JP4314367B2 - Novel compound of carborane derivative and self-assembled film comprising the same - Google Patents
Novel compound of carborane derivative and self-assembled film comprising the same Download PDFInfo
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- JP4314367B2 JP4314367B2 JP2004090620A JP2004090620A JP4314367B2 JP 4314367 B2 JP4314367 B2 JP 4314367B2 JP 2004090620 A JP2004090620 A JP 2004090620A JP 2004090620 A JP2004090620 A JP 2004090620A JP 4314367 B2 JP4314367 B2 JP 4314367B2
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- 150000001875 compounds Chemical class 0.000 title description 34
- 239000000758 substrate Substances 0.000 claims description 16
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 13
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- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 125000003827 glycol group Chemical group 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 4
- 239000010408 film Substances 0.000 description 38
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- 239000002904 solvent Substances 0.000 description 17
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- 238000006243 chemical reaction Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 239000012528 membrane Substances 0.000 description 8
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- 229910052751 metal Inorganic materials 0.000 description 7
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- 238000004458 analytical method Methods 0.000 description 6
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- 239000012044 organic layer Substances 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- -1 alkyl disulfide Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 125000002228 disulfide group Chemical group 0.000 description 4
- 150000002019 disulfides Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
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- 239000007864 aqueous solution Substances 0.000 description 3
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical group C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229910000510 noble metal Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 125000004492 methyl ester group Chemical group 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000009774 resonance method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- IMCDMHGUWUJTTD-UHFFFAOYSA-N 1-sulfanylethane-1,2-diol Chemical compound OCC(O)S IMCDMHGUWUJTTD-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HMIWAIPIMMYWHU-UHFFFAOYSA-N BrC(COCCOCCOCC(Br)O)O Chemical compound BrC(COCCOCCOCC(Br)O)O HMIWAIPIMMYWHU-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000004996 alkyl benzenes Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
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- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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Description
本発明は、カルボラン誘導体新規化合物及びそれからなる自己組織化膜に関するものである。 The present invention relates to a novel compound of a carborane derivative and a self-assembled film comprising the same.
アルキル基を有するジスルフィドもしくはチオール誘導体は、金またはその他、貴金属表面上に金（その他、貴金属）− 硫黄結合を介して選択的に吸着され、その表面に密な構造を作り出すことが知られている(非特許文献１)。また、長鎖アルキルジスルフィドもしくはチオール誘導体を用いて作製された薄膜が、金を基板とした結晶構表面に選択的に吸着され、凝集状態を示すことが知られている(非特許文献２)。
これらの膜は、いずれも自己組織化膜と呼ばれる。これらはチオール類とジスルフィド類を用いて作られるが、どちらも、膜を構成する分子は密に詰まった構造となっていることが確認されている。これらの内で、チオール類は反応中に空気酸化を受けジスルフィドになりやすいので、あらかじめジスルフィド類を原料として合成した方が、目的物質はより安定な化合物として得ることができる。
Disulfide or thiol derivatives with alkyl groups are known to be selectively adsorbed on gold or other noble metal surfaces via gold (other noble metal) -sulfur bonds, creating a dense structure on the surface. (Non-Patent Document 1). In addition, it is known that a thin film prepared using a long-chain alkyl disulfide or a thiol derivative is selectively adsorbed on a crystal structure surface using gold as a substrate and exhibits an aggregation state (Non-patent Document 2).
These films are all called self-assembled films. These are made using thiols and disulfides, both of which have been confirmed to have a tightly packed structure of the molecules that make up the membrane. Among these, since thiols easily undergo air oxidation during the reaction to be converted into disulfides, the target substance can be obtained as a more stable compound by previously synthesizing the disulfides as raw materials.
これらの自己組織化膜は、その膜の厚みが分子１個分に相当する程度のものであり、超薄膜であること知られている。従って、これらジスルフィドもしくはチオール化合物を用いることにより得られる誘導体は、極微量用いるだけで貴金属表面の改質剤としての目的を達成することができる。このような特性を生かすことにより、バイオセンサーの検出表面（特許文献１）、表面プラズモン測定との組み合わせによるバイオセンサー（特許文献２）、電気化学センサー（特許文献３）への応用等の発明が知られている。又、金属表面同士の接着を行う金属表面処理剤（特許文献４）の発明が知られている。 These self-assembled films have a thickness equivalent to that of one molecule, and are known to be ultrathin films. Accordingly, the derivatives obtained by using these disulfide or thiol compounds can achieve the purpose as a modifier for the surface of the noble metal only by using a very small amount. By making use of such characteristics, inventions such as biosensor detection surfaces (Patent Document 1), biosensors (Patent Document 2) in combination with surface plasmon measurement, and electrochemical sensors (Patent Document 3) are disclosed. Are known. Moreover, the invention of the metal surface treating agent (patent document 4) which adhere | attaches metal surfaces is known.
