proneolytic leukemia cells: human myeloid leukemia cells) was tested.
ＨＬ−６０細胞の培養には、４ｍＭグルタミン（Ｌ−Ｇｌｕｔａｍｉｎｅ シグマアルドリッチジャパン社製）、１０％ウシ胎児血清（Ｆｏｅｔａｌ Ｂｏｖｉｎｅ Ｓｅｒｕｍ：ＦＢＳ Ｂｉｏｌｏｇｉｃａｌ ｉｎｄｕｓｔｒｉｅｓ社製）を含む高栄養培地「ＲＰＭＩ−１６４０」（シグマアルドリッチジャパン社製）を使用した。試験には細胞培養用96ウェルプレート（コーニングジャパン（株）製）を用い、５×１０5ｃｅｌｌｓ／ｍＬとなるように細胞数を調整したＨＬ−６０細胞を１ウェルあたり１００μＬずつ播種して試験に使用した。 For the culture of HL-60 cells, a high nutrient medium “RPMI-1640” (Sigma) containing 4 mM glutamine (manufactured by L-Glutamine Sigma-Aldrich Japan), 10% fetal bovine serum (manufactured by Foetal Bovine Serum: FBS Biological industries). Aldrich Japan) was used. In the test, a 96-well plate for cell culture (manufactured by Corning Japan Co., Ltd.) was used and seeded with 100 μL per well of HL-60 cells, the number of cells of which was adjusted to 5 × 10 5 cells / mL. Used for.
試料は、レスベラトロール、シナピン酸及び本発明品であるＵＨＡ１０２８の３種類を用いた。試料調製は、各々の化合物をジメチルスルホキシド（Ｄｉｍｅｔｈｙｌ ｓｕｌｆｏｘｉｄｅ：ＤＭＳＯ、和光純薬工業（株）製）にて溶解し、ＨＬ−６０細胞培養液中の最終濃度がそれぞれ６．３μＭ、１２．５μＭ、２５μＭ、５０μＭ、及び1００μＭとなるように添加して、３７℃、５％ＣＯ2の培養条件下で試験を開始した。なお、溶媒であるＤＭＳＯのみを同量添加したものをネガティブコントロールとした。 Three types of samples were used: resveratrol, sinapinic acid, and UHA1028 of the present invention. In the sample preparation, each compound was dissolved in dimethyl sulfoxide (DMSO, manufactured by Wako Pure Chemical Industries, Ltd.), and the final concentrations in the HL-60 cell culture solution were 6.3 μM, 12.5 μM, The test was started under the culture conditions of 37 ° C. and 5% CO 2 by adding 25 μM, 50 μM, and 100 μM. A negative control was prepared by adding the same amount of DMSO as a solvent.
生存細胞数の定量は「Ｃｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８」（（株）同人化学研究所製）を用いたＭＴＴ法にて行った。つまり、試験開始より２４時間後、各ウェルにＣｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８溶液を１０μＬ添加し、よく攪拌した。３７℃、５％ＣＯ2条件下で１時間の遮光反応を行った。その後にプレートリーダー（「ＢＩＯ−ＲＡＤ Ｍｏｄｅｌ ６８０」、バイオ・ラッドラボラトリーズ社製）を用いて測定波長４５０ｎｍの吸光度測定を行い、得られたデータをもとに細胞生存率を算出した。細胞生存率とは、溶媒であるＤＭＳＯのみを添加した培養液の生存細胞数を１００％とし、各化合物の濃度下における細胞の生存細胞数を相対値として算出した値である。各化合物濃度と細胞生存率の関係から、細胞増殖を５０％抑制する濃度ＩＣ50（ｈａｌｆ ｍａｘｉｍａｌ ｉｎｈｉｂｉｔｏｒｙ ｃｏｎｃｅｎｔｒａｔｉｏｎ：５０％阻害濃度）を算出した（表２）。これらの結果から、ＵＨＡ１０２８に優れた癌細胞増殖抑制能が認められた。この効果は、シナピン酸には全く認められず、さらにレスベラトロールよりも高い活性を示した。したがってレスベラトロールとシナピン酸を新規レスベラトロール誘導体に変換する高い有意性が示された。 The number of viable cells was quantified by the MTT method using “Cell counting kit-8” (manufactured by Dojin Chemical Laboratory). That is, 24 hours after the start of the test, 10 μL of the Cell counting kit-8 solution was added to each well and stirred well. The light-shielding reaction was performed for 1 hour at 37 ° C. and 5% CO 2 . Thereafter, absorbance at a measurement wavelength of 450 nm was measured using a plate reader (“BIO-RAD Model 680”, manufactured by Bio-Rad Laboratories), and the cell viability was calculated based on the obtained data. The cell viability is a value calculated by setting the number of viable cells in a culture solution to which only DMSO as a solvent is added as 100% and the number of viable cells in each compound concentration as a relative value. From the relationship between the concentration of each compound and the cell viability, a concentration IC 50 (half maximum inhibitory concentration: 50% inhibitory concentration) that suppresses cell proliferation by 50% was calculated (Table 2). From these results, cancer cell growth suppressing ability superior to UHA1028 was recognized. This effect was not observed at all with sinapinic acid, and was more active than resveratrol. Therefore, the high significance of converting resveratrol and sinapinic acid into novel resveratrol derivatives was shown.
