JP5995207B2 - Boron-containing porphyrin derivatives - Google Patents
Boron-containing porphyrin derivatives Download PDFInfo
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- JP5995207B2 JP5995207B2 JP2014240667A JP2014240667A JP5995207B2 JP 5995207 B2 JP5995207 B2 JP 5995207B2 JP 2014240667 A JP2014240667 A JP 2014240667A JP 2014240667 A JP2014240667 A JP 2014240667A JP 5995207 B2 JP5995207 B2 JP 5995207B2
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- compound
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- boron
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- mhz
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- 150000004033 porphyrin derivatives Chemical class 0.000 title claims description 53
- 229910052796 boron Inorganic materials 0.000 title description 51
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title description 50
- 108010003533 Viral Envelope Proteins Proteins 0.000 claims description 16
- 239000002502 liposome Substances 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 230000004927 fusion Effects 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 210000004779 membrane envelope Anatomy 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 36
- 150000001875 compounds Chemical class 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 32
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- -1 carboxyethyl groups Chemical group 0.000 description 22
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
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- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
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Description
本発明は、光線力学療法やホウ素中性子捕捉療法の有効成分として有用な含ホウ素ポルフィリン誘導体に関する。 The present invention relates to a boron-containing porphyrin derivative useful as an active ingredient in photodynamic therapy and boron neutron capture therapy.
ポルフィリン骨格を有する化合物は、腫瘍細胞親和性と光感受性を有し、レーザー光照射により励起三重項状態の分子となり、（１）他の分子への電子移動や他の分子からの水素引き抜きによるラジカル反応を起こし、最終的には過酸化物を生成せしめて腫瘍細胞を傷害する経路、および、（２）周囲に存在する酸素分子への電子移動によって励起一重項酸素分子を生成せしめ、腫瘍細胞を酸化して傷害する経路により、腫瘍細胞を壊死させることができることから、光線力学療法（ＰＤＴ：Ｐｈｏｔｏｄｙｎａｍｉｃ Ｔｈｅｒａｐｙ）の有効成分として有用であり、ポルフィリン誘導体の１つであるレザフィリンは、２００３年に我が国において認可され、早期肺がん患者の治療に用いられている。 A compound having a porphyrin skeleton has a tumor cell affinity and photosensitivity, becomes a molecule in an excited triplet state by laser light irradiation, and (1) radicals due to electron transfer to other molecules or hydrogen abstraction from other molecules. A reaction that ultimately generates peroxide and damages tumor cells, and (2) generates excited singlet oxygen molecules by electron transfer to surrounding oxygen molecules, Since the tumor cells can be necrotized by the oxidative and injured pathway, Rezaphyrin, which is useful as an active ingredient of photodynamic therapy (PDT), is one of the porphyrin derivatives in Japan in 2003. Approved and used to treat patients with early lung cancer.
近年、ポルフィリン骨格を有する化合物にホウ素を導入することで水溶性を高めた含ホウ素ポルフィリン誘導体が開発されている。中でもＫａｈｌらによって開発された下記の構造式で表されるＢＯＰＰ（非特許文献１）は、Ｃ６グリオーマＸｅｎｏｇｒａｆｔモデルマウスに対して１００ｍｇ／ｋｇの用量でｉ．ｐ．投与およびｉ．ｖ．投与した場合、９０ｐｐｍも腫瘍に蓄積することから臨床応用が期待されたが、臨床第１相試験において血小板減少などの副作用により開発が断念された。
一方、放射性アイソトープを利用した新しいがんの治療方法として、ホウ素中性子捕捉療法（ＢＮＣＴ：Ｂｏｒｏｎ Ｎｅｕｔｒｏｎ Ｃａｐｔｕｒｅ Ｔｈｅｒａｐｙ）が注目されている。ホウ素中性子捕捉療法は、ホウ素１０同位体（１０Ｂ）を含むホウ素化合物を腫瘍細胞に取り込ませ、低エネルギーの中性子線（例えば熱中性子）を照射することで、細胞内で起こる核反応により局所的に腫瘍細胞を破壊する治療方法である。この治療方法では、１０Ｂを含むホウ素化合物を腫瘍に選択的に蓄積させることが、治療効果を高める上で重要であるため、含ホウ素ポルフィリン誘導体はそのような性質を有するホウ素化合物として期待されている。 On the other hand, boron neutron capture therapy (BNCT) has attracted attention as a new cancer treatment method using radioactive isotopes. In boron neutron capture therapy, a boron compound containing a boron 10 isotope ( 10 B) is taken into a tumor cell and irradiated with a low-energy neutron beam (for example, thermal neutron), thereby causing local reaction due to a nuclear reaction occurring in the cell. It is a treatment method that destroys tumor cells. In this treatment method, it is important for enhancing the therapeutic effect that the boron compound containing 10 B is selectively accumulated in the tumor. Therefore, the boron-containing porphyrin derivative is expected as a boron compound having such properties. Yes.
以上のような背景のもと、腫瘍細胞親和性に優れ、かつ、毒性が低いことで高用量の投与が可能である、光線力学療法やホウ素中性子捕捉療法の有効成分として有用な含ホウ素ポルフィリン誘導体が望まれており、既にそのような化合物の提案もあるが（特許文献１）、より優れた含ホウ素ポルフィリン誘導体が望まれている。 Based on the above background, boron-containing porphyrin derivatives useful as an active ingredient in photodynamic therapy and boron neutron capture therapy, which have excellent tumor cell affinity and can be administered at high doses due to low toxicity Although there is already a proposal of such a compound (Patent Document 1), a more excellent boron-containing porphyrin derivative is desired.
そこで本発明は、腫瘍細胞親和性に優れ、かつ、毒性が低いことで高用量の投与が可能である、光線力学療法やホウ素中性子捕捉療法の有効成分として有用な含ホウ素ポルフィリン誘導体を提供することを目的とする。 Accordingly, the present invention provides a boron-containing porphyrin derivative useful as an active ingredient in photodynamic therapy and boron neutron capture therapy, which is excellent in tumor cell affinity and can be administered at a high dose due to low toxicity. With the goal.
本発明者は、上記の点に鑑みて鋭意研究を重ねた結果、プロトポルフィリンが有する２つのカルボキシエチル基のうちの少なくとも１つのカルボキシル基に、ＢＳＨ（ｍｅｒｃａｐｔｏｕｎｄｅｃａｈｙｄｒｏｄｏｄｅｃａｂｏｒａｔｅ：Ｂ１２Ｈ１１ＳＨ）などのカゴ状のホウ素イオンクラスターを結合した化合物は、腫瘍細胞親和性に優れるとともに低毒性であり、光線力学療法やホウ素中性子捕捉療法の有効成分として有用であること、さらに、２つのビニル基のうちの少なくとも１つを化学変換して当該部分の脂溶性（疎水性）を高めると、ホウ素イオンクラスターを結合させたカルボキシエチル基が結合したピロール環のサイドが有する親水性と相俟って分子が両親媒性を示し、その結果、ウイルスエンベロープやリポソームなどのナノ粒子（直径が１〜１００ｎｍ程度の粒子）との融合性や自己集合性を有するようになることを知見した。 As a result of intensive studies in view of the above points, the present inventor has found that at least one carboxyl group of two carboxyethyl groups possessed by protoporphyrin has a cage such as BSH (mercaptodecahydrodeborate: B 12 H 11 SH). The compound bound with the boron ion cluster is excellent in tumor cell affinity and low toxicity, and is useful as an active ingredient in photodynamic therapy and boron neutron capture therapy, and at least of two vinyl groups. When one is chemically transformed to increase the lipophilicity (hydrophobicity) of the part, the molecule becomes amphiphilic in combination with the hydrophilicity of the side of the pyrrole ring to which the carboxyethyl group bound to the boron ion cluster is bound. As a result, virus envelopes and liposomes It has been found that it has fusion properties and self-assembly properties with which nanoparticles (particles having a diameter of about 1 to 100 nm).
上記の知見に基づいてなされた本発明は、請求項１記載の通り、下記の一般式（２）で表されるポルフィリン誘導体を、ウイルスエンベロープおよび／またはリポソームと融合させることによる、前記のポルフィリン誘導体と、ウイルスエンベロープおよび／またはリポソームの融合物の製造方法である。
また、請求項２記載の製造方法は、請求項１記載の製造方法において、Ｒ １ 、Ｒ ２ の少なくとも１つは炭素数が１０以上であるアルコキシ基によって置換されたアルキル基である。
また、本発明は、請求項３記載の通り、下記の一般式（２）で表されるポルフィリン誘導体を、ウイルスエンベロープおよび／またはリポソームと融合させることによる、前記のポルフィリン誘導体の、ウイルスエンベロープおよび／またはリポソームとの融合物を製造するための使用である。
また、本発明は、請求項４記載の通り、上記の一般式（２）で表されるポルフィリン誘導体を、ウイルスエンベロープおよび／またはリポソームと融合させることによる、前記のポルフィリン誘導体を有効成分とする光線力学療法剤の製造方法である。
The present invention made on the basis of the above-mentioned knowledge is the above-mentioned porphyrin derivative obtained by fusing a porphyrin derivative represented by the following general formula (2) with a virus envelope and / or a liposome as described in claim 1. And a method for producing a fusion product of a viral envelope and / or a liposome.
The production method according to claim 2 is the production method according to claim 1, wherein at least one of R 1 and R 2 is an alkyl group substituted by an alkoxy group having 10 or more carbon atoms .
Further, according to the present invention, as described in claim 3, the porphyrin derivative represented by the following general formula (2) is fused with the virus envelope and / or the liposome to produce the virus envelope and / or Or use to produce fusions with liposomes.
Further, the present invention provides a light beam comprising the porphyrin derivative as an active ingredient by fusing the porphyrin derivative represented by the general formula (2) with a virus envelope and / or a liposome as described in claim 4. It is a manufacturing method of a kinetic therapy agent.
本発明によれば、腫瘍細胞親和性に優れ、かつ、毒性が低いことで高用量の投与が可能である、光線力学療法やホウ素中性子捕捉療法の有効成分として有用な含ホウ素ポルフィリン誘導体を提供することができる。 According to the present invention, a boron-containing porphyrin derivative useful as an active ingredient in photodynamic therapy and boron neutron capture therapy, which is excellent in tumor cell affinity and can be administered at a high dose due to low toxicity, is provided. be able to.
本発明の含ホウ素ポルフィリン誘導体は、下記の一般式（１）で表されるアニオン化合物の塩であることを特徴とするものである。
上記の一般式（１）において、Ｒ１、Ｒ２における置換されていてもよいアルキル基のアルキル基としては、炭素数１〜２０の直鎖状または分岐鎖状のアルキル基が例示され、具体的にはメチル基、エチル基、ｎ−プロピル基、ｉｓｏ−プロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘキシル基、オクチル基、デカニル基、ドデカニル基、テトラデカニル基、ヘキサデカニル基、オクタデカニル基、イコサニル基などが挙げられる。アルキル基が有していてもよい置換基としては、水酸基、ハロゲン原子（塩素原子や臭素原子など）、アルコキシ基（メトキシ基、エトキシ基、ｎ−プロポキシ基、ｉｓｏ−プロポキシ基、ｎ−ブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、オクチルオキシ基、デカニルオキシ基、ドデカニルオキシ基、テトラデカニルオキシ基、ヘキサデカニルオキシ基、オクタデカニルオキシ基、イコサニルオキシ基などの例えば炭素数１〜２０の直鎖状または分岐鎖状のもの）などが挙げられる。 In the above general formula (1), the alkyl group of the alkyl group which may be substituted in R 1 and R 2 is exemplified by a linear or branched alkyl group having 1 to 20 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, octyl group, decanyl group, dodecanyl group, tetradecanyl group Group, hexadecanyl group, octadecanyl group, icosanyl group and the like. Examples of the substituent that the alkyl group may have include a hydroxyl group, a halogen atom (such as a chlorine atom or a bromine atom), an alkoxy group (a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group, an n-butoxy group). , Sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, octyloxy group, decanyloxy group, dodecanyloxy group, tetradecanyloxy group, hexadecanyloxy group, octadecanyloxy group, icosanyloxy group A straight chain or branched chain having 1 to 20 carbon atoms).
上記の一般式（１）で表されるアニオン化合物の塩としては、ナトリウム塩やカリウム塩などのアルカリ金属塩、マグネシウム塩やカルシウム塩などのアルカリ土類金属塩、アルミニウム塩の他、テトラメチルアンモニウム塩やメチルトリフェニルフォスフォニウム塩などが挙げられるが、水溶性に優れるとともに毒性が低いアルカリ金属塩やアルカリ土類金属塩を好適に採用することができる。 Examples of the salt of the anion compound represented by the general formula (1) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and tetramethylammonium salt. Examples thereof include salts and methyltriphenylphosphonium salts. Alkali metal salts and alkaline earth metal salts having excellent water solubility and low toxicity can be preferably used.