この種の自己組織化膜は非常に密な構造をとっている。従って、膜に機能を発現させるために、分子構造を変化させようとしても、膜構造中に変化のための必要な自由空間が存在しないために、分子構造を変化させることができないとされていた（特許文献５）。
例えば、アゾベンゼン基を有するアルカンチオール類を金表面に吸着させてなる自己組織化膜は、紫外光を照射したところでトランス体からシス体への構造変化を起こそうとしても、起こらない。これは、上述したようにアゾベンゼン部位がトランス体からシス体へ異性化するための十分な自由空間が確保されていない事によるものである。
This type of self-assembled film has a very dense structure. Therefore, even if an attempt is made to change the molecular structure in order to express the function in the membrane, the molecular structure cannot be changed because there is no free space required for the change in the membrane structure. (Patent Document 5).
For example, a self-assembled film formed by adsorbing an alkanethiol having an azobenzene group on a gold surface does not occur even when an attempt is made to change the structure from a trans form to a cis form when irradiated with ultraviolet light. This is because, as described above, sufficient free space for isomerization of the azobenzene moiety from the trans isomer to the cis isomer is not ensured.
非対称ジスルフィドをユニット分子として用いることによって、これらの問題を解決して、高い光応答性を確保することが提案されている。吸着後の自己組織化膜は、二成分分子から構成されているため、時間や熱とともに相分離を起こして光応答性を示さなくなる。相分離を抑制して安定な光応答性を確保するために、アゾベンゼン基側面にメチル基を導入した分子を自己組織化膜のユニット分子として用いる方法が報告されている。この場合には、メチル基の立体反発によって、隣接分子間に異性化可能な自由空間が形成される。しかしながら、自己組織化膜のユニット分子によっては制限が生じるために、一般性は高くないことが指摘されている。 It has been proposed to solve these problems and secure high photoresponsiveness by using asymmetric disulfides as unit molecules. Since the self-assembled film after adsorption is composed of two-component molecules, it undergoes phase separation with time and heat and does not exhibit photoresponsiveness. In order to suppress phase separation and ensure stable photoresponsiveness, a method using a molecule having a methyl group introduced on the side surface of an azobenzene group as a unit molecule of a self-assembled film has been reported. In this case, a free space capable of isomerization is formed between adjacent molecules by steric repulsion of the methyl group. However, it is pointed out that the generality is not high because there are limitations depending on the unit molecules of the self-assembled film.
本発明者らは、自己組織化膜を構成するアルキル基、アルキルベンゼン基を主鎖に有するスルフィド又はジスルフィド、エチレングリコキシベンゼンを主鎖にもつスルフィド又はジスルフィドの集合体からなる自己組織化膜を新たに作り出た。エチレングリコキシベンゼンを主鎖にもつスルフィド又はジスルフィドの集合体の構造であれば、水溶性であることにより、自己組織化膜の能力について従来以上のものとなり、かつ自由度についても、問題がなくなるのではないかと考えた。
しかしながら、自己組織化膜に導入した機能性の基を有する自己組織化膜において、これに機能性分子を反応させて、その反応を利用する自己組織化膜を考える場合には、自己組織化膜上の分子は密に凝集した状態となっており、自己組織化膜を機能性分子と結合させて利用する場合には機能性分子が近づくことできず、反応に支障が生ずることがわかった。
The present inventors newly developed a self-assembled film comprising an aggregate of an alkyl group, a sulfide or disulfide having an alkylbenzene group in the main chain, and a sulfide or disulfide having ethyleneglycoxybenzene in the main chain constituting the self-assembled film. Produced. If it is a structure of sulfide or disulfide aggregate having ethyleneglycoxybenzene in the main chain, it will be more water-soluble than the conventional one, and there will be no problem with the degree of freedom. I thought that.
However, in a self-assembled film having a functional group introduced into the self-assembled film, when a functional molecule is reacted with this and a self-assembled film utilizing the reaction is considered, the self-assembled film The upper molecules are in a densely aggregated state, and it has been found that when the self-assembled film is used in combination with a functional molecule, the functional molecule cannot approach and hinder the reaction.
本発明の課題は、反応性の機能性分子を有するアルキル基、アルキルアゾベンゼン基、フエノキシエチレングリコキシベンゼン、又はエチレングリコキシベンゼンを主鎖にもつスルフィド又はジスルフィド反応性の自己組織化膜において、他の機能性分子と反応させて利用するに際して、他の機能性分子との反応が阻害されることなく進行させる事ができる組織化膜を提供することである。 An object of the present invention is to provide an alkyl group having a reactive functional molecule, an alkylazobenzene group, phenoxyethyleneglycoxybenzene, or a sulfide or disulfide reactive self-assembled film having ethyleneglycoxybenzene in the main chain. An object of the present invention is to provide an organized film that can be used without reacting with other functional molecules when used by reacting with other functional molecules.