（実施例５：ＵＨＡ１０２８のヒト口腔癌細胞に対する抗癌作用）
次に癌細胞に対する各化合物の効果を見るため、ＳＣＣ−４細胞（ヒト舌扁平上皮癌細胞、ＡＴＣＣ社製）を用いた癌細胞増殖抑制作用について試験した。
(Example 5: Anticancer effect of UHA1028 on human oral cancer cells)
Next, in order to see the effect of each compound on cancer cells, the cancer cell proliferation inhibitory action using SCC-4 cells (human tongue squamous cell carcinoma cells, manufactured by ATCC) was tested.
ＳＣＣ−４細胞の培養には、４００ｎｇ／ｍＬヒドロコルチソン（Ｈｙｄｒｏｃｏｒｔｉｓｏｎｅ、シグマアルドリッチジャパン社製）、１％アンチバイオティック−アンチマイコティック（Ａｎｔｉｂｉｏｔｉｃ−Ａｎｔｉｍｙｃｏｔｉｃ、ギブコ（ＧＩＢＣＯ）社製）、１０％ＦＢＳ（ＡＴＣＣ社製）を含むＤＭＥＭ／Ｆ−１２（１：１）培地（ギブコ社製）を使用した。試験には細胞培養用コラーゲンＩコート９６ウェルプレート（日本ＢＤ社製）を用い、５×１０5ｃｅｌｌｓ／ｍＬとなるように細胞数を調整したＳＣＣ−４細胞を１ウェルあたり１００μＬずつ播種した。これを３７℃、５％ＣＯ2条件下で２４時間培養し、８０％コンフルエント以上の状態で試験に使用した。 For the culture of SCC-4 cells, 400 ng / mL hydrocortisone (Hydrocortisone, manufactured by Sigma-Aldrich Japan), 1% antibiotic-antimycotic (manufactured by Antibiotic-Antilytic, Gibco (GIBCO)), 10% FBS DMEM / F-12 (1: 1) medium (Gibco) containing (ATCC) was used. For the test, a collagen I-coated 96-well plate for cell culture (manufactured by BD Japan) was used, and 100 μL of SCC-4 cells adjusted to have a cell number of 5 × 10 5 cells / mL were seeded per well. This was cultured for 24 hours under conditions of 37 ° C. and 5% CO 2 , and used for testing in a state of 80% confluence or higher.
試料は、レスベラトロール、シナピン酸、ＳＣＣ−４細胞に抗癌活性を有する天然物であるルテオリン（和光純薬工業（株）製）、レスベラトロール誘導体であるε―ビニフェリン（和光純薬工業（株）製）、及び本発明品であるＵＨＡ１０２８の５種類を用いた。試料調製は、各々の化合物をＤＭＳＯにて溶解し、０．６３ｍＭ、１．２５ｍＭ、２．５ｍＭ、５ｍＭ、１０ｍＭとなるように調製した。これをＳＣＣ−４細胞培養液中の最終濃度がそれぞれ６．３μＭ、１２．５μＭ、２５μＭ、５０μＭ、及び１００μＭとなるように添加して３７℃、５％ＣＯ2培養条件下で試験を開始した。なお溶媒であるＤＭＳＯのみを同量添加したものをネガティブコントロールとした。 Samples are resveratrol, sinapinic acid, luteolin (manufactured by Wako Pure Chemical Industries, Ltd.) which is a natural product having anticancer activity against SCC-4 cells, and resveratrol derivative ε-viniferin (Wako Pure Chemical Industries, Ltd.). And 5 types of UHA1028 which is the product of the present invention were used. Samples were prepared by dissolving each compound in DMSO to 0.63 mM, 1.25 mM, 2.5 mM, 5 mM, and 10 mM. This was added so that the final concentrations in the SCC-4 cell culture medium were 6.3 μM, 12.5 μM, 25 μM, 50 μM, and 100 μM, respectively, and the test was started under 37 ° C. and 5% CO 2 culture conditions. . A negative control was prepared by adding the same amount of DMSO as a solvent.