上記の一般式（１）で表されるアニオン化合物の塩である本発明の含ホウ素ポルフィリン誘導体の合成ルートの一例を以下に示す。
本発明の含ホウ素ポルフィリン誘導体のうち、Ｒ１、Ｒ２のいずれもがビニル基である化合物（本発明化合物Ａ）は、例えば、プロトポルフィリンとＢ１２Ｈ１１ＸＨ（Ｘは前記と同義である）の塩（テトラメチルアンモニウム塩やメチルトリフェニルフォスフォニウム塩など）を反応させることで合成することができる。Ｒ１、Ｒ２の少なくとも１つが置換されていてもよいアルキル基である化合物（本発明化合物Ｂ）は、例えば、プロトポルフィリンが有する２つのビニル基のうちの少なくとも１つを置換されていてもよいアルキル基に化学変換した後（中間体Ｃ）、Ｂ１２Ｈ１１ＸＨの塩を反応させることで合成することができる。なお、各工程においては、カルボキシル基の活性化のためのクロロカルボニル基への変換、保護基の導入とその脱保護などの自体公知の有機化学的手法を用いることができる。 Of the boron-containing porphyrin derivatives of the present invention, the compound in which both R 1 and R 2 are vinyl groups (the present compound A) is, for example, protoporphyrin and B 12 H 11 XH (X is as defined above). ) Salt (tetramethylammonium salt, methyltriphenylphosphonium salt, etc.) can be synthesized. In the compound in which at least one of R 1 and R 2 is an optionally substituted alkyl group (the present compound B), for example, at least one of two vinyl groups of protoporphyrin may be substituted. After chemical conversion to a good alkyl group (intermediate C), it can be synthesized by reacting a salt of B 12 H 11 XH. In each step, per se known organic chemical techniques such as conversion to a chlorocarbonyl group for activation of a carboxyl group, introduction of a protecting group, and deprotection thereof can be used.
上記の本発明の含ホウ素ポルフィリン誘導体の合成ルートに従えば、下記の一般式（２）で表されるポルフィリン誘導体は、Ｒ１、Ｒ２の少なくとも１つが置換されていてもよいアルキル基である本発明の含ホウ素ポルフィリン誘導体の合成中間体として有用である。
上記の一般式（２）において、Ｒ１３、Ｒ１４におけるアルコキシ基としては、炭素数１〜２０の直鎖状または分岐鎖状のアルコキシ基が例示され、具体的にはメトキシ基、エトキシ基、ｎ−プロポキシ基、ｉｓｏ−プロポキシ基、ｎ−ブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、オクチルオキシ基、デカニルオキシ基、ドデカニルオキシ基、テトラデカニルオキシ基、ヘキサデカニルオキシ基、オクタデカニルオキシ基、イコサニルオキシ基などが挙げられる。 In the above general formula (2), the alkoxy group in R 13 and R 14 is exemplified by a linear or branched alkoxy group having 1 to 20 carbon atoms, specifically, a methoxy group, an ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, octyloxy group, decanyloxy group, dodecanyloxy group, tetradecanyloxy group , Hexadecanyloxy group, octadecanyloxy group, icosanyloxy group and the like.
本発明の含ホウ素ポルフィリン誘導体は、腫瘍細胞親和性に優れるとともに低毒性であるので、光線力学療法の有効成分として有用である。また、分子中のホウ素原子の少なくとも１つを１０Ｂとすることで、ホウ素中性子捕捉療法の有効成分となる。さらに、ガドリニウムやマンガンなどの遷移金属と錯体を形成させることで、腫瘍細胞の検出や診断のためのＭＲＩ造影剤として用いることもできる。特筆すべきは、例えば、Ｒ１、Ｒ２の少なくとも１つをアルコキシ基によって置換されたアルキル基（１−アルコキシエチル基など）とし、アルコキシ基の炭素数を多くすることによって当該部分の脂溶性を高めると（炭素数は５以上が望ましく１０以上がより望ましい）、一般式（１）で表されるアニオン化合物を上下に２分して見た場合の上側半分が疎水性、下側半分が親水性となり、分子が両親媒性を示すことで、ウイルスエンベロープやリポソームなどのナノ粒子との融合性や自己集合性を有するようになることである。従って、このような化合物デザインが行われた本発明の含ホウ素ポリフィリン誘導体は、これらのナノ粒子に融合させたり自己集合させたりすることで、腫瘍細胞親和性や腫瘍細胞に対する取り込み性などの向上を図ることができるので、結果として、がん治療効果の改善や副作用としての光毒性の軽減などが可能となる。具体例を挙げると、例えば、本発明の含ホウ素ポリフィリン誘導体をセンダイウイルスエンベロープ（ＨＶＪ）と融合させることで、ＨＶＪが有する強い細胞膜融合能を利用して本発明の含ホウ素ポリフィリン誘導体の腫瘍細胞に対する取り込み性の向上を図ることができるとともに、ＨＶＪが持つ免疫賦活作用をがん治療効果に寄与させることができる。また、本発明の含ホウ素ポリフィリン誘導体をリポソームと融合させたり、自己集合させたりすることで、腫瘍細胞親和性の向上を図ることができる。ＢＯＰＰをはじめとするこれまでに知られている含ホウ素ポルフィリン誘導体で、このような化合物デザインが行われたものは、本発明者が知る限りにおいて存在しない。 Since the boron-containing porphyrin derivative of the present invention is excellent in tumor cell affinity and low toxicity, it is useful as an active ingredient in photodynamic therapy. Moreover, it becomes an active ingredient of boron neutron capture therapy by setting at least one of the boron atoms in the molecule to 10 B. Furthermore, by forming a complex with a transition metal such as gadolinium or manganese, it can also be used as an MRI contrast agent for detection and diagnosis of tumor cells. It should be noted that, for example, at least one of R 1 and R 2 is an alkyl group substituted with an alkoxy group (such as a 1-alkoxyethyl group), and by increasing the number of carbon atoms of the alkoxy group, the lipophilicity of the part (The carbon number is preferably 5 or more, and more preferably 10 or more), when the anion compound represented by the general formula (1) is divided into two parts in the vertical direction, the upper half is hydrophobic and the lower half is It becomes hydrophilic and the molecule exhibits amphipathic properties, so that it has a fusion property and self-assembly property with nanoparticles such as virus envelopes and liposomes. Therefore, the boron-containing porphyrin derivative of the present invention in which such a compound design is carried out can be improved in tumor cell affinity or uptake into tumor cells by fusing or self-assembling these nanoparticles. As a result, it is possible to improve the cancer treatment effect and reduce phototoxicity as a side effect. Specific examples include, for example, the fusion of the boron-containing porphyrin derivative of the present invention with the Sendai virus envelope (HVJ), thereby utilizing the strong cell membrane fusion ability of the HVJ to the tumor cells. The uptake can be improved and the immunostimulatory action of HVJ can contribute to the cancer treatment effect. Furthermore, the affinity for tumor cells can be improved by fusing the boron-containing porphyrin derivative of the present invention with liposomes or by self-assembly. As far as the present inventors know, there is no boron-containing porphyrin derivative known so far, such as BOPP, for which such a compound design has been performed.
本発明の含ホウ素ポルフィリン誘導体の医薬品製剤化は、例えば、本発明の含ホウ素ポルフィリン誘導体を蒸留水や生理食塩水に溶解することで行うことができる。製剤中には自体公知のｐＨ調節剤や防腐剤などを添加してもよい。その用法・用量は、例えばレザフィリンの用法・用量に準じることができる。 The pharmaceutical preparation of the boron-containing porphyrin derivative of the present invention can be performed, for example, by dissolving the boron-containing porphyrin derivative of the present invention in distilled water or physiological saline. A known pH adjuster, preservative and the like may be added to the preparation. The usage / dose can be based on, for example, the usage / dose of resaphyrin.
以下、本発明を実施例によって詳細に説明するが、本発明は以下の記載に限定して解釈されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is limited to the following description and is not interpreted.
実施例１：
以下の化学反応式に従って本発明の含ホウ素ポルフィリン誘導体１ａ，１ｂ，２ａ，２ｂを合成した。
Boron-containing porphyrin derivatives 1a, 1b, 2a, 2b of the present invention were synthesized according to the following chemical reaction formula.
（１）化合物1aの合成
プロトポルフィリンIX (0.16 mmol)を塩化メチレン(10 mL)に溶かし、オギザリルクロリド(0.7 mL)を加えた。反応混合物を室温で20分攪拌後、過剰量のオギザリルクロリドを含む塩化メチレン溶媒を減圧下で除いた。残さをアセトニトリル(15 mL)に溶かし、B12H11SHのテトラメチルアンモニウム塩(0.25 mmol, 80 mg)を加え、続いてピリジン(0.3 mL)を加え、室温で72時間攪拌した。減圧下で溶媒を溜去した後、粗生成物を薄層クロマトグラフ(メタノール30%/塩化メチレン70%)で精製し、化合物1aを紫色の固体として71mg, 51%の収率で得た。
IR νmax(KBr disc)/cm-1 3587s, 3375s, 3228s (OH/NH), 3025w (CH), 2495s (BH), 1725, 1685s (C=O), 1618s (C=C), 1605s (NH), 1410s (CH3), 1152s (CN), 1050s (B-B); UV/Vis(CH3CN): λmax: 417, 526, 535, 592, 637 nm; 11B NMR (96.3 MHz; CD3CN) δ -15.37, -11.97, -9.78, -5.49; 1H NMR (300 MHz; CD3CN) δ 10.29, 10.22, 10.2, 10.15 (4H, m, meso H), 8.49 (2H, q, CH=CH2), 6.45 (2H, d, J = 16.0 Hz, CH=CH2), 6.17 (2H, d, J = 12.0 Hz, CH=CH2), 4.32 (4H, m, porphyrin-CH2), 3.77, 3.73, 3.66, 3.64 (12H, s, CH3), 3.24 (4H, m, CH2COOH), 3.08 (24H, s, N(CH3)4), 0.55-1.82 (11H, bs, B12H11), -3.85 (s, 2H, NH); 13C NMR (75 MHz; CD3CN) δ 176.43, 176.69 (2C, CO), 145.39, 143.54, 142.37, 137.03, 136.85, 136.74, 130.61, 126.77 (16C, C pyrrole), 97.92-97.14 (4C, meso-C), 56.73, 56.6 (4C, CH=CH2), 54.59 (8C, N(CH3)4), 31.27, 30.56 (2C, CH2COOH), 23.28, 22.67 (2C, CH2CH2COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH3); MS(ESI, negative): m/z(%): 359.22 (100) [M-/2]; elemental analysis calcd(%) for C42H68N6B12O3S (868.62): C 58.20, H 7.91, N 9.70; found: C 58.05, H 7.73, N 9.49.
(1) Synthesis of Compound 1a Protoporphyrin IX (0.16 mmol) was dissolved in methylene chloride (10 mL), and oxalyl chloride (0.7 mL) was added. After stirring the reaction mixture at room temperature for 20 minutes, the methylene chloride solvent containing an excess amount of oxalyl chloride was removed under reduced pressure. The residue was dissolved in acetonitrile (15 mL), tetramethylammonium salt of B 12 H 11 SH (0.25 mmol, 80 mg) was added, pyridine (0.3 mL) was added, and the mixture was stirred at room temperature for 72 hours. After distilling off the solvent under reduced pressure, the crude product was purified by thin layer chromatography (methanol 30% / methylene chloride 70%) to obtain Compound 1a as a purple solid in 71 mg, 51% yield.
IR ν max (KBr disc) / cm -1 3587s, 3375s, 3228s (OH / NH), 3025w (CH), 2495s (BH), 1725, 1685s (C = O), 1618s (C = C), 1605s ( NH), 1410s (CH 3 ), 1152s (CN), 1050s (BB); UV / Vis (CH 3 CN): λ max : 417, 526, 535, 592, 637 nm; 11 B NMR (96.3 MHz; CD 3 CN) δ -15.37, -11.97, -9.78, -5.49; 1 H NMR (300 MHz; CD 3 CN) δ 10.29, 10.22, 10.2, 10.15 (4H, m, meso H), 8.49 (2H, q, CH = CH 2 ), 6.45 (2H, d, J = 16.0 Hz, CH = CH 2 ), 6.17 (2H, d, J = 12.0 Hz, CH = CH 2 ), 4.32 (4H, m, porphyrin-CH 2 ), 3.77, 3.73, 3.66, 3.64 (12H, s, CH 3 ), 3.24 (4H, m, CH 2 COOH), 3.08 (24H, s, N (CH 3 ) 4 ), 0.55-1.82 (11H, bs , B 12 H 11 ), -3.85 (s, 2H, NH); 13 C NMR (75 MHz; CD 3 CN) δ 176.43, 176.69 (2C, CO), 145.39, 143.54, 142.37, 137.03, 136.85, 136.74, 130.61, 126.77 (16C, C pyrrole), 97.92-97.14 (4C, meso-C), 56.73, 56.6 (4C, CH = CH 2 ), 54.59 (8C, N (CH 3 ) 4 ), 31.27, 30.56 (2C , CH 2 COOH), 23.28, 22.67 (2C, CH 2 CH 2 COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH 3 ); MS (ESI, negative): m / z (%): 359.22 (100 ) [M - / 2]; elem ental analysis calcd (%) for C 42 H 68 N 6 B 12 O 3 S (868.62): C 58.20, H 7.91, N 9.70; found: C 58.05, H 7.73, N 9.49.