本発明者らは、前記課題について鋭意検討し、アルキル基、アルキルアゾベンゼン基、フエノキシエチレングリコキシベンゼン、又はエチレングリコキシベンゼンを主鎖にもつスルフィド又はジスルフィドにおいて、スルフィド又はジスルフィド基からもっとも離れた末端部位に、反応性の機能性分子を有するカルボラン又はその誘導体を前記主鎖の部分に取り込んだ自己組織化膜は、カルボランの作用により、自己組織化膜を構成する分子相互では、凝集する状態を離れて、自由に機能性分子が近づくことができるようになるために、自己組織化膜と反応しようとする機能性分子との反応を阻害することなく、反応を進行させることができることを見出した。
すなわち、本発明によれば、以下の発明が提供される。
The present inventors diligently studied the above problems, and in the sulfide or disulfide having an alkyl group, an alkylazobenzene group, phenoxyethyleneglycoxybenzene, or ethyleneglycoxybenzene in the main chain, the most distant from the sulfide or disulfide group. Self-assembled membranes in which carborane or a derivative thereof having a reactive functional molecule at the terminal site is incorporated into the main chain part aggregate with each other constituting the self-assembled membrane by the action of carborane. Since the functional molecules can freely move away from the state, the reaction can proceed without hindering the reaction with the functional molecules to be reacted with the self-assembled film. I found it.
That is, according to the present invention, the following inventions are provided.
（１）構造式（１）で表されるジスルフィド。
（２）前記（１）記載の構造式（１）で表されるジスルフィドを基板上に固定されていることを特徴とする自己組織化膜。
(1) A disulfide represented by the structural formula (1).
(2) wherein (1) self-assembled film, characterized in that the distearate sulfide represented by the structural formula (1) according immobilized on a substrate.
本発明によれば、フェノキシポリエチレングリコール基又はポリエチレングリコール基を主鎖にもつジスルフィドにおいて、ジスルフィド基からもっとも離れた末端部位に、反応性の機能性置換基であるカルボン酸基を有するカルボランを前記主鎖の部分に取り込んだ自己組織化膜は、カルボランの作用により、自己組織化膜を構成する分子相互では、凝集する状態を離れて、自由に機能性分子が近づくことができるようになるために、自己組織化膜と反応しようとする機能性分子との反応を阻害することなく、反応を進行させることができる。 According to the present invention, Karubora having in Tsuji sulfide in the main chain of phenoxy polyethylene glycol groups or polyethylene glycol group, the most distant terminal site from disulfide groups, carboxylic acid groups are reactive functional substituent The self-assembled film in which the main chain is incorporated into the main chain part can leave the agglomerated state between the molecules constituting the self-assembled film by the action of carborane so that the functional molecule can freely approach. Therefore, the reaction can proceed without inhibiting the reaction with the functional molecule to be reacted with the self-assembled film.
本発明のカルボラン誘導体化合物は、以下の構造式（１）で表されるジスルフィドである。
前記カルボラン化合物誘導体の製造方法は、Ｒを構成している基によって相違する。
（１）Ｒが、ｎエチレングリコール基であるジスルフィドの場合
カルボランを、ｎ−ブチルリチウムの存在下にクロロギ酸メチルと反応させてカルボランンの１位にメチルエステル基を導入する。炭酸カリウムの存在下にジブロモアルカンと反応させてブロモアルキルカルボランを合成し、水酸化カリウムにより１位のメチルエステルを加水分解して、ギ酸に変え、次にチオ尿素と反応させて、メルカプトエチレングリコールカルボランを製造する。
（２）Ｒが、フェノキシ−ｎエチレングリコール基であるジスルフィドの場合
ｎがテトラの場合について説明する。
パラカルボランと４−ヨードアニソールとを反応させて、１−（４−メトキシフェニル）−１，１２−カルボランを得る工程（２を製造する工程）、１−（４−メトキシフェニル）−１，１２−カルボランの１２位にメチルエステルを導入して、１−（４−メトキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボランを得る工程（３を製造する工程）、１−（４−メトキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボランと三臭化ホウ素とを反応させて、１−（４−ヒドロキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボランを得る工程（４を製造する工程）、１−（４−ヒドロキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボランと１、１１−ジブロモテトラエチレングリコールを反応させて１−（１２−ギ酸メチルエステル−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼンを得る工程（５を製造する工程）、１−（１２−ギ酸メチルエステル−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼンを加水分解して、１−（１２−ギ酸−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼンを得る工程（６を製造する工程）、１−（１２−ギ酸−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼンとチオ尿素を反応させて、１２−（４−（１２−ギ酸メチルエステル−１，１２−カルボラン）−フェノキシ）−テトラエチレングリコール−ジスルフィドを得る工程（７を製造する工程）
Ｒは、炭素数が１〜２０のポリエチレングリコール基をあらわす。
(1) When R is a disulfide in which n is an ethylene glycol group Carborane is reacted with methyl chloroformate in the presence of n-butyl lithium to introduce a methyl ester group at the 1-position of carborane. A bromoalkylcarborane is synthesized by reacting with dibromoalkane in the presence of potassium carbonate, hydrolyzing the methyl ester in
(2) When R is a disulfide in which R is a phenoxy-n ethylene glycol group The case where n is tetra will be described.