生存細胞数の定量は、実施例４と同様に、「Ｃｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８」を用いたＭＴＴ法にて行った。つまり、試験開始より４８時間後、各ウェルにＣｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８溶液を１０μＬ添加して、よく攪拌した。３７℃、５％ＣＯ2条件下で１時間の遮光反応後にプレートリーダーを用いて測定波長４５０ｎｍの吸光度測定を行い、得られたデータをもとに細胞生存率を算出した。各化合物濃度と細胞生存率の関係から、細胞増殖を５０％抑制する濃度ＩＣ50を算出した（表３）。これらの結果から、ＵＨＡ１０２８のＩＣ50が最も低かったことから、強い口腔癌細胞増殖抑制能が認められた。この効果は、レスベラトロール及びシナピン酸には全く認められず、さらにルテオリン及びε―ビニフェリンよりも高い活性を示した。したがってレスベラトロールとシナピン酸を新規レスベラトロール誘導体に変換する高い有意性が示された。 The number of viable cells was quantified by the MTT method using “Cell counting kit-8” in the same manner as in Example 4. That is, 48 hours after the start of the test, 10 μL of the Cell counting kit-8 solution was added to each well and well stirred. After a light-shielding reaction at 37 ° C. and 5% CO 2 for 1 hour, the absorbance at a measurement wavelength of 450 nm was measured using a plate reader, and the cell viability was calculated based on the obtained data. From the relationship between the concentration of each compound and the cell viability, the concentration IC 50 that suppresses cell proliferation by 50% was calculated (Table 3). From these results, since the IC 50 of UHA1028 it had the lowest, a strong oral cancer cell growth suppressing ability was observed. This effect was not observed at all for resveratrol and sinapinic acid, and further showed higher activity than luteolin and ε-biniferin. Therefore, the high significance of converting resveratrol and sinapinic acid into novel resveratrol derivatives was shown.
（実施例６：加熱温度によるＵＨＡ１０２８の生成量の違い）
レスベラトロール１００ｍｇ、シナピン酸１００ｍｇ、エタノール２ｍＬ、ミネラルウォーター２ｍＬの混合溶液（ｐＨ＝４．９）を、オートクレーブにて７０℃、９０℃、１１０℃、１３０℃の各温度条件で２０分間加熱した。それぞれの温度条件で得られた反応後組成物１ｍＬをメタノールにて５０ｍＬにメスアップし、実施例１と同様にＨＰＬＣにより分析した。
(Example 6: Difference in production amount of UHA1028 depending on heating temperature)
A mixed solution of 100 mg resveratrol, 100 mg sinapinic acid, 2 mL ethanol, and 2 mL mineral water (pH = 4.9) was heated in an autoclave at 70 ° C., 90 ° C., 110 ° C., and 130 ° C. for 20 minutes. . 1 mL of the post-reaction composition obtained under each temperature condition was diluted to 50 mL with methanol and analyzed by HPLC in the same manner as in Example 1.
その結果、１１０℃以上でＵＨＡ１０２８の生成は確認できた。レスベラトロールおよびシナピン酸の合計量からの生成比率（重量％）は、７０℃、９０℃が非生成、１１０℃が極微量、１３０℃が６．５％となり、１３０℃での加熱がもっとも多くＵＨＡ１０２８が生成していた。 As a result, the formation of UHA1028 was confirmed at 110 ° C. or higher. The production ratio (% by weight) from the total amount of resveratrol and sinapinic acid is 70 ° C., 90 ° C. is not produced, 110 ° C. is extremely small, 130 ° C. is 6.5%, and heating at 130 ° C. is the most. Many UHA1028s were produced.
（実施例７：ＵＨＡ１０２８含有エキスの調製）
ブドウ果皮抽出エキスパウダー（レスベラトロール含有素材）１０ｇ、りんご濃縮７倍果汁（シナピン酸含有素材）１５ｇ、エタノール１０ｍＬ、ミネラルウォーター１０ｍＬを加えて調製した混合溶液（ｐＨ＝３．５）を、オートクレーブにて１３０℃、９０分間加熱した。得られた反応溶液を減圧加熱させて乾固し、ＵＨＡ１０２８含有エキスを２０ｇ得た。得られたＵＨＡ１０２８含有エキス２０ｇ中には、実施例３と同様の手法で確認したところＵＨＡ１０２８が０．０６５ｇ含有されていた。必要に応じてこの作業を繰り返した。
(Example 7: Preparation of UHA1028-containing extract)
Grape peel extract powder (resveratrol-containing material) 10g, apple concentrated 7 times fruit juice (sinapic acid-containing material) 15g, ethanol 10mL, mineral water 10mL mixed solution (pH = 3.5) prepared by autoclaving At 130 ° C. for 90 minutes. The obtained reaction solution was heated to dryness under reduced pressure to obtain 20 g of UHA1028-containing extract. When 20 g of the obtained UHA1028-containing extract was confirmed by the same method as in Example 3, 0.065 g of UHA1028 was contained. This work was repeated as necessary.