（２）化合物1bの合成
プロトポルフィリンIX (0.16 mmol)を塩化メチレン(10 mL)に溶かし、オギザリルクロリド(1.5 mL)を加えた。反応混合物を室温で20分攪拌後、過剰量のオギザリルクロリドを含む塩化メチレン溶媒を減圧下で除いた。残さをアセトニトリル(15 mL)に溶かし、B12H11SHのテトラメチルアンモニウム塩(0.5 mmol, 0.16 g)を加え、続いてピリジン(0.5 mL)を加え、室温で72時間攪拌した。減圧下で溶媒を溜去した後、粗生成物を薄層クロマトグラフ(メタノール30%/塩化メチレン70%)で精製し、化合物1bを紫色の固体として140mg, 74%の収率で得た。
IR νmax(KBr disc)/cm-1 3254s (NH), 3026w (CH), 2499s (BH), 1682s (C=O), 1620s (C=C), 1609s (NH), 1416s (CH3), 1160s (CN), 1053s (B-B); UV/Vis(CH3CN): λmax: 415, 523, 536, 595, 639 nm; 11B NMR (96.3 MHz; CD3CN) δ -15.35, -11.94, -9.71, -5.53; 1H NMR (300 MHz; CD3CN) δ 10.45, 10.39, 10.26, 10.35 (4H, m, meso H), 8.59 (2H, q, CH=CH2), 6.39 (2H, d, J = 14.0 Hz, CH=CH2), 6.21 (2H, d, J = 9.0 Hz, CH=CH2), 4.35 (4H, m, porphyrin-CH2), 3.75, 3.70, 3.65, 3.60 (12H, s, CH3), 3.26 (4H, m, CH2COOH), 3.07 (24H, s, N(CH3)4), 0.51-1.85 (11H, bs, B12H11), -3.89 (s, 2H, NH); 13C NMR (75 MHz; CD3CN) δ 202.13 (2C, CO), 146.56, 145.17, 143.25, 137.14, 136.92, 135.56, 131.66, 127.72 (16C, C pyrrole), 98.19-97.05 (4C, meso-C), 56.96, 56.62 (4C, CH=CH2), 55.07 (8C, N(CH3)4), 31.45, 29.99 (2C, CH2COOH), 23.65, 23.02 (2C, CH2CH2COOH), 13.59, 12.59, 11.49, 11.74 (4C, CH3); MS(ESI, negative): m/z(%): 436.65 (100) [M-/2]; elemental analysis calcd(%) for C50H102N8B24O2S2 (1170.99): C 51.28, H 8.78, N 9.57; found: C 51.12, H 8.75, N 9.38.
(2) Synthesis of Compound 1b Protoporphyrin IX (0.16 mmol) was dissolved in methylene chloride (10 mL), and oxalyl chloride (1.5 mL) was added. After stirring the reaction mixture at room temperature for 20 minutes, the methylene chloride solvent containing an excess amount of oxalyl chloride was removed under reduced pressure. The residue was dissolved in acetonitrile (15 mL), tetramethylammonium salt of B 12 H 11 SH (0.5 mmol, 0.16 g) was added, pyridine (0.5 mL) was added, and the mixture was stirred at room temperature for 72 hours. After distilling off the solvent under reduced pressure, the crude product was purified by thin layer chromatography (methanol 30% / methylene chloride 70%) to obtain Compound 1b as a purple solid in a yield of 140 mg and 74%.
IR ν max (KBr disc) / cm -1 3254s (NH), 3026w (CH), 2499s (BH), 1682s (C = O), 1620s (C = C), 1609s (NH), 1416s (CH 3 ) , 1160s (CN), 1053s (BB); UV / Vis (CH 3 CN): λ max : 415, 523, 536, 595, 639 nm; 11 B NMR (96.3 MHz; CD 3 CN) δ -15.35,- 11.94, -9.71, -5.53; 1 H NMR (300 MHz; CD 3 CN) δ 10.45, 10.39, 10.26, 10.35 (4H, m, meso H), 8.59 (2H, q, CH = CH 2 ), 6.39 ( 2H, d, J = 14.0 Hz, CH = CH 2 ), 6.21 (2H, d, J = 9.0 Hz, CH = CH 2 ), 4.35 (4H, m, porphyrin-CH 2 ), 3.75, 3.70, 3.65, 3.60 (12H, s, CH 3 ), 3.26 (4H, m, CH 2 COOH), 3.07 (24H, s, N (CH 3 ) 4 ), 0.51-1.85 (11H, bs, B 12 H 11 ),- 3.89 (s, 2H, NH); 13 C NMR (75 MHz; CD 3 CN) δ 202.13 (2C, CO), 146.56, 145.17, 143.25, 137.14, 136.92, 135.56, 131.66, 127.72 (16C, C pyrrole), 98.19-97.05 (4C, meso-C), 56.96, 56.62 (4C, CH = CH 2 ), 55.07 (8C, N (CH 3 ) 4 ), 31.45, 29.99 (2C, CH 2 COOH), 23.65, 23.02 ( 2C, CH 2 CH 2 COOH) , 13.59, 12.59, 11.49, 11.74 (4C, CH 3); MS (ESI, negative): m / z (%): 436.65 (100) [M - / 2]; elemental analysis calcd (%) for C 50 H 102 N 8 B 24 O 2 S 2 (1170.99): C 51.28, H 8.78, N 9.57; found: C 51.12, H 8.75, N 9.38.
（３）化合物2aの合成
化合物1a (0.081 mmol)をアセトニトリル/水(1:1)に溶かし、アンバーライト120R Na+ formを加え、一晩攪拌した後、アンバーライトをろ過し、減圧下で溶媒を溜去し、化合物2aを紫色の固体として20mg, 32%の収率で得た。
UV/Vis(H2O): λmax: 411, 515, 535, 583, 637 nm; 11B NMR (96.3 MHz; d6-DMSO) δ -15.24, -11.85, -9.95, -5.65; 1H NMR (300 MHz; d6-DMSO) δ 10.44, 10.34, 10.28, 10.25 (4H, m, meso H), 8.52 (2H, m, CH=CH2), 6.44 (2H, d, J = 18.0 Hz, CH=CH2), 6.21 (2H, d, J = 9.0 Hz, CH=CH2), 4.25 (4H, m, porphyrin-CH2), 3.74, 3.71, 3.65, 3.62 (12H, s, CH3), 3.13 (4H, m, CH2COOH), 0.55-1.81 (11H, bs, B12H11), -3.84 (s, 2H, NH); 13C NMR (75 MHz; d6-DMSO) δ 176.43, 176.69 (2C, CO), 145.39, 143.54, 142.37, 137.03, 136.85, 136.74, 130.61, 126.77 (16C, C pyrrole), 97.92-97.14 (4C, meso-C), 56.73, 56.6 (4C, CH=CH2), 31.27, 30.56 (2C, CH2COOH), 23.28, 22.67 (2C, CH2CH2COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH3).
(3) Synthesis of Compound 2a Compound 1a (0.081 mmol) was dissolved in acetonitrile / water (1: 1), Amberlite 120R Na + form was added and stirred overnight, then Amberlite was filtered, and the solvent was removed under reduced pressure. The compound 2a was obtained as a purple solid in 20 mg, 32% yield.
UV / Vis (H 2 O): λ max : 411, 515, 535, 583, 637 nm; 11 B NMR (96.3 MHz; d 6 -DMSO) δ -15.24, -11.85, -9.95, -5.65; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.44, 10.34, 10.28, 10.25 (4H, m, meso H), 8.52 (2H, m, CH = CH 2 ), 6.44 (2H, d, J = 18.0 Hz, CH = CH 2 ), 6.21 (2H, d, J = 9.0 Hz, CH = CH 2 ), 4.25 (4H, m, porphyrin-CH 2 ), 3.74, 3.71, 3.65, 3.62 (12H, s, CH 3 ) , 3.13 (4H, m, CH 2 COOH), 0.55-1.81 (11H, bs, B 12 H 11 ), -3.84 (s, 2H, NH); 13 C NMR (75 MHz; d 6 -DMSO) δ 176.43 , 176.69 (2C, CO), 145.39, 143.54, 142.37, 137.03, 136.85, 136.74, 130.61, 126.77 (16C, C pyrrole), 97.92-97.14 (4C, meso-C), 56.73, 56.6 (4C, CH = CH 2 ), 31.27, 30.56 (2C, CH 2 COOH), 23.28, 22.67 (2C, CH 2 CH 2 COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH 3 ).
（４）化合物2bの合成
化合物1b (0.12 mmol)をアセトニトリル/水(1:1)に溶かし、アンバーライト120R Na+ formを加え、一晩攪拌した後、アンバーライトをろ過し、減圧下で溶媒を溜去し、化合物2bを紫色の固体として100mg, 65%の収率で得た。
UV/Vis(H2O): λmax: 415, 522, 536, 591, 639 nm; 11B NMR (96.3 MHz; d6-DMSO) δ -15.21, -11.89, -10.05, -5.72; 1H NMR (300 MHz; d6-DMSO) δ 10.37, 10.27, 10.15, 10.01 (4H, m, meso H), 8.52 (2H, m, CH=CH2), 6.46 (2H, d, J = 18.0 Hz, CH=CH2), 6.14 (2H, d, J = 18.0 Hz, CH=CH2), 4.34 (4H, m, porphyrin-CH2), 3.73, 3.71, 3.60, 3.57 (12H, s, CH3), 3.15 (4H, m, CH2COOH), 0.19-1.65 (11H, bs, B12H11), -3.81 (s, 2H, NH); 13C NMR (75 MHz; d6-DMSO) δ 179.79 (2C, CO), 146.41, 144.64, 142.47, 136.98, 136.52, 136.12, 130.3, 127.07 (16C, C pyrrole), 97.95-97.33 (4C, meso-C), 56.79, 56.65 (4C, CH=CH2), 32.25, 31.02 (2C, CH2COOH), 23.19, 22.87 (2C, CH2CH2COOH), 14.05, 12.97, 11.59, 11.56 (4C, CH3).
(4) Synthesis of Compound 2b Compound 1b (0.12 mmol) was dissolved in acetonitrile / water (1: 1), Amberlite 120R Na + form was added, and the mixture was stirred overnight, then the amberlite was filtered and the solvent was removed under reduced pressure. The compound 2b was obtained as a purple solid in a yield of 100 mg, 65%.
UV / Vis (H 2 O): λ max : 415, 522, 536, 591, 639 nm; 11 B NMR (96.3 MHz; d 6 -DMSO) δ -15.21, -11.89, -10.05, -5.72; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.37, 10.27, 10.15, 10.01 (4H, m, meso H), 8.52 (2H, m, CH = CH 2 ), 6.46 (2H, d, J = 18.0 Hz, CH = CH 2 ), 6.14 (2H, d, J = 18.0 Hz, CH = CH 2 ), 4.34 (4H, m, porphyrin-CH 2 ), 3.73, 3.71, 3.60, 3.57 (12H, s, CH 3 ) , 3.15 (4H, m, CH 2 COOH), 0.19-1.65 (11H, bs, B 12 H 11 ), -3.81 (s, 2H, NH); 13 C NMR (75 MHz; d 6 -DMSO) δ 179.79 (2C, CO), 146.41, 144.64, 142.47, 136.98, 136.52, 136.12, 130.3, 127.07 (16C, C pyrrole), 97.95-97.33 (4C, meso-C), 56.79, 56.65 (4C, CH = CH 2 ) , 32.25, 31.02 (2C, CH 2 COOH), 23.19, 22.87 (2C, CH 2 CH 2 COOH), 14.05, 12.97, 11.59, 11.56 (4C, CH 3 ).
実施例２：
以下の化学反応式に従って本発明の含ホウ素ポルフィリン誘導体５ａ，５ｂ，６ａ，６ｂを合成した。
Boron-containing porphyrin derivatives 5a, 5b, 6a and 6b of the present invention were synthesized according to the following chemical reaction formula.