A step of reacting paracarborane and 4-iodoanisole to obtain 1- (4-methoxyphenyl) -1,12-carborane (step of producing 2), 1- (4-methoxyphenyl) -1,12 -A step of introducing 1- (4-methoxyphenyl) -12-formic acid methyl ester-1,12-carborane by introducing a methyl ester at the 12-position of carborane (step of producing 3), 1- (4-methoxy (Phenyl) -12-formic acid methyl ester-1,12-carborane and boron tribromide are reacted to obtain 1- (4-hydroxyphenyl) -12-formic acid methyl ester-1,12-carborane (4 1- (4-hydroxyphenyl) -12-formic acid methyl ester-1,12-carborane and 1,11-dibromotetraethylene glycol A step of reacting to obtain 1- (12-formic acid methyl ester-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene (step of producing 5), 1- (methyl 12-formate) Ester-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene is hydrolyzed to give 1- (12-formic acid-1,12-carborane) -4- (1-bromo)- Step of obtaining tetraethyleneglycoxybenzene (step of producing 6), reacting 1- (12-formic acid-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene with thiourea , 12- (4- (12-formic acid methyl ester-1,12-carborane) -phenoxy) -tetraethylene glycol disulfide (step for producing 7)
R represents a polyethylene glycol group having 1 to 20 carbon atoms.
本発明の自己組織化膜は、前記構造式（１）で表されるジスルフィドを基板上に固定されているものである。
基板には、ガラスなどの板に金属を蒸着して得られるものが用いられる。
金属には、金、銀、ニッケル、パラジウム、白金、鉄、コバルト、インジウムなどの金属を挙げることができる。
構造式（１）で表されるジスルフィドを溶剤に溶解させて、希薄溶液を作り、前記基板と接触させて、室温下に数時間に渡り放置する。その後、基板に過剰に付着した前記化合物を除去する。
このようにして金属基板の表面に吸着させた自己組織化膜を得ることができる。
具体的には、前記の工程により得られる１２−（４−（１２−ギ酸メチルエステル−１，１２―カルボラン）フェノキシ）−テトラエチレングリコール−ジスルフィドを、金属と共存させた状態に保つことによって、金属基板の表面に吸着させて自己組織化膜を形成する。
前記工程で得られた１２−（４−（１２−ギ酸メチルエステル−１，１２―カルボラン）フェノキシ）−テトラエチレングリコール−ジスルフィドを、溶剤に溶解させて、希薄溶液を作り、前記基板と接触させて、室温下に数時間に渡り放置する。その後、基板に過剰に付着した前記化合物を除去する。
このようにして自己組織化膜が得られる。
溶媒は、適宜選択して使用することができる。具体的には、ジクロロメタンなどに溶解させて１ｍＭの溶液とし、室温で、２から１２時間程度放置する。
Self-assembled film of the present invention, the represented distearate sulfide by the structural formula (1) in which are fixed on the substrate.
A substrate obtained by vapor-depositing a metal on a plate such as glass is used.
Examples of the metal include gold, silver, nickel, palladium, platinum, iron, cobalt, and indium.
The distearate sulfide represented by the structural formula (1) is dissolved in a solvent, to make a dilute solution, in contact with the substrate, allowed to stand for several hours at room temperature. Thereafter, the compound excessively attached to the substrate is removed.
In this way, a self-assembled film adsorbed on the surface of the metal substrate can be obtained.
Specifically, by maintaining 12- (4- (12-formic acid methyl ester-1,12-carborane) phenoxy) -tetraethylene glycol-disulfide obtained by the above process in a state coexisting with the metal, A self-assembled film is formed by adsorbing on the surface of the metal substrate.
The 12- (4- (12-formic acid methyl ester-1,12-carborane) phenoxy) -tetraethylene glycol disulfide obtained in the above step is dissolved in a solvent to form a dilute solution and brought into contact with the substrate. Leave at room temperature for several hours. Thereafter, the compound excessively attached to the substrate is removed.
In this way, a self-assembled film is obtained.
The solvent can be appropriately selected and used. Specifically, it is dissolved in dichloromethane or the like to form a 1 mM solution and left at room temperature for about 2 to 12 hours.