（実施例８：ＵＨＡ１０２８を含有する食品）
実施例７で得たＵＨＡ１０２８含有エキス１ｇをあらかじめ１００ｍＬのエタノールに溶解させ、これに砂糖５００ｇ、水飴４００ｇを混合溶解し、生クリーム１００ｇ、バター２０ｇ、練乳７０ｇ、乳化剤１．０ｇを混合した後、真空釜にて−５５０ｍｍＨｇ減圧させ、１１５℃の条件下で濃縮し、水分値３．０重量％のミルクハードキャンディを得た。このミルクハードキャンディは、菓子として食べ易いものであることはもちろん、癌患者における癌の拡散のリスクを低減したり、癌の発症のリスクを低減したり、癌の予防を期待した機能性食品としても利用できる。
(Example 8: Food containing UHA1028)
1 g of UHA1028-containing extract obtained in Example 7 was dissolved in 100 mL of ethanol in advance, 500 g of sugar and 400 g of starch syrup were mixed and dissolved therein, and after mixing 100 g of fresh cream, 20 g of butter, 70 g of condensed milk, and 1.0 g of emulsifier, The pressure was reduced by −550 mmHg in a vacuum kettle and concentrated under a condition of 115 ° C. to obtain a milk hard candy having a moisture value of 3.0% by weight. This milk hard candy is easy to eat as a confectionery, as well as reducing the risk of cancer spread in cancer patients, reducing the risk of developing cancer, and as a functional food that is expected to prevent cancer. Can also be used.
（実施例９：ＵＨＡ１０２８を含有する医薬品）
実施例２，３と同様の方法で得たＵＨＡ１０２８をエタノールに溶解し、これを微結晶セルロースに添加して吸着させた後に、減圧乾燥させた。この吸着物を用いて常法に従い、打錠品を得た。処方は、ＵＨＡ１０２８を１０重量部、コーンスターチ２３重量部、乳糖１２重量部、カルボキシメチルセルロース８重量部、微結晶セルロース３２重量部、ポリビニルピロリドン４重量部、ステアリン酸マグネシウム３重量部、タルク８重量部の通りである。本打錠品は、癌の治癒を目的とする医薬品として有効に利用できる。
(Example 9: Drug containing UHA1028)
UHA1028 obtained by the same method as in Examples 2 and 3 was dissolved in ethanol, added to microcrystalline cellulose and adsorbed, and then dried under reduced pressure. Using this adsorbent, a tableted product was obtained according to a conventional method. The formulation is 10 parts by weight of UHA1028, 23 parts by weight of corn starch, 12 parts by weight of lactose, 8 parts by weight of carboxymethyl cellulose, 32 parts by weight of microcrystalline cellulose, 4 parts by weight of polyvinylpyrrolidone, 3 parts by weight of magnesium stearate, 8 parts by weight of talc. Street. This tableted product can be effectively used as a pharmaceutical for the purpose of healing cancer.
（実施例１０：ＵＨＡ１０２８を含有する医薬部外品）
実施例２、３の方法で得たＵＨＡ１０２８ １．２ｇを１０ｍＬのエタノールに溶解し、これにタウリン２０ｇ、ビタミンＢ１硝酸塩０．１２ｇ、安息香酸ナトリウム０．６ｇ、クエン酸４ｇ、砂糖６０ｇ、ポリビニルピロリドン１０ｇを溶解させた精製水を混合し、さらに精製水で１０００ｍＬにメスアップした。なお、ｐＨは、希塩酸を用いて３．２に調整した。得られた溶液１０００ｍＬのうち５０ｍＬをガラス瓶に充填し、８０℃で３０分間滅菌して、医薬部外品であるドリンク剤を完成させた。本ドリンク剤は、栄養補給の目的に加えて、癌患者における癌の拡散のリスクを低減したり、癌の発症のリスクを低減したり、癌の予防を目的とする医薬部外品として有効に利用できる。
(Example 10: Quasi-drug containing UHA1028)
1.2 g of UHA1028 obtained by the methods of Examples 2 and 3 was dissolved in 10 mL of ethanol, to which 20 g of taurine, 0.12 g of vitamin B1 nitrate, 0.6 g of sodium benzoate, 4 g of citric acid, 60 g of sugar, polyvinylpyrrolidone Purified water in which 10 g was dissolved was mixed, and further made up to 1000 mL with purified water. The pH was adjusted to 3.2 using dilute hydrochloric acid. 50 ml of 1000 ml of the obtained solution was filled in a glass bottle and sterilized at 80 ° C. for 30 minutes to complete a quasi-drug drink. In addition to the purpose of nutritional supplementation, this drink is effective as a quasi-drug for the purpose of reducing the risk of cancer spread in cancer patients, reducing the risk of developing cancer, and preventing cancer. Available.
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