（１）化合物3の合成
プロトポルフィリン・ジメチルエステル(1.0 mmol, 0.59 g)を過剰量の臭化水素を含む酢酸(10 mL)中に加え、2時間室温で攪拌した。酢酸を減圧下で溜去した後、得られた緑色の残さ(臭素化プロトポルフィリン・ジメチルエステル)を塩化メチレン(10 mL)に溶かし、炭酸カリウム(1 g)と1-ペンタノールまたは1-ドデカノール(2.2 mmol)を加え、室温で1時間攪拌した。反応混合物をろ過した後、ろ液を減圧下で濃縮し、化合物3を粗生成物として得た。
化合物3a: 収率92%, IR νmax(KBr disc)/cm-1 3310w (CH), 2989s, 2927s (NH), 1755s (C=O), 1710s (C=C), 1605s (NH), 1415s (CH3), 11495s (CN), 2965m, 2895m, 1475m, 1442m, 1409m, 1169m, 1098s, 752m (δ, γ of CH2-groups); UV/Vis(CH3CN): λmax: 415, 523, 537, 594, 635 nm; 1H NMR (300 MHz; d6-DMSO) δ 10.58-10.36 (4H, s, meso H), 6.12 (2H, m, α-CH), 4.28 (4H, m, porphyrin-CH2), 3.89, 3.82 (6H, s, COOMe), 3.71, 3.69, 3.68, 3.62 (12H, s, CH3), 3.48 (4H, t, CH2COOH), 3.12 (4H, m, OCH2), 2.22 (6H, d, J = 7.0 Hz, CH3), 1.75, 1.41, 1.21 (12H, m, CH2), 0.78 (6H, t, CH3), -3.95 (s, 2H, NH); 13C NMR (75 MHz; d6-DMSO) δ 177.08 (2C, CO), 145.2, 144.98, 144.05, 143.87, 139.15, 136.85, 136.18, 125.03 (16C, C pyrrole), 98.54, 98.02, 97.98, 97.74 (4C, meso-C), 75.14, 73.16 (2C, O-CH), 61.27, 57.19 (2C, OCH2), 47.86 (2C, COOMe), 31.98, 30.79 (2C, CH2COOH), 28.56, 28.06, 27.47, 27.17, 26.25, 25.74 (6C, -CH2-), 23.21, 23.25 (2C, CH2CH2COOH), 21.57, 21.65, 14.02, 13.63, 11.36, 11.86 (8C, CH3); MS(ESI, positive): m/z(%) 767 (100) [M+]; elemental analysis calcd (%) for C46H62N4O6 (767.01): C 72.03, H 8.15, N 7.30; found: C 71.96, H 8.12, N 7.27.
化合物3b: 収率97%, IR νmax(KBr disc)/cm-1 3310w (CH), 3300s, 2950s (NH), 1755s (C=O), 1681s (C=C), 1609s (NH), 1417s (CH3), 1152s (CN), 2965m, 2866m, 1479s, 1454s, 1412m, 1316m, 1168m, 1100s, 885m, 715m (CH2-groups); UV/Vis(CH3CN): λmax: 419, 526, 538, 595, 639 nm; 1H NMR (300 MHz; d6-DMSO) δ 10.65, 10.57, 10.35, 10.12 (4H, s, meso H), 6.08 (2H, m, α-CH), 4.34 (4H, m, porphyrin-CH2), 3.85, 3.79 (6H, s, COOMe), 3.67, 3.64, 3.59, 3.50 (12H, s, CH3), 3.01 (4H, m, CH2COOH), 2.56 (4H, m, OCH2), 2.13 (6H, d, J = 6.0 Hz, CH3), 1.71-1.17 (20H, m, CH2), 0.83 (6H, t, CH3), -3.95 (s, 2H, NH); 13C NMR (75 MHz; d6-DMSO) δ 179.02 (2C, CO), 147.26, 147.05, 146.23, 145.14, 141.15, 134.65, 133.92, 124.95 (16C, C pyrrole), 99.21, 98.25, 97.65, 97.47 (4C, meso-C), 75.03 (2C, O-CH), 57.07 (2C, OCH2), 48.35 (2C, COOMe), 31.47, 30.13 (2C, CH2COOH), 29.01-25.36 (20C, -CH2-), 24.99, 24.12 (2C, CH2CH2COOH), 23.16, 22.06, 14.95, 13.14, 11.36, 11.43 (8C, CH3); MS(ESI, positive): m/z (%): 963 (100) [M+]; elemental analysis calcd(%) for C60H90N4O6 (963.38): C 74.8, H 9.42, N 5.82; Found: C 74.69, H 9.38, N 5.77.
(1) Synthesis of Compound 3 Protoporphyrin dimethyl ester (1.0 mmol, 0.59 g) was added to acetic acid (10 mL) containing an excessive amount of hydrogen bromide, and the mixture was stirred at room temperature for 2 hours. After acetic acid was distilled off under reduced pressure, the resulting green residue (brominated protoporphyrin dimethyl ester) was dissolved in methylene chloride (10 mL), potassium carbonate (1 g) and 1-pentanol or 1-dodecanol. (2.2 mmol) was added and stirred at room temperature for 1 hour. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 3 as a crude product.
Compound 3a: Yield 92%, IR ν max (KBr disc) / cm -1 3310w (CH), 2989s, 2927s (NH), 1755s (C = O), 1710s (C = C), 1605s (NH), 1415s (CH 3 ), 11495s (CN), 2965m, 2895m, 1475m, 1442m, 1409m, 1169m, 1098s, 752m (δ, γ of CH 2 -groups); UV / Vis (CH 3 CN): λ max : 415 , 523, 537, 594, 635 nm; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.58-10.36 (4H, s, meso H), 6.12 (2H, m, α-CH), 4.28 (4H, m, porphyrin-CH 2 ), 3.89, 3.82 (6H, s, COOMe), 3.71, 3.69, 3.68, 3.62 (12H, s, CH 3 ), 3.48 (4H, t, CH 2 COOH), 3.12 (4H, m, OCH 2 ), 2.22 (6H, d, J = 7.0 Hz, CH 3 ), 1.75, 1.41, 1.21 (12H, m, CH 2 ), 0.78 (6H, t, CH 3 ), -3.95 (s, 2H, NH); 13 C NMR (75 MHz; d 6 -DMSO) δ 177.08 (2C, CO), 145.2, 144.98, 144.05, 143.87, 139.15, 136.85, 136.18, 125.03 (16C, C pyrrole), 98.54, 98.02 , 97.98, 97.74 (4C, meso-C), 75.14, 73.16 (2C, O-CH), 61.27, 57.19 (2C, OCH 2 ), 47.86 (2C, COOMe), 31.98, 30.79 (2C, CH 2 COOH) , 28.56, 28.06, 27.47, 27.17, 26.25, 25.74 (6C, -CH 2- ), 23.21, 23.25 (2C, CH 2 CH 2 COOH), 21.57, 21.65, 14.02, 1 3.63, 11.36, 11.86 (8C, CH 3 ); MS (ESI, positive): m / z (%) 767 (100) [M + ]; elemental analysis calcd (%) for C 46 H 62 N 4 O 6 ( 767.01): C 72.03, H 8.15, N 7.30; found: C 71.96, H 8.12, N 7.27.
Compound 3b: Yield 97%, IR ν max (KBr disc) / cm -1 3310w (CH), 3300s, 2950s (NH), 1755s (C = O), 1681s (C = C), 1609s (NH), 1417s (CH 3 ), 1152s (CN), 2965m, 2866m, 1479s, 1454s, 1412m, 1316m, 1168m, 1100s, 885m, 715m (CH 2 -groups); UV / Vis (CH 3 CN): λ max : 419 , 526, 538, 595, 639 nm; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.65, 10.57, 10.35, 10.12 (4H, s, meso H), 6.08 (2H, m, α-CH), 4.34 (4H, m, porphyrin-CH 2 ), 3.85, 3.79 (6H, s, COOMe), 3.67, 3.64, 3.59, 3.50 (12H, s, CH 3 ), 3.01 (4H, m, CH 2 COOH), 2.56 (4H, m, OCH 2 ), 2.13 (6H, d, J = 6.0 Hz, CH 3 ), 1.71-1.17 (20H, m, CH 2 ), 0.83 (6H, t, CH 3 ), -3.95 ( s, 2H, NH); 13 C NMR (75 MHz; d 6 -DMSO) δ 179.02 (2C, CO), 147.26, 147.05, 146.23, 145.14, 141.15, 134.65, 133.92, 124.95 (16C, C pyrrole), 99.21 , 98.25, 97.65, 97.47 (4C, meso-C), 75.03 (2C, O-CH), 57.07 (2C, OCH 2 ), 48.35 (2C, COOMe), 31.47, 30.13 (2C, CH 2 COOH), 29.01 -25.36 (20C, -CH 2- ), 24.99, 24.12 (2C, CH 2 CH 2 COOH), 23.16, 22.06, 14.95, 13.14, 11.36, 11.43 (8C, CH 3 ); MS (ESI, positive): m / z (%): 963 (100) [M + ]; elemental analysis calcd (%) for C 60 H 90 N 4 O 6 (963.38): C 74.8, H 9.42, N 5.82 ; Found: C 74.69, H 9.38, N 5.77.
（２）化合物4の合成
化合物3 (1 mmol)をTHF (15 mL)に溶かし、メタノール/水(1:1)の混合溶媒に溶かした水酸化リチウム(0.092 g)を加え、室温で6時間攪拌した。反応混合物をろ過した後、ろ液を減圧下で濃縮した。粗生成物を薄層クロマトグラフ(メタノール10%/塩化メチレン90%)で精製し、化合物4を濃紫色の固体として得た。
化合物4a: 収率87%, IR νmax(KBr disc)/cm-1 3309w (CH), 2987s, 2927s, 2860s (OH/NH), 1745s (C=O), 1706s (C=C), 1600s (NH), 1410s (CH3), 1145s (CN), 2961m, 2889m, 1471m, 1439m, 1405m, 1165m, 1093s, 749m (δ, γ of CH2-groups); UV/Vis(CH3CN): λmax: 415, 520, 539, 595, 639 nm; 1H NMR (300 MHz; d6-DMSO) δ 10.65-10.43 (4H, s, meso H), 6.14 (2H, m, α-CH), 4.33 (4H, m, porphyrin-CH2), 3.69, 3.67, 3.65, 3.63 (12H, s, CH3), 3.54 (4H, t, CH2COOH), 3.08 (4H, m, OCH2), 2.17 (6H, d, J = 8.0 Hz, CH3), 1.73, 1.35, 1.16 (12H, m, CH2), 0.7 (6H, t, CH3), -3.96 (s, 2H, NH); 13C NMR (300 MHz; d6-DMSO) δ 175.11 (2C, CO), 147.2, 146.51, 145.79, 145.78, 140.02, 136.92, 136.28, 124.88 (16C, C pyrrole), 98.39, 97.97, 97.72, 97.36 (4C, meso-C), 74.05, 72.47 (2C, O-CH), 60.67, 56.61 (2C, OCH2), 32.18, 30.4 (2C, CH2COOH), 29.4, 29.21, 28.12, 27.7, 25.25, 25.08 (6C, -CH2-), 22.32, 22.22 (2C, CH2CH2COOH), 21.99, 21.88, 13.92, 13.73, 11.2, 11.56 (8C, CH3); MS(ESI, positive): m/z (%): 739 (100) [M+]; elemental analysis calcd (%) for C44H58N4O6 (738.95): C 71.52, H 7.91, N 7.58; found: C 71.33, H 7.81, N 7.49.
化合物4b: 収率90%, IR νmax(KBr disc)/cm-1 3310w (CH), 3197s, 2927s, 2856s (OH/NH), 1745s (C=O), 1675s (C=C), 1605s (NH), 1415s (CH3), 1150s (CN), 2965m, 2856m, 1475s, 1452s, 1405m, 1313m, 1165m, 1100s, 883m, 705m (CH2-groups); UV/Vis(CH3CN): λmax: 415, 523, 537, 593, 638 nm; 1H NMR (300 MHz; d6-DMSO) δ 10.59, 10.5, 10.47, 10.15 (4H, s, meso H), 6.07 (2H, m, α-CH), 4.37 (4H, m, porphyrin-CH2), 3.71, 3.68, 3.65, 3.63 (12H, s, CH3), 2.95 (4H, m, CH2COOH), 2.61 (4H, m, OCH2), 2.18 (6H, d, J = 6.0 Hz, CH3), 1.85-0.81 (20H, m, CH2), 0.72 (6H, t, CH3), -3.92 (s, 2H, NH); 13C NMR (300 MHz; d6-DMSO) δ 177.82 (2C, CO), 148.78, 147.35, 146.33, 145.6, 141.12, 134.76, 133.73, 125.14 (16C, C pyrrole), 98.39, 97.97, 97.72, 97.36 (4C, meso-C), 74.72 (2C, O-CH), 56.17 (2C, OCH2), 31.27, 30.56 (2C, CH2COOH), 29.5-25.95 (20C, -CH2-), 25.57, 24.29 (2C, CH2CH2COOH), 24.26, 22.06, 16.65, 13.92, 11.65, 11.54 (8C, CH3); MS(ESI, positive): m/z(%): 936 (100) [M++1]; elemental analysis calcd(%) for C58H86N4O6 (935.33): C 74.48, H 9.27, N 5.99; found: C 74.37, H 9.01, N 5.82.
(2) Synthesis of Compound 4 Compound 3 (1 mmol) was dissolved in THF (15 mL), lithium hydroxide (0.092 g) dissolved in a mixed solvent of methanol / water (1: 1) was added, and the mixture was stirred at room temperature for 6 hours. Stir. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (methanol 10% / methylene chloride 90%) to give compound 4 as a dark purple solid.