前記工程で得られた機能性置換基を有するカルボラン化合物誘導体を有する生成物を基板に固定した自己組織化膜を、機能性分子と反応させる際にカルボラン化合物誘導体の作用により実際に反応を阻害されることがないかを確認する。
本発明では機能性分子に核酸、特にＤＮＡを用いて確認を行なう。本発明では、機能性置換基を有するカルボラン化合物誘導体を有する生成物を基板に固定した自己組織化膜を、アミノ化ＤＮＡと縮合剤を用いて反応させることにより、ＤＮＡを導入することができる。この縮合剤には４−（４，６−ジメトキシー１，３，５−トリアジン−２−イル）−４−メチルモルホリニウムクロライド（ＤＭＴ−ＭＭ）、ＤＣＣ（Ｎ，Ｎ−ジシクロヘキシルカルボジイミド（ＤＣＣ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ）などが用いられる。
このようにして得られた基板上にＤＮＡが固定された状態で水溶液に溶解させた状態で、ターゲットＤＮＡをハイブリダーゼーションさせて、自由に反応させることができるかどうかを確認する。具体的には、ハイブリダイゼーションが生起していれば反応を阻害していないというとことがわかる。これには、ハイブリダイゼーションの確認には、表面プラズモン共鳴法、水晶振動子法などが適宜採用される。本発明では、表面プラズモン法によりハイブリダイゼーションが生起していることを確認している。
具体的には、特開２００２−２２６５３に記載されているような表面プラズモン共鳴分光法により、自己組織化膜の反射率の変化をモニターすることによって観察することができる。
本発明では、後で述べるように比較例としては、同じく末端に機能性置換基を有するものの、カルボラン化合物誘導体を有していない、従来から用いられてきた自己組織化膜を用いて同じく基板上にＤＮＡが固定された状態で水溶液に溶解させた状態で、ターゲットＤＮＡをハイブリダーゼーションさせて得られた結果を調べたものである。
When the self-assembled film in which the product having a carborane compound derivative having a functional substituent obtained in the above step is immobilized on a substrate is reacted with a functional molecule, the reaction is actually inhibited by the action of the carborane compound derivative. Check that there is no problem.
In the present invention, confirmation is performed using a nucleic acid, particularly DNA, as a functional molecule. In the present invention, DNA can be introduced by reacting a self-assembled film in which a product having a carborane compound derivative having a functional substituent is immobilized on a substrate using a condensing agent and aminated DNA. This condensing agent includes 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), DCC (N, N-dicyclohexylcarbodiimide (DCC)). 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and the like are used.
It is confirmed whether the target DNA can be allowed to react freely by hybridizing in a state where the DNA is fixed on the substrate thus obtained and dissolved in an aqueous solution. Specifically, it can be understood that the reaction is not inhibited if hybridization occurs. For this purpose, a surface plasmon resonance method, a crystal resonator method, or the like is appropriately employed for confirmation of hybridization. In the present invention, it has been confirmed that hybridization has occurred by the surface plasmon method.
Specifically, it can be observed by monitoring the change in reflectance of the self-assembled film by surface plasmon resonance spectroscopy as described in JP-A-2002-22653.
In the present invention, as will be described later, as a comparative example, a self-assembled film which has a functional substituent at the terminal but does not have a carborane compound derivative and has been conventionally used is also used on the substrate. The results obtained by hybridizing the target DNA in a state in which the DNA is fixed and dissolved in an aqueous solution are examined.
１−（４−メトキシフェニル）−１，１２−カルボラン（化合物２）の合成方法
窒素雰囲気下、パラカルボラン(1.44 g, 10 mmol)に100 mlの無水１，２−ジメトキシエタンを加えた後、0℃で1.57 mM、n-ブチルリチウム(7.0 ml, 11 mmol)をゆっくり滴下し、室温で１時間撹拌した。その後、ヨウ化銅（I）(1.1 g, 11 mmol)を加えて２時間、さらにピリジン(6 ml)を加えて３０分間室温で撹拌することで、銅（I）−パラカルボラン溶液を調整した。この溶液に４−ヨードアニソール(2.34 g, 10 mmol)を加えて110℃で４日間加熱還流させた。その後溶媒を減圧留去し、粗生成物をジエチルエーテルで抽出した。有機層を硫酸マグネシウムで乾燥させ、溶媒を減圧留去した後、ヘキサンとジエチルエーテル(15 : 1)を展開溶媒にしてシリカゲルカラムクロマト分離により単離精製し、化合物２番を４０％の収率で得た。以下の分析結果から、表記の化合物１−（４−メトキシフェニル）−１，１２−カルボランであることを確認した。
1H NMR (500 MHz, CDCl3)δ 7.09 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H), 2.72 (s, 1H) ; ; IR (KBr)2837, 2613, 1614, 1515, 1302, 1263, 1184, 1140, 1086, 1040, 1024, 843, 808, 737cm-1; HRMS (EI) Calcd for C9H18B10O: 250.2362. Found: 250.2449.