Compound 4a: Yield 87%, IR ν max (KBr disc) / cm -1 3309w (CH), 2987s, 2927s, 2860s (OH / NH), 1745s (C = O), 1706s (C = C), 1600s (NH), 1410s (CH 3 ), 1145s (CN), 2961m, 2889m, 1471m, 1439m, 1405m, 1165m, 1093s, 749m (δ, γ of CH 2 -groups); UV / Vis (CH 3 CN): λ max : 415, 520, 539, 595, 639 nm; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.65-10.43 (4H, s, meso H), 6.14 (2H, m, α-CH), 4.33 (4H, m, porphyrin-CH 2 ), 3.69, 3.67, 3.65, 3.63 (12H, s, CH 3 ), 3.54 (4H, t, CH 2 COOH), 3.08 (4H, m, OCH 2 ), 2.17 (6H, d, J = 8.0 Hz, CH 3 ), 1.73, 1.35, 1.16 (12H, m, CH 2 ), 0.7 (6H, t, CH 3 ), -3.96 (s, 2H, NH); 13 C NMR (300 MHz; d 6 -DMSO) δ 175.11 (2C, CO), 147.2, 146.51, 145.79, 145.78, 140.02, 136.92, 136.28, 124.88 (16C, C pyrrole), 98.39, 97.97, 97.72, 97.36 (4C, meso-C), 74.05, 72.47 (2C, O-CH), 60.67, 56.61 (2C, OCH 2 ), 32.18, 30.4 (2C, CH 2 COOH), 29.4, 29.21, 28.12, 27.7, 25.25, 25.08 (6C , -CH 2- ), 22.32, 22.22 (2C, CH 2 CH 2 COOH), 21.99, 21.88, 13.92, 13.73, 11.2, 11.56 (8C, CH 3 ); MS (ESI, p ositive): m / z (%): 739 (100) [M + ]; elemental analysis calcd (%) for C 44 H 58 N 4 O 6 (738.95): C 71.52, H 7.91, N 7.58; found: C 71.33, H 7.81, N 7.49.
Compound 4b: Yield 90%, IR ν max (KBr disc) / cm -1 3310w (CH), 3197s, 2927s, 2856s (OH / NH), 1745s (C = O), 1675s (C = C), 1605s (NH), 1415s (CH 3 ), 1150s (CN), 2965m, 2856m, 1475s, 1452s, 1405m, 1313m, 1165m, 1100s, 883m, 705m (CH 2 -groups); UV / Vis (CH 3 CN): λ max : 415, 523, 537, 593, 638 nm; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.59, 10.5, 10.47, 10.15 (4H, s, meso H), 6.07 (2H, m, α -CH), 4.37 (4H, m, porphyrin-CH 2 ), 3.71, 3.68, 3.65, 3.63 (12H, s, CH 3 ), 2.95 (4H, m, CH 2 COOH), 2.61 (4H, m, OCH 2 ), 2.18 (6H, d, J = 6.0 Hz, CH 3 ), 1.85-0.81 (20H, m, CH 2 ), 0.72 (6H, t, CH 3 ), -3.92 (s, 2H, NH); 13 C NMR (300 MHz; d 6 -DMSO) δ 177.82 (2C, CO), 148.78, 147.35, 146.33, 145.6, 141.12, 134.76, 133.73, 125.14 (16C, C pyrrole), 98.39, 97.97, 97.72, 97.36 ( 4C, meso-C), 74.72 (2C, O-CH), 56.17 (2C, OCH 2 ), 31.27, 30.56 (2C, CH 2 COOH), 29.5-25.95 (20C, -CH 2- ), 25.57, 24.29 (2C, CH 2 CH 2 COOH), 24.26, 22.06, 16.65, 13.92, 11.65, 11.54 (8C, CH 3 ); MS (ESI, positive): m / z (%): 936 (100) [M + +1]; elemental analysis calcd (%) for C 58 H 86 N 4 O 6 (935.33): C 74.48, H 9.27, N 5.99; found: C 74.37, H 9.01, N 5.82.
（３）化合物5の合成
化合物4 (0.16 mmol)を塩化メチレン(10 mL)に溶かし、オギザリルクロリド(0.7 mL)を加えた。反応混合物を室温で1時間攪拌後、過剰量のオギザリルクロリドを含む塩化メチレン溶媒を減圧下で除いた。残さをアセトニトリル(15 mL)に溶かし、B12H11SHのテトラメチルアンモニウム塩(0.25 mmol, 80 mg)を加え、続いてピリジン(0.3 mL)を加え、室温で72時間攪拌した。減圧下で溶媒を溜去した後、粗生成物を薄層クロマトグラフ(メタノール30%/塩化メチレン70%)で精製し、化合物5を赤紫色の固体として得た。
化合物5a: 収率55%, IR νmax(KBr disc)/cm-1 3568s, 3421s (OH/NH), 3311w (CH), 2500s (BH), 1722, 1685s (C=O), 1620s (C=C), 1608s (NH), 1386s (CH3), 1157s (CN), 1080s (B-B), 2986m, 2864m, 1471m, 1440m, 1400m, 1185m, 1093s, 721m (δ, γ of CH2-groups); UV/Vis(CH3CN): λmax: 414, 522, 538, 592, 635 nm; 11B NMR (300 MHz; CD3CN) δ -14.39, -10.91, -9.58, -5.89; 1H NMR (300 MHz; CD3CN) δ 10.65, 10.56, 10.49, 10.12 (4H, s, meso H), 6.16 (2H, m, α-CH), 4.37 (4H, m, porphyrin-CH2), 3.74, 3.69, 3.66, 3.65 (12H, s, CH3), 3.3 (4H, t, CH2COOH), 3.0 (4H, t, OCH2), 2.98 (24H, s, N(CH3)4), 2.42 (6H, s, CH3), 1.75, 1.39, 1.21 (12H, m, CH2), 0.75 (6H, t, CH3), -0.48 (s, 2H, NH); 13C NMR (300 MHz; CD3CN) δ 210.86, 178.47 (2C, CO), 149.19, 148.67, 147.45, 146.77, 142.06, 141.08, 138.11, 118.2 (16C, C pyrrole), 100.17, 99.38, 98.29, 97.61 (4C, meso-C), 74.12, 73.85 (2C, O-CH), 60.67 (2C, OCH2), 50.7 (8C, N(CH3)4), 30.8, 30.54 (2C, CH2COOH), 29.37, 29.33, 25.68, 25.46 (6C, -CH2-), 23.95, 23.71 (2C, CH2CH2COOH), 22.31, 23.05, 14.13, 14.1, 11.98, 11.92, 11.8, 11.65 (8C, CH3); elemental analysis calcd (%) for C52H92N6B12O3S (1011.12): C 61.77, H 9.17, N 8.31; found: C 61.49, H 8.96, N 8.19.
化合物5b: 収率57%, IR νmax(KBr disc)/cm-1 3568s, 3423s (OH/NH), 3305w (CH), 1735s, 1689 (C=O), 1635s (C=C), 1611s (NH), 1458s (CH3), 1125s (CN), 1080s (B-B), 2995m, 2854m, 1475s, 1458s, 1410m, 1282m, 1165m, 1058s, 885m, 721m (CH2-groups); UV/Vis(CH3CN): λmax: 412, 520, 535, 591, 634 nm; 11B NMR (300 MHz; CD3CN) δ -15.35, -11.98, -9.75, -5.45; 1H NMR (300 MHz; CD3CN) δ 10.55, 10.42, 10.12, 10.0 (4H, s, meso H), 5.94 (2H, m, α-CH), 4.25 (4H, m, porphyrin-CH2), 3.69, 3.67, 3.63, 3.6 (12H, s, CH3), 3.37 (4H, m, CH2COOH), 3.15 (24H, s, N(CH3)4), 2.61 (4H, m, OCH2), 2.2 (6H, d, J = 6.0 Hz, CH3), 1.74-0.75 (20H, m, CH2), 0.71 (6H, t, CH3), -0.69 (s, 2H, NH); 13C NMR (300 MHz; CD3CN) δ 213.41, 213.08 (2C, CO), 149.19, 148.60, 147.51, 146.76, 142.06, 141.95, 138.73, 138.19 (16C, C pyrrole), 99.78, 99.61, 98.36, 97.41 (4C, meso-C), 73.99, 69.61 (2C, O-CH), 50.73 (2C, OCH2), 34.96, 32.33 (2C, CH2COOH), 29.94-26.99 (20C, -CH2-), 25.66, 24.26 (2C, CH2CH2COOH), 24.26, 23.11, 16.65, 14.21, 11.93, 11.65 (8C, CH3); MS(ESI, negative): m/z(%): 936 (100) [M++2]; elemental analysis calcd (%) for C66H120N6B12O3S (1207.49): C 65.65, H 10.02, N 6.96; found: C 65.34, H 9.83, N 6.7.
(3) Synthesis of Compound 5 Compound 4 (0.16 mmol) was dissolved in methylene chloride (10 mL), and oxalyl chloride (0.7 mL) was added. After stirring the reaction mixture at room temperature for 1 hour, the methylene chloride solvent containing an excess amount of oxalyl chloride was removed under reduced pressure. The residue was dissolved in acetonitrile (15 mL), tetramethylammonium salt of B 12 H 11 SH (0.25 mmol, 80 mg) was added, pyridine (0.3 mL) was added, and the mixture was stirred at room temperature for 72 hours. After distilling off the solvent under reduced pressure, the crude product was purified by thin layer chromatography (methanol 30% / methylene chloride 70%) to obtain compound 5 as a red-purple solid.
Compound 5a: Yield 55%, IR ν max (KBr disc) / cm -1 3568s, 3421s (OH / NH), 3311w (CH), 2500s (BH), 1722, 1685s (C = O), 1620s (C = C), 1608s (NH), 1386s (CH 3 ), 1157s (CN), 1080s (BB), 2986m, 2864m, 1471m, 1440m, 1400m, 1185m, 1093s, 721m (δ, γ of CH 2 -groups) ; UV / Vis (CH 3 CN): λ max : 414, 522, 538, 592, 635 nm; 11 B NMR (300 MHz; CD 3 CN) δ -14.39, -10.91, -9.58, -5.89; 1 H NMR (300 MHz; CD 3 CN) δ 10.65, 10.56, 10.49, 10.12 (4H, s, meso H), 6.16 (2H, m, α-CH), 4.37 (4H, m, porphyrin-CH 2 ), 3.74 , 3.69, 3.66, 3.65 (12H, s, CH 3 ), 3.3 (4H, t, CH 2 COOH), 3.0 (4H, t, OCH 2 ), 2.98 (24H, s, N (CH 3 ) 4 ), 2.42 (6H, s, CH 3 ), 1.75, 1.39, 1.21 (12H, m, CH 2 ), 0.75 (6H, t, CH 3 ), -0.48 (s, 2H, NH); 13 C NMR (300 MHz ; CD 3 CN) δ 210.86, 178.47 (2C, CO), 149.19, 148.67, 147.45, 146.77, 142.06, 141.08, 138.11, 118.2 (16C, C pyrrole), 100.17, 99.38, 98.29, 97.61 (4C, meso-C ), 74.12, 73.85 (2C, O-CH), 60.67 (2C, OCH 2 ), 50.7 (8C, N (CH 3 ) 4 ), 30.8, 30.54 (2C, CH 2 COOH), 29.37, 29.33, 2 5.68, 25.46 (6C, -CH 2- ), 23.95, 23.71 (2C, CH 2 CH 2 COOH), 22.31, 23.05, 14.13, 14.1, 11.98, 11.92, 11.8, 11.65 (8C, CH 3 ); elemental analysis calcd (%) for C 52 H 92 N 6 B 12 O 3 S (1011.12): C 61.77, H 9.17, N 8.31; found: C 61.49, H 8.96, N 8.19.
Compound 5b: Yield 57%, IR ν max (KBr disc) / cm -1 3568s, 3423s (OH / NH), 3305w (CH), 1735s, 1689 (C = O), 1635s (C = C), 1611s (NH), 1458s (CH 3 ), 1125s (CN), 1080s (BB), 2995m, 2854m, 1475s, 1458s, 1410m, 1282m, 1165m, 1058s, 885m, 721m (CH 2 -groups); UV / Vis ( CH 3 CN): λ max : 412, 520, 535, 591, 634 nm; 11 B NMR (300 MHz; CD 3 CN) δ -15.35, -11.98, -9.75, -5.45; 1 H NMR (300 MHz; CD 3 CN) δ 10.55, 10.42, 10.12, 10.0 (4H, s, meso H), 5.94 (2H, m, α-CH), 4.25 (4H, m, porphyrin-CH 2 ), 3.69, 3.67, 3.63, 3.6 (12H, s, CH 3 ), 3.37 (4H, m, CH 2 COOH), 3.15 (24H, s, N (CH 3 ) 4 ), 2.61 (4H, m, OCH 2 ), 2.2 (6H, d , J = 6.0 Hz, CH 3 ), 1.74-0.75 (20H, m, CH 2 ), 0.71 (6H, t, CH 3 ), -0.69 (s, 2H, NH); 13 C NMR (300 MHz; CD 3 CN) δ 213.41, 213.08 (2C, CO), 149.19, 148.60, 147.51, 146.76, 142.06, 141.95, 138.73, 138.19 (16C, C pyrrole), 99.78, 99.61, 98.36, 97.41 (4C, meso-C), 73.99, 69.61 (2C, O-CH), 50.73 (2C, OCH 2 ), 34.96, 32.33 (2C, CH 2 COOH), 29.94-26.99 (20C, -CH 2- ), 25.66, 24.26 (2 C, CH 2 CH 2 COOH), 24.26, 23.11, 16.65, 14.21, 11.93, 11.65 (8C, CH 3 ); MS (ESI, negative): m / z (%): 936 (100) [M + +2 ]; elemental analysis calcd (%) for C 66 H 120 N 6 B 12 O 3 S (1207.49): C 65.65, H 10.02, N 6.96; found: C 65.34, H 9.83, N 6.7.
（４）化合物6の合成
化合物5をアセトニトリル/水(1:1)に溶かし、アンバーライト120R Na+ formを加え、一晩攪拌した後、アンバーライトをろ過し、減圧下で溶媒を溜去し、化合物6を濃赤色の固体として得た。
化合物6a: 収率37%, UV/Vis(H2O): λmax: 410, 517, 536, 585, 635 nm; 11B NMR (300 MHz; CD3CN) δ -14.39, -10.91, -9.58, -5.89; 1H NMR (300 MHz; CD3CN) δ 12.05 (1H, s, COOH), 10.73, 10.64, 10.52, 10.24 (4H, m, meso H), 6.17 (2H, m, α-CH), 4.32 (4H, m, porphyrin-CH2), 3.72, 3.66, 3.64, 3.62 (12H, s, CH3), 3.35 (4H, t, CH2COOH), 2.97 (4H, t, OCH2), 2.35 (6H, s, CH3), 1.7, 1.35, 1.25 (12H, m, CH2), 0.7 (6H, t, CH3), -3.91 (s, 2H, NH); 13C NMR (300 MHz; CD3CN) δ 208.93, 177.47 (2C, CO), 148.15, 147.14, 146.21, 146.77, 142.06, 141.08, 138.11, 118.45 (16C, C pyrrole), 98.29, 97.61 (4C, meso-C), 73.78, 72.46 (2C, O-CH), 68.47 (2C, OCH2), 30.82 (2C, CH2COOH), 29.32, 29.27, 25.46, 25.19 (6C, -CH2-), 22.98, 22.64 (2C, CH2CH2COOH), 22.05, 21.97, 14.17, 14.09, 11.96, 11.91, 11.76, 11.68 (8C, CH3).
化合物6b: 収率35%, UV/Vis(H2O): λmax: 412, 520, 535, 591, 634 nm; 11B NMR (300 MHz; CD3CN) δ -15.40, -11.95, -9.85, -5.42; 1H NMR (300 MHz; CD3CN) δ 10.57, 10.45, 10.21, 10.12 (4H, s, meso H), 6.11 (2H, m, α-CH), 4.34 (4H, m, porphyrin-CH2), 3.68, 3.66, 3.64, 3.61 (12H, s, CH3), 3.35 (4H, m, CH2COOH), 2.85 (4H, m, OCH2), 2.18 (6H, d, J = 6.0 Hz, CH3), 1.85-0.81 (20H, m, CH2), 0.76 (6H, t, CH3), -3.92 (s, 2H, NH); 13C NMR (300 MHz; CD3CN) δ 207.41, 168.42 (2C, CO), 149.19, 148.60, 147.51, 146.76, 142.06, 141.95, 138.73, 118.25 (16C, C pyrrole), 98.56, 98.05, 96.85, 96.54 (4C, meso-C), 72.85, 71.65 (2C, O-CH), 52.65 (2C, OCH2), 31.86, 28.89 (2C, CH2COOH), 27.86-22.74 (20C, -CH2-), 25.66, 24.26 (2C, CH2CH2COOH), 22.54, 21.19, 15.75, 12.41, 11.52 (8C, CH3).
(4) Synthesis of Compound 6 Compound 5 was dissolved in acetonitrile / water (1: 1), Amberlite 120R Na + form was added and stirred overnight, then Amberlite was filtered and the solvent was distilled off under reduced pressure. Compound 6 was obtained as a dark red solid.
Compound 6a: Yield 37%, UV / Vis (H 2 O): λ max : 410, 517, 536, 585, 635 nm; 11 B NMR (300 MHz; CD 3 CN) δ -14.39, -10.91,- 9.58, -5.89; 1 H NMR (300 MHz; CD 3 CN) δ 12.05 (1H, s, COOH), 10.73, 10.64, 10.52, 10.24 (4H, m, meso H), 6.17 (2H, m, α- CH), 4.32 (4H, m, porphyrin-CH 2 ), 3.72, 3.66, 3.64, 3.62 (12H, s, CH 3 ), 3.35 (4H, t, CH 2 COOH), 2.97 (4H, t, OCH 2 ), 2.35 (6H, s, CH 3 ), 1.7, 1.35, 1.25 (12H, m, CH 2 ), 0.7 (6H, t, CH 3 ), -3.91 (s, 2H, NH); 13 C NMR ( 300 MHz; CD 3 CN) δ 208.93, 177.47 (2C, CO), 148.15, 147.14, 146.21, 146.77, 142.06, 141.08, 138.11, 118.45 (16C, C pyrrole), 98.29, 97.61 (4C, meso-C), 73.78, 72.46 (2C, O-CH), 68.47 (2C, OCH 2 ), 30.82 (2C, CH 2 COOH), 29.32, 29.27, 25.46, 25.19 (6C, -CH 2- ), 22.98, 22.64 (2C, CH 2 CH 2 COOH), 22.05 , 21.97, 14.17, 14.09, 11.96, 11.91, 11.76, 11.68 (8C, CH 3).
Compound 6b: Yield 35%, UV / Vis (H 2 O): λ max : 412, 520, 535, 591, 634 nm; 11 B NMR (300 MHz; CD 3 CN) δ -15.40, -11.95,- 9.85, -5.42; 1 H NMR (300 MHz; CD 3 CN) δ 10.57, 10.45, 10.21, 10.12 (4H, s, meso H), 6.11 (2H, m, α-CH), 4.34 (4H, m, porphyrin-CH 2 ), 3.68, 3.66, 3.64, 3.61 (12H, s, CH 3 ), 3.35 (4H, m, CH 2 COOH), 2.85 (4H, m, OCH 2 ), 2.18 (6H, d, J = 6.0 Hz, CH 3 ), 1.85-0.81 (20H, m, CH 2 ), 0.76 (6H, t, CH 3 ), -3.92 (s, 2H, NH); 13 C NMR (300 MHz; CD 3 CN ) δ 207.41, 168.42 (2C, CO), 149.19, 148.60, 147.51, 146.76, 142.06, 141.95, 138.73, 118.25 (16C, C pyrrole), 98.56, 98.05, 96.85, 96.54 (4C, meso-C), 72.85, 71.65 (2C, O-CH), 52.65 (2C, OCH 2 ), 31.86, 28.89 (2C, CH 2 COOH), 27.86-22.74 (20C, -CH 2- ), 25.66, 24.26 (2C, CH 2 CH 2 COOH), 22.54, 21.19, 15.75, 12.41, 11.52 (8C, CH 3 ).
実施例３：
以下の化学反応式に従って本発明の含ホウ素ポルフィリン誘導体７ａ，７ｂ，８ａ，８ｂを合成した。
Boron-containing porphyrin derivatives 7a, 7b, 8a and 8b of the present invention were synthesized according to the following chemical reaction formula.
（１）化合物7の合成
化合物4 (0.16 mmol)を塩化メチレン(10 mL)に溶かし、オギザリルクロリド(1.5 mL)を加えた。反応混合物を室温で20分攪拌後、過剰量のオギザリルクロリドを含む塩化メチレン溶媒を減圧下で除いた。残さをアセトニトリル(15 mL)に溶かし、B12H11SHのテトラメチルアンモニウム塩(0.5 mmol, 0.16 g)を加え、続いてピリジン(0.5 mL)を加え、室温で72時間攪拌した。減圧下で溶媒を溜去した後、粗生成物を薄層クロマトグラフ(メタノール30%/塩化メチレン70%)で精製し、化合物7を赤紫色の固体として得た。
化合物7a: 収率39%, 11B NMR (300 MHz; CD3CN) δ -5.71, -10.74; 1H NMR (300 MHz; CD3CN) δ 10.18 (d, 4H, meso-H), 8.43 (m, 2H, CH=CH2), 6.38, 6.14 (d, 4H, CH=CH2), 4.37, 4.29 (m, 4H, CH2), 3.72 (t, 4H, CH2-CO), 3.6 (s, 12H, CH3), 2.35 (s, 48H, N(CH3)4), 1.55-0.88 (bs, BHs), 0.08 (s, 2H, NH).
化合物7b: 収率38%, 11B NMR (300 MHz; CD3CN) δ -6.54, -10.92; 1H NMR (300 MHz; CD3CN) δ 10.66, 10.08 (m, 4H, meso-H), 6.15, 5.83 (m, 2H, CH), 4.33 (t, 8H, CH2), 3.7 (m, 12H, CH3), 3.64 (m, 4H, CH2), 2.27 (s, 48H, N(CH3)4), 1.89 (t, 6H, CH3), 1.73 (bs, 4H, CH2), 1.7-0.75 (bs, BHs), 0.75 (s, 2H, NH).
(1) Synthesis of Compound 7 Compound 4 (0.16 mmol) was dissolved in methylene chloride (10 mL), and oxalyl chloride (1.5 mL) was added. After stirring the reaction mixture at room temperature for 20 minutes, the methylene chloride solvent containing an excess amount of oxalyl chloride was removed under reduced pressure. The residue was dissolved in acetonitrile (15 mL), tetramethylammonium salt of B 12 H 11 SH (0.5 mmol, 0.16 g) was added, pyridine (0.5 mL) was added, and the mixture was stirred at room temperature for 72 hours. After distilling off the solvent under reduced pressure, the crude product was purified by thin layer chromatography (methanol 30% / methylene chloride 70%) to obtain Compound 7 as a red-purple solid.
Compound 7a: Yield 39%, 11 B NMR (300 MHz; CD 3 CN) δ -5.71, -10.74; 1 H NMR (300 MHz; CD 3 CN) δ 10.18 (d, 4H, meso-H), 8.43 (m, 2H, CH = CH 2 ), 6.38, 6.14 (d, 4H, CH = CH 2 ), 4.37, 4.29 (m, 4H, CH 2 ), 3.72 (t, 4H, CH 2 -CO), 3.6 (s, 12H, CH 3 ), 2.35 (s, 48H, N (CH 3 ) 4 ), 1.55-0.88 (bs, BHs), 0.08 (s, 2H, NH).
Compound 7b: Yield 38%, 11 B NMR (300 MHz; CD 3 CN) δ -6.54, -10.92; 1 H NMR (300 MHz; CD 3 CN) δ 10.66, 10.08 (m, 4H, meso-H) , 6.15, 5.83 (m, 2H, CH), 4.33 (t, 8H, CH 2 ), 3.7 (m, 12H, CH 3 ), 3.64 (m, 4H, CH 2 ), 2.27 (s, 48H, N ( CH 3 ) 4 ), 1.89 (t, 6H, CH 3 ), 1.73 (bs, 4H, CH 2 ), 1.7-0.75 (bs, BHs), 0.75 (s, 2H, NH).
（２）化合物8の合成
化合物7をアセトニトリル/水(1:1)に溶かし、アンバーライト120R Na+ formを加え、一晩攪拌した後、アンバーライトをろ過し、減圧下で溶媒を溜去し、化合物8を赤紫色の固体として得た。
化合物8a: 収率33%, 11B NMR (300 MHz; d6-DMSO) δ -6.67, -10.90; 1H NMR (300 MHz; d6-DMSO) δ 10.26-10.03 (m, 4H, meso-H), 6.16 (m, 2H, CH), 4.19 (t, 8H, CH2), 3.69 (m, 4H, CH2), 3.63 (m, 12H, CH3), 2.07 (s, 4H, CH2), 1.69 (t, 6H, CH3), 1.55 (bs, 4H, CH2), 1.35-0.25 (bs, BHs), 0.65 (s, 2H, NH); 13C NMR (300 MHz; d6-DMSO) δ 205.32 (2C, CO), 147.58-140.49 (8C, C-N pyrrole), 136.6, 136.49 (8C, C-pyrrole), 96.96, 95.0 (4C, meso-C), 72.8 (2C, O-CH), 68.41 (2C, OCH), 47.49, 46.86 (2C, O-CH2), 29.48, 28.18 (6C, CH2), 25.38, 21.93 (6C, CH3), 13.88, 11.33 (2C, CH3).