Synthesis method of 1- (4-methoxyphenyl) -1,12-carborane (compound 2) After adding 100 ml of
1 H NMR (500 MHz, CDCl 3 ) δ 7.09 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H), 2.72 (s, 1H);; IR (KBr) 2837, 2613, 1614, 1515, 1302, 1263, 1184, 1140, 1086, 1040, 1024, 843, 808, 737cm -1 ; HRMS (EI) Calcd for C 9 H 18 B 10 O: 250.2362. Found: 250.2449.
１−（４−メトキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボラン（化合物３）の合成方法
続いて窒素雰囲気下、化合物２番(0.75 g, 3.0 mmol)に50 mlの無水テトラヒドロフランを加えた後、0℃で1.57mM、n-ブチルリチウム(2.3 ml, 3.6 mmol)をゆっくり滴下し、室温で１時間撹拌した。その後、クロロギ酸メチル(0.28 ml, 3.6mmol)を加え、室温で５時間撹拌させた。その後溶媒を減圧留去し、粗生成物をジエチルエーテルで抽出した。有機層を硫酸ナトリウムで乾燥させ、溶媒を減圧留去した後、ヘキサンと酢酸エチル(10 : 1) を展開溶媒にしてフラッシュシリカゲルカラムクロマト分離により単離精製し、化合物３番を８９％の収率で得た。以下の分析結果から、表記の化合物１−（４−メトキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボランであることを確認した。
1H NMR (500 MHz, CDCl3) δ 7.06(d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H),3.63 (s, 3H); HRMS (EI) Calcd for C11H20B10O3:308.3880. Found: 308.3821.
Method for synthesizing 1- (4-methoxyphenyl) -12-formic acid methyl ester-1,12-carborane (compound 3) Subsequently, 50 ml of anhydrous tetrahydrofuran was added to compound 2 (0.75 g, 3.0 mmol) under a nitrogen atmosphere. After the addition, 1.57 mM, n-butyllithium (2.3 ml, 3.6 mmol) was slowly added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Thereafter, methyl chloroformate (0.28 ml, 3.6 mmol) was added and allowed to stir at room temperature for 5 hours. Thereafter, the solvent was distilled off under reduced pressure, and the crude product was extracted with diethyl ether. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by flash silica gel column chromatography separation using hexane and ethyl acetate (10: 1) as eluents. Obtained at a rate. From the following analysis results, it was confirmed that the compound was the indicated compound 1- (4-methoxyphenyl) -12-formic acid methyl ester-1,12-carborane.
1 H NMR (500 MHz, CDCl 3 ) δ 7.06 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H), 3.63 (s, 3H); HRMS (EI) Calcd for C 11 H 20 B 10 O 3 : 308.3880. Found: 308.3821.
１−（４−ヒドロキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボラン（化合物４）の合成方法
続いて窒素雰囲気下、化合物３番(0.62 g, 2.0 mmol)に40 mlの無水ジクロロメタンを加えた後、0℃で三臭化ホウ素(0.38 ml, 4.0 mmol)をゆっくり滴下し、0℃で５時間撹拌した。その後溶媒を減圧留去し、粗生成物をジエチルエーテルで抽出した。有機層を硫酸ナトリウムで乾燥させ、溶媒を減圧留去した後、ヘキサンと酢酸エチル(10 : 1) を展開溶媒にしてフラッシュシリカゲルカラムクロマト分離により単離精製し、化合物４番を１００％の収率で得た。以下の分析結果から、表記の化合物１−（４−ヒドロキシフェニル）−１２−ギ酸メチルエステル−１，１２−カルボランであることを確認した。
1H NMR (500 MHz, CDCl3) δ 7.06(d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.63 (s, 3H); HRMS(EI) Calcd for C10H18B10O3:294.3611. Found: 294.3610.
Method for synthesizing 1- (4-hydroxyphenyl) -12-formic acid methyl ester-1,12-carborane (compound 4) Subsequently, 40 ml of anhydrous dichloromethane was added to compound No. 3 (0.62 g, 2.0 mmol) under a nitrogen atmosphere. After the addition, boron tribromide (0.38 ml, 4.0 mmol) was slowly added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 5 hours. Thereafter, the solvent was distilled off under reduced pressure, and the crude product was extracted with diethyl ether. The organic layer is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is isolated and purified by flash silica gel column chromatography separation using hexane and ethyl acetate (10: 1) as developing solvents. Obtained at a rate. From the following analysis results, it was confirmed that the compound was the indicated compound 1- (4-hydroxyphenyl) -12-formic acid methyl ester-1,12-carborane.