化合物8b: 収率37%, 11B NMR (300 MHz; d6-DMSO) δ -6.54, -10.92; 1H NMR (300 MHz; d6-DMSO) δ 10.26, 10.5, 10.03 (m, 4H, meso-H), 6.16 (m, 2H, CH), 4.19 (t, 8H, CH2), 3.65 (m, 12H, CH3), 3.64 (m, 4H, CH2), 2.16 (s, 6H, CH3), 2.07 (bs, 4H, CH2), 1.69-0.74 (m, other CH2), 1.35-0.25 (bs, BHs), -0.57 (s, 2H, NH); 13C NMR (300 MHz; d6-DMSO) δ 205.44 (2C, CO), 166.9, 147.68, 147.6, 146.63, 145.83, 145.35, 145.33, 140.56, 140.49, 140.42, 136.6, 136.58, 136.53, 136.46, 131.70, 128.64 (16C, C pyrrole), 98.46, 98.09, 96.9, 96.63 (4C, meso-C), 74.5, 70.18 (2C, O-CH), 67.4, 62.48 (2C, OCH2), 52.22, 47.55, 40.33, 29.79, 28.35, 25.43 (other CH2), 23.24, 23.04, 22.37, 13.85, 11.67, 11.61, 11.34, 10.87 (8C, CH3).
(2) Synthesis of Compound 8 Compound 7 is dissolved in acetonitrile / water (1: 1), Amberlite 120R Na + form is added and stirred overnight, then Amberlite is filtered and the solvent is distilled off under reduced pressure. Compound 8 was obtained as a red-purple solid.
Compound 8a: Yield 33%, 11 B NMR (300 MHz; d 6 -DMSO) δ -6.67, -10.90; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.26-10.03 (m, 4H, meso- H), 6.16 (m, 2H, CH), 4.19 (t, 8H, CH 2 ), 3.69 (m, 4H, CH 2 ), 3.63 (m, 12H, CH 3 ), 2.07 (s, 4H, CH 2 ), 1.69 (t, 6H, CH 3 ), 1.55 (bs, 4H, CH 2 ), 1.35-0.25 (bs, BHs), 0.65 (s, 2H, NH); 13 C NMR (300 MHz; d 6- DMSO) δ 205.32 (2C, CO), 147.58-140.49 (8C, CN pyrrole), 136.6, 136.49 (8C, C-pyrrole), 96.96, 95.0 (4C, meso-C), 72.8 (2C, O-CH) , 68.41 (2C, OCH), 47.49, 46.86 (2C, O-CH 2 ), 29.48, 28.18 (6C, CH 2 ), 25.38, 21.93 (6C, CH 3 ), 13.88, 11.33 (2C, CH 3 ).
Compound 8b: Yield 37%, 11 B NMR (300 MHz; d 6 -DMSO) δ -6.54, -10.92; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.26, 10.5, 10.03 (m, 4H, meso-H), 6.16 (m, 2H, CH), 4.19 (t, 8H, CH 2 ), 3.65 (m, 12H, CH 3 ), 3.64 (m, 4H, CH 2 ), 2.16 (s, 6H, CH 3 ), 2.07 (bs, 4H, CH 2 ), 1.69-0.74 (m, other CH 2 ), 1.35-0.25 (bs, BHs), -0.57 (s, 2H, NH); 13 C NMR (300 MHz ; d 6 -DMSO) δ 205.44 (2C, CO), 166.9, 147.68, 147.6, 146.63, 145.83, 145.35, 145.33, 140.56, 140.49, 140.42, 136.6, 136.58, 136.53, 136.46, 131.70, 128.64 (16C, C pyrrole ), 98.46, 98.09, 96.9, 96.63 (4C, meso-C), 74.5, 70.18 (2C, O-CH), 67.4, 62.48 (2C, OCH 2 ), 52.22, 47.55, 40.33, 29.79, 28.35, 25.43 ( other CH 2 ), 23.24, 23.04, 22.37, 13.85, 11.67, 11.61, 11.34, 10.87 (8C, CH 3 ).
実施例４：
下記の構造式で表される化合物9および化合物10を、実施例1における化合物1aおよび化合物2aの合成のために用いたB12H11SHのテトラメチルアンモニウム塩の代わりにB12H11OHのメチルトリフェニルフォスフォニウム塩を用い、同様の方法によってそれぞれ赤紫色の固体として得た。
化合物10: 収率58%, UV/Vis(H2O): λmax: 415, 525, 535, 595, 639 nm; 11B NMR (300 MHz; d6-DMSO) δ -6.51, -14.9, -17.63, -23.73; 1H NMR (300 MHz; d6-DMSO) δ 10.3, 10.25, 10.19, 10.13 (4H, s, meso CH), 8.5 (2H, q, CH=CH2), 6.46 (2H, d, J = 16 Hz, CH=CH2), 6.14 (2H, d, J = 12 Hz, CH=CH2), 4.34 (4H, m, porphyrin-CH2), 3.73-3.60 (12H, s, β-CH3), 3.21 (4H, m, CH2COOH), 0.21-1.55 (11H, bs, B12H11), -3.81 (s, 2H, NH); 13C NMR (300 MHz; d6-DMSO) δ 176.43, 176.69 (2C, CO), 145.39, 143.54, 142.37, 137.03, 136.85, 136.74, 130.61, 126.77 (16C, C pyrrole), 97.92-97.14 (4C, meso-C), 56.73, 56.6 (2C, CH=CH2), 31.27, 30.56 (2C, CH2COOH), 23.28, 22.67 (2C, CH2CH2COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH3).
Example 4:
Compound 9 and Compound 10 represented by the following structural formulas were replaced with B 12 H 11 OH instead of the tetramethylammonium salt of B 12 H 11 SH used for the synthesis of Compound 1a and Compound 2a in Example 1. Using methyltriphenylphosphonium salt, each was obtained as a red-purple solid by the same method.
Compound 10: Yield 58%, UV / Vis (H 2 O): λ max : 415, 525, 535, 595, 639 nm; 11 B NMR (300 MHz; d 6 -DMSO) δ -6.51, -14.9, -17.63, -23.73; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.3, 10.25, 10.19, 10.13 (4H, s, meso CH), 8.5 (2H, q, CH = CH 2 ), 6.46 (2H , d, J = 16 Hz, CH = CH 2 ), 6.14 (2H, d, J = 12 Hz, CH = CH 2 ), 4.34 (4H, m, porphyrin-CH 2 ), 3.73-3.60 (12H, s , β-CH 3 ), 3.21 (4H, m, CH 2 COOH), 0.21-1.55 (11H, bs, B 12 H 11 ), -3.81 (s, 2H, NH); 13 C NMR (300 MHz; d 6- DMSO) δ 176.43, 176.69 (2C, CO), 145.39, 143.54, 142.37, 137.03, 136.85, 136.74, 130.61, 126.77 (16C, C pyrrole), 97.92-97.14 (4C, meso-C), 56.73, 56.6 (2C, CH = CH 2 ), 31.27, 30.56 (2C, CH 2 COOH), 23.28, 22.67 (2C, CH 2 CH 2 COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH 3 ).
実施例５：
下記の構造式で表される化合物11および化合物12を以下のようにして合成した。
化合物11: 収率65%, IR νmax(KBr disc)/cm-1 3565s, 3382s, 3246s (OH/NH), 2985w (CH), 2493s (BH), 1710s, 1675s (C=O), 1616s (C=C), 1605s (NH), 1406s (CH3), 1165s (CN), 1065s (B-B); UV/Vis(CH3CN): λmax: 415, 524, 536, 595, 639 nm; 11B NMR (96.3 MHz; CD3CN) δ -15.37, -11.97, -9.78, -5.49; 1H NMR (300 MHz; CD3CN) δ 9.59, 9.28, 10.12 (4H, m, meso H), 8.02 (2H, m, CH=CH2), 6.11 (4H, m, CH=CH2), 4.74 (2H, s, NH2), 4.28 (4H, m, porphyrin-CH2), 4.07, 3.88 (12H, m, β-CH3), 3.48, 3.27 (4H, m, CH2COOH), 2.88 (12H, s, N(CH3)4), 0.45-1.7 (11H, bs, B12H11), -3.77 (s, 2H, NH); 13C NMR (75 MHz; CD3CN) δ 176.89, 176.21 (2C, CO), 145.42, 143.93, 141.73, 140.34, 136.63, 136.33, 135.85, 130.14 (16C, C pyrrole), 97.46-97.04 (4C, meso-C), 54.35, 56.6 (2C, CH=CH2), 54.31 (4C, N(CH3)4), 33.0, 30.56 (2C, CH2COOH), 23.28, 23.0 (2C, CH2CH2COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH3); (ESI): m/z(%) 701.6 (100) [M]; elemental analysis calcd(%) for C38H56N6B12O3 (776.64): C 58.77, H 7.53, N 10.82; Found: C 58.47, H 7.26, N 10.67.
化合物12: 収率49%, UV/Vis(H2O): λmax: 415, 525, 535, 595, 639 nm; 11B NMR (300 MHz; d6-DMSO) δ -15.25, -11.80, -9.95, -5.65; 1H NMR (300 MHz; d6-DMSO) δ 10.39, 10.3, 10.26, 10.22 (4H, s, meso H), 8.47 (2H, m, CH=CH2), 6.46 (2H, d, J = 15 Hz, CH=CH2), 6.22 (2H, d, J = 12 Hz, CH=CH2), 5.57 (2H, s, NH2), 4.28 (4H, m, porphyrin-CH2), 3.71-3.61 (12H, s, β-CH3), 2.93 (4H, m, CH2COOH), 0.27-1.89 (11H, bs, B12H11), -3.82 (s, 2H, NH); 13C NMR (300 MHz; d6-DMSO) δ 176.55, 175.04 (2C, CO), 146.38, 145.41, 143.38, 140.12, 137.65, 136.96, 133.14 (16C, C pyrrole), 97.99-97.41 (4C, meso-C), 56.64, 56.23 (2C, CH=CH2), 33.17, 30.87 (2C, CH2COOH), 22.98, 22.05 (2C, CH2CH2COOH), 14.12, 13.57, 11.36, 11.05 (4C, CH3), (ESI): m/z(%) 702.6 (100) [M].
Example 5:
Compound 11 and compound 12 represented by the following structural formula were synthesized as follows.
Compound 11: Yield 65%, IR ν max (KBr disc) / cm -1 3565s, 3382s, 3246s (OH / NH), 2985w (CH), 2493s (BH), 1710s, 1675s (C = O), 1616s (C = C), 1605s (NH), 1406s (CH 3 ), 1165s (CN), 1065s (BB); UV / Vis (CH 3 CN): λ max : 415, 524, 536, 595, 639 nm; 11 B NMR (96.3 MHz; CD 3 CN) δ -15.37, -11.97, -9.78, -5.49; 1 H NMR (300 MHz; CD 3 CN) δ 9.59, 9.28, 10.12 (4H, m, meso H), 8.02 (2H, m, CH = CH 2 ), 6.11 (4H, m, CH = CH 2 ), 4.74 (2H, s, NH 2 ), 4.28 (4H, m, porphyrin-CH 2 ), 4.07, 3.88 ( 12H, m, β-CH 3 ), 3.48, 3.27 (4H, m, CH 2 COOH), 2.88 (12H, s, N (CH 3 ) 4 ), 0.45-1.7 (11H, bs, B 12 H 11 ) , -3.77 (s, 2H, NH); 13 C NMR (75 MHz; CD 3 CN) δ 176.89, 176.21 (2C, CO), 145.42, 143.93, 141.73, 140.34, 136.63, 136.33, 135.85, 130.14 (16C, C pyrrole), 97.46-97.04 (4C, meso-C), 54.35, 56.6 (2C, CH = CH 2 ), 54.31 (4C, N (CH 3 ) 4 ), 33.0, 30.56 (2C, CH 2 COOH), 23.28, 23.0 (2C, CH 2 CH 2 COOH), 13.45, 12.57, 11.56, 11.28 (4C, CH 3 ); (ESI): m / z (%) 701.6 (100) [M]; elemental analysis calcd (% ) for C 38 H 56 N 6 B 12 O 3 (776.64): C 58.77, H 7.53, N 10.82; Found: C 58.47, H 7.26, N 10.67.