1 H NMR (500 MHz, CDCl 3 ) δ 7.06 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.63 (s, 3H); HRMS (EI) Calcd for C 10 H 18 B 10 O 3 : 294.3611. Found: 294.3610.
１−（１２−ギ酸メチルエステル−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼン（化合物５）の合成方法
続いて化合物４番(0.44 g, 1.5 mmol)と１、１１−ジブロモテトラエチレングリコール(0.72g, 2.25 mmol)と炭酸カリウム(0.63 g, 4.5 mmol)に20 mlのアセトンを加えて１日加熱還流した。その後溶媒を減圧留去し、粗生成物をジエチルエーテルで抽出した。有機層を硫酸ナトリウムで乾燥させ、溶媒を減圧留去した後、ヘキサンと酢酸エチル(2 : 1) を展開溶媒にしてフラッシュシリカゲルカラムクロマト分離により単離精製し、化合物５番を５５％の収率で得た。以下の分析結果から、表記の化合物１−（１２−ギ酸メチルエステル−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼンであることを確認した。
1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 9.0 Hz, 2H), 6.66(d, J = 9.0 Hz, 2H), 4.04 (t, J = 4.9 Hz, 2H), 3.76-3.80 (m, 4H),3.63 (s, 3H), 3.63-3.67 (m, 8H), 3.43 (t, J = 6.4 Hz, 2H); 13C NMR (500MHz, CDCl3) δ 159.0, 128.1, 114.0, 71.2, 70.8, 70.7, 70.6, 70.5, 69.6, 67.4, 54.1, 30.3; HRMS (EI) Calcd for C18H33B10O6Br: 533.4704. Found: 533.4701.
Method for synthesizing 1- (12-formic acid methyl ester-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene (Compound 5) Subsequently, Compound No. 4 (0.44 g, 1.5 mmol) and 1 20 ml of acetone was added to 11-dibromotetraethylene glycol (0.72 g, 2.25 mmol) and potassium carbonate (0.63 g, 4.5 mmol), and the mixture was heated to reflux for 1 day. Thereafter, the solvent was distilled off under reduced pressure, and the crude product was extracted with diethyl ether. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by flash silica gel column chromatography separation using hexane and ethyl acetate (2: 1) as developing solvents. Obtained at a rate. From the following analysis results, it was confirmed that it was the title compound 1- (12-formic acid methyl ester-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene.
1 H NMR (500 MHz, CDCl 3 ) δ 7.06 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 4.04 (t, J = 4.9 Hz, 2H), 3.76-3.80 (m, 4H), 3.63 (s, 3H ), 3.63-3.67 (m, 8H), 3.43 (t, J = 6.4 Hz, 2H); 13 C NMR (500 MHz, CDCl 3 ) δ 159.0, 128.1, 114.0, 71.2, 70.8, 70.7, 70.6, 70.5, 69.6 , 67.4, 54.1, 30.3; HRMS (EI) Calcd for C 18 H 33 B 10 O 6 Br: 533.4704. Found: 533.4701.
１−（１２−ギ酸−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼン（化合物６）の合成方法
続いて化合物５番(0.37 g, 0.7 mmol)と水酸化カリウム(0.2 g, 3.5 mmol)に 20 mlのテトラヒドロフランと水(1 : 1)を加えて１日攪拌した。その後溶媒を減圧留去し、粗生成物を酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥させ、溶媒を減圧留去した後、酢酸エチルを展開溶媒にしてフラッシュシリカゲルカラムクロマト分離により単離精製し、化合物６番を１００％の収率で得た。以下の分析結果から、表記の化合物１−（１２−ギ酸−１，１２−カルボラン）−４−（１−ブロモ）−テトラエチレングリコキシベンゼンであることを確認した。
1H NMR (500 MHz, CDCl3) δ 7.05 (d, J = 9.0 Hz, 2H), 6.67(d, J = 9.0 Hz, 2H), 4.04 (t, J = 4.9 Hz, 2H), 3.76-3.80 (m, 4H),3.63-3.67 (m, 8H), 3.43 (t, J = 6.4 Hz, 2H); HRMS (EI) Calcd for C17H31B10O6Br:519.4435. Found: 519.4433.
Method for synthesizing 1- (12-formic acid-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene (Compound 6) Subsequently, Compound No. 5 (0.37 g, 0.7 mmol) and potassium hydroxide (0.2 g, 3.5 mmol) was added with 20 ml of tetrahydrofuran and water (1: 1) and stirred for 1 day. Thereafter, the solvent was distilled off under reduced pressure, and the crude product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by flash silica gel column chromatography separation using ethyl acetate as a developing solvent to obtain compound 6 in 100% yield. From the following analysis results, it was confirmed that the compound was the indicated compound 1- (12-formic acid-1,12-carborane) -4- (1-bromo) -tetraethyleneglycoxybenzene.
1 H NMR (500 MHz, CDCl 3 ) δ 7.05 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 4.04 (t, J = 4.9 Hz, 2H), 3.76-3.80 (m, 4H), 3.63-3.67 (m , 8H), 3.43 (t, J = 6.4 Hz, 2H); HRMS (EI) Calcd for C 17 H 31 B 10 O 6 Br: 519.4435. Found: 519.4433.
１２−（４−（１２−ギ酸メチルエステル−１，１２−カルボラン）−フェノキシ）−テトラエチレングリコール−ジスルフィド（化合物７）の合成方法
続いて化合物６番(0.1 g, 0.2 mmol)とチオ尿素(0.06 g, 0.8 mmol)に20 mlのエタノールを加えて、６時間加熱還流する。その後、3 mlの１０％水酸化ナトリウム水溶液を滴下し、３時間過熱還流する。その後、反応溶液を中和させ、粗生成物を酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥させ、化合物7番を１００％の収率で得た。以下の分析結果から、表記の化合物１２−（４−（１２−ギ酸メチルエステル−１，１２−カルボラン）−フェノキシ）−テトラエチレングリコール−ジスルフィドであることを確認した。
1H NMR (500 MHz, CDCl3) δ 7.05 (d, J = 9.0 Hz, 4H), 6.67 (d, J = 9.0 Hz, 4H), 4.04 (t, J = 4.9 Hz, 4H), 3.76-3.78 (m, 4H), 3.56-3.70 (m, 20H), 2.83 (t, J = 4.0 Hz, 4H); HRMS (EI) Calcd for C17H31B10O6Br: 943.2110. Found: 943.2104.
Synthesis method of 12- (4- (12-formic acid methyl ester-1,12-carborane) -phenoxy) -tetraethylene glycol disulfide (Compound 7) Subsequently, Compound No. 6 (0.1 g, 0.2 mmol) and thiourea ( 0.06 g, 0.8 mmol) is added with 20 ml of ethanol and heated to reflux for 6 hours. Thereafter, 3 ml of 10% aqueous sodium hydroxide solution is added dropwise, and the mixture is refluxed for 3 hours. Thereafter, the reaction solution was neutralized, and the crude product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate to obtain
1 H NMR (500 MHz, CDCl 3 ) δ 7.05 (d, J = 9.0 Hz, 4H), 6.67 (d, J = 9.0 Hz, 4H), 4.04 (t, J = 4.9 Hz, 4H), 3.76-3.78 (m, 4H), 3.56-3.70 (m , 20H), 2.83 (t, J = 4.0 Hz, 4H); HRMS (EI) Calcd for C 17 H 31 B 10 O 6 Br: 943.2110. Found: 943.2104.
金基板上に自己組織化膜を形成させた。この自己組織化膜にアミノ修飾したDNAと縮合剤として4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) を用いて金基板上でアミド反応を行った。カルボン酸と縮合剤（DMT-MM）により形成される中間体を考慮すると、カルボランの立体効果により、DNAの一級アミン部位が中間体に近づくのに有利であると考えられる。このプローブDNAに相補する塩基配列を持ったターゲットDNAが20 mM MgCl2水溶液中で相補対を形成することを表面プラズモン共鳴法により観察した（図１）。この結果により前記化合物が金表面に固定化されたことが確認された。
（比較例１）
A self-assembled film was formed on the gold substrate. This self-assembled membrane is amino-modified with DNA and 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM) as a condensing agent. The amide reaction was performed above. Considering the intermediate formed by the carboxylic acid and the condensing agent (DMT-MM), it is considered that the primary amine site of DNA is close to the intermediate due to the steric effect of carborane. It was observed by a surface plasmon resonance method that a target DNA having a base sequence complementary to the probe DNA forms a complementary pair in a 20 mM MgCl 2 aqueous solution (FIG. 1). This result confirmed that the compound was immobilized on the gold surface.
(Comparative Example 1)
比較例に従来から自己組織化膜として用いられていたカルボンラン化合物を有していないＣＯＯＨ基を置換基として有するテトラエチレングリコキシベンゼンを主鎖にもつ化合物の自己組織化膜を用いて同様の実験を行なった。その結果、前記実施例１の結果に比較して反射率が低い結果となっている（図２）。両者の結果を対比すると、本発明のカルボラン化合物を有する自己組織化膜の効果が確認できる。 In the comparative example, a self-assembled film of a compound having a main chain of tetraethyleneglycoxybenzene having a COOH group as a substituent which does not have a carboxrane compound which has been conventionally used as a self-assembled film is used. The experiment was conducted. As a result, the reflectance is lower than that of Example 1 (FIG. 2). Comparing both results, the effect of the self-assembled film having the carborane compound of the present invention can be confirmed.
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