Compound 12: Yield 49%, UV / Vis (H 2 O): λ max : 415, 525, 535, 595, 639 nm; 11 B NMR (300 MHz; d 6 -DMSO) δ -15.25, -11.80, -9.95, -5.65; 1 H NMR (300 MHz; d 6 -DMSO) δ 10.39, 10.3, 10.26, 10.22 (4H, s, meso H), 8.47 (2H, m, CH = CH 2 ), 6.46 (2H , d, J = 15 Hz, CH = CH 2 ), 6.22 (2H, d, J = 12 Hz, CH = CH 2 ), 5.57 (2H, s, NH 2 ), 4.28 (4H, m, porphyrin-CH 2 ), 3.71-3.61 (12H, s, β-CH 3 ), 2.93 (4H, m, CH 2 COOH), 0.27-1.89 (11H, bs, B 12 H 11 ), -3.82 (s, 2H, NH ); 13 C NMR (300 MHz; d 6 -DMSO) δ 176.55, 175.04 (2C, CO), 146.38, 145.41, 143.38, 140.12, 137.65, 136.96, 133.14 (16C, C pyrrole), 97.99-97.41 (4C, meso-C), 56.64, 56.23 (2C, CH = CH 2 ), 33.17, 30.87 (2C, CH 2 COOH), 22.98, 22.05 (2C, CH 2 CH 2 COOH), 14.12, 13.57, 11.36, 11.05 (4C , CH 3 ), (ESI): m / z (%) 702.6 (100) [M].
試験例１：本発明の含ホウ素ポルフィリン誘導体のがん細胞に対する細胞増殖阻害試験
５種類の本発明の含ホウ素ポルフィリン誘導体の各種濃度の存在下、種々のがん細胞を９６穴プレート上で３７℃で７２時間培養した後（５×１０３ｃｅｌｌｓ／ｗｅｌｌ，培地：ＲＰＭＩ−１６４０）、生存細胞をＭＴＴ法によって検出し、それぞれの化合物のＧＩ５０（５０％細胞増殖阻害濃度、以下同じ）を求めた。結果をＢＯＰＰのＧＩ５０とともに表１に示す。表１から明らかなように、５種類の化合物のうち、化合物２ａ，１０，１２は、いずれのがん細胞に対してもＧＩ５０がＢＯＰＰよりも大きかった（但し化合物１０のＣ６細胞に対するＧＩ５０は除く）。また、化合物６ａ，６ｂも、ＨｅｐＧ２細胞に対してはＧＩ５０がＢＯＰＰよりも大きく、化合物６ａは、ＨｅＬａ細胞に対してもＧＩ５０がＢＯＰＰよりも大きかった。以上の結果と、化合物２ｂ，８ａ，８ｂについての別途の同様の試験の結果から、本発明の含ホウ素ポルフィリン誘導体は、総じてＢＯＰＰよりも毒性が低いことがわかった。
Test Example 1: Cell Growth Inhibition Test for Cancer Cells of Boron-Containing Porphyrin Derivatives of the Present Invention In the presence of various concentrations of five kinds of boron-containing porphyrin derivatives of the present invention, various cancer cells were cultured on a 96-well plate at 37 ° After culturing for 72 hours (5 × 10 3 cells / well, medium: RPMI-1640), viable cells were detected by MTT method, and GI 50 (50% cell growth inhibitory concentration, the same applies hereinafter) of each compound was determined. It was. The results are shown in Table 1 together with the BOPP GI 50 . As is clear from Table 1, among the five types of compounds, compounds 2a, 10, and 12 had a GI 50 greater than BOPP for any cancer cell (however, GI 50 of compound 10 for C6 cells). Except). Compounds 6a and 6b also had a GI 50 greater than BOPP for HepG2 cells, and Compound 6a also had a GI 50 greater than BOPP for HeLa cells. From the above results and the results of separate similar tests on the compounds 2b, 8a and 8b, it was found that the boron-containing porphyrin derivatives of the present invention are generally less toxic than BOPP.
試験例２：本発明の含ホウ素ポルフィリン誘導体のがん細胞に対する取り込み試験
５種類の本発明の含ホウ素ポルフィリン誘導体のホウ素濃度が１０ｐｐｍまたは１００ｐｐｍの存在下、ＨｅＬａ細胞を３７℃で３時間培養した後（１×１０６ｃｅｌｌｓ，培地：ＲＰＭＩ−１６４０）、過塩素酸／過酸化水素で細胞を灰化し、誘導結合プラズマ発光分光法（ＩＣＰ−ＡＥＳ）によって灰化液に含まれるホウ素量を測定することで、本発明の含ホウ素ポルフィリン誘導体のＨｅＬａ細胞に対する取り込み性を評価した。結果をＢＯＰＰの結果とともに図１に示す。図１から明らかなように、５種類の化合物のうち、化合物２ａ，６ａはＢＯＰＰと同じ程度に、化合物６ｂ，１０，１２はＢＯＰＰの約４倍、濃度依存的にＨｅＬａ細胞に取り込まれたことから、本発明の含ホウ素ポルフィリン誘導体は、腫瘍細胞親和性に優れ、腫瘍に選択的に蓄積することがわかった。
Test Example 2: Uptake test of boron-containing porphyrin derivative of the present invention for cancer cells After culturing HeLa cells at 37 ° C. for 3 hours in the presence of five boron-containing porphyrin derivatives of the present invention having a boron concentration of 10 ppm or 100 ppm (1 × 10 6 cells, medium: RPMI-1640), cells are incinerated with perchloric acid / hydrogen peroxide, and the amount of boron contained in the incinerated solution is measured by inductively coupled plasma emission spectroscopy (ICP-AES). Thus, the uptake of the boron-containing porphyrin derivative of the present invention into HeLa cells was evaluated. The results are shown in FIG. 1 together with the results of BOPP. As is apparent from FIG. 1, among the five types of compounds, compounds 2a and 6a were taken up into HeLa cells in a concentration-dependent manner, with compounds 6b, 10 and 12 being about 4 times BOPP. Thus, it was found that the boron-containing porphyrin derivative of the present invention is excellent in tumor cell affinity and selectively accumulates in tumors.
試験例３：本発明の含ホウ素ポルフィリン誘導体を用いたがん細胞の蛍光イメージング試験
本発明の含ホウ素ポルフィリン誘導体（化合物１２）またはＢＯＰＰの１００μＭの存在下、ＨｅＬａ細胞を３７℃で３時間培養した後（１×１０３ｃｅｌｌｓ，培地：ＲＰＭＩ−１６４０）、４％のパラホルムアルデヒドを用いて細胞を固定してから４’，６−ジアミジノ−２−フェニルインドール（ＤＡＰＩ）で細胞を染色し、蛍光顕微鏡観察を行った。その結果、化合物１２またはＢＯＰＰの単独造影，ＤＡＰＩの単独造影，化合物１２またはＢＯＰＰとＤＡＰＩの混合造影を比較することで、化合物１２とＢＯＰＰは、主に細胞質ゾルに蓄積することがわかった。
Test Example 3: Fluorescence imaging test of cancer cells using the boron-containing porphyrin derivative of the present invention HeLa cells were cultured at 37 ° C. for 3 hours in the presence of 100 μM of the boron-containing porphyrin derivative of the present invention (Compound 12) or BOPP. After (1 × 10 3 cells, medium: RPMI-1640), cells were fixed with 4% paraformaldehyde, and then stained with 4 ′, 6-diamidino-2-phenylindole (DAPI), and fluorescent. Microscopic observation was performed. As a result, it was found that Compound 12 and BOPP mainly accumulate in the cytosol by comparing Compound 12 or BOPP single contrast, DAPI single contrast, Compound 12 or BOPP and DAPI mixed contrast.
試験例４：本発明の含ホウ素ポルフィリン誘導体の光線力学療法への適用試験
５種類の本発明の含ホウ素ポルフィリン誘導体の各種濃度の存在下、ＨｅＬａ細胞を３７℃で３時間培養した後（１×１０４ｃｅｌｌｓ，培地：ＲＰＭＩ−１６４０）、キセノンランプを用いて平均２．４ｍＷ／ｃｍ２のレーザー光（波長：４００〜８００ｎｍ）を５分間細胞に照射し、さらに１２時間培養した後の生存細胞をＭＴＴ法によって検出し、それぞれの化合物のＧＩ５０を求めた。結果をＢＯＰＰのＧＩ５０とともに表２に示す。表２から明らかなように、５種類の化合物のうち、化合物１０，１２のＧＩ５０は、ＢＯＰＰよりもはるかに小さく、レーザー光の照射による細胞傷害効果が非常に強いことがわかったが、試験例２の結果を考慮すれば、この効果は、これらの化合物のＨｅＬａ細胞に対する取り込み性の高さが寄与していると考えられた。
Test Example 4: Test of application of boron-containing porphyrin derivative of the present invention to photodynamic therapy After culturing HeLa cells at 37 ° C. for 3 hours in the presence of various concentrations of the five boron-containing porphyrin derivatives of the present invention (1 × 10 4 cells, medium: RPMI-1640), using a xenon lamp, an average of 2.4 mW / cm 2 of laser light (wavelength: 400-800 nm) was irradiated onto the cells for 5 minutes, and the cells were further cultured for 12 hours. Was detected by the MTT method, and the GI 50 of each compound was determined. The results are shown in Table 2 along with the BOPP GI 50 . As is clear from Table 2, among the five compounds, GI 50 of compounds 10 and 12 was much smaller than BOPP, and it was found that the cytotoxic effect by laser light irradiation was very strong. Considering the results of Example 2, it was considered that this effect was attributed to the high uptake of these compounds into HeLa cells.
実施例６：
下記の構造式で表される化合物13を、実施例2における化合物4aの合成のために用いた1-ペンタノールの代わりに1-ヘプタデカノールを用い、同様の方法によって赤紫色の固体として得た。
Compound 13 represented by the following structural formula was obtained as a red-purple solid by the same method using 1-heptadecanol instead of 1-pentanol used for the synthesis of compound 4a in Example 2. It was.
試験例５：本発明のポルフィリン誘導体のウイルスエンベロープとの融合試験
化合物１３（０．５ｍｇ／４３．５μＬ）とセンダイウイルスエンベロープ（５０００ＨＡＵ／６５０μＬ）を４℃で混合し、遠心分離を４℃で１３２００ｒｐｍで１０分間行った。得られた沈殿物を１００μＬのＰＢＳ溶液に懸濁し、再び遠心分離を同じ条件で行い、化合物１３とセンダイウイルスエンベロープの融合物を赤紫色の沈殿物として得た。この化合物１３とセンダイウイルスエンベロープの融合物（化合物１３の濃度：３０μＭ）の存在下、ＨｅＬａ細胞を３７℃で１時間培養した後（５×１０３ｃｅｌｌｓ，培地：ＲＰＭＩ−１６４０）、４％のパラホルムアルデヒドを用いて細胞を固定してから蛍光顕微鏡観察を行ったところ、化合物１３単独を同じ濃度でＨｅＬａ細胞に接触させた場合に比較して細胞からの蛍光強度が強かった。従って、化合物１３をセンダイウイルスエンベロープと融合させることで、ＨｅＬａ細胞に対する取り込み性の向上を図ることができることがわかった。この結果は、化合物１３を用いて合成された本発明の含ホウ素ポリフィリン誘導体でも同様であった。以上の結果から、本発明のポルフィリン誘導体は、本発明の含ホウ素ポリフィリン誘導体の合成中間体として有用であるのみならず、それ自体も光線力学療法の有効成分として有用であることがわかった（化合物４ａ，４ｂ，１３の種々のがん細胞に対するＧＩ５０を表３に示す）。
Test Example 5 Fusion Test of Porphyrin Derivative of the Present Invention with Virus Envelope Compound 13 (0.5 mg / 43.5 μL) and Sendai virus envelope (5000 HAU / 650 μL) were mixed at 4 ° C., and the centrifugation was 13200 rpm at 4 ° C. For 10 minutes. The obtained precipitate was suspended in 100 μL of PBS solution and centrifuged again under the same conditions to obtain a fusion product of Compound 13 and Sendai virus envelope as a red-purple precipitate. After culturing HeLa cells at 37 ° C. for 1 hour in the presence of a fusion of this compound 13 and Sendai virus envelope (compound 13 concentration: 30 μM) (5 × 10 3 cells, medium: RPMI-1640), 4% When the cells were fixed with paraformaldehyde and observed under a fluorescence microscope, the fluorescence intensity from the cells was stronger than when Compound 13 alone was contacted with HeLa cells at the same concentration. Therefore, it was found that the compound 13 can be fused with the Sendai virus envelope to improve the uptake of HeLa cells. This result was the same for the boron-containing porphyrin derivative of the present invention synthesized using Compound 13. These results, porphyrin derivatives of the present invention is not only useful as a synthetic intermediate for boron-containing porphyrin derivative of the present invention per se has also been found to be useful as an active ingredient of photodynamic therapy ( The GI 50 for various cancer cells of compounds 4a, 4b and 13 is shown in Table 3).
本発明は、腫瘍細胞親和性に優れ、かつ、毒性が低いことで高用量の投与が可能である、光線力学療法やホウ素中性子捕捉療法の有効成分として有用な含ホウ素ポルフィリン誘導体を提供することができる点において産業上の利用可能性を有する。 The present invention provides a boron-containing porphyrin derivative useful as an active ingredient in photodynamic therapy and boron neutron capture therapy, which is excellent in tumor cell affinity and can be administered at a high dose due to low toxicity. It has industrial applicability in terms of what it can do.
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