Meso-四萘基卟啉的选择性硝化、衍生物的合成及其对癌细胞的光灭活作用
摘要
不对称卟啉的合成与应用是目前的热点之一。硝基卟啉非常重要,不仅因为目前关于卟啉的取代反应很少报道,更重要的是硝基卟啉以及它的还原产物氨基卟啉是一些生物活性分子有用的前体。本论文对四萘基卟啉(TNP)的选择性硝化以及卟啉衍生物的光动力学进行了研究。光动力学治疗是目前最有前途的肿瘤检测和治疗的方法之一。用65%的硝酸作为硝化试剂,对四萘基卟啉的选择性硝化进行了深入研究。研究发现本反应可以选择性高产率(＞80%)生成单硝化产物(5-(4-硝基萘基)-10,15,20-三萘基卟啉1)、二硝化产物(5,10-二(4-硝基萘基)-,15,20-二萘基卟啉2(a)和5,15-二(4-硝基萘基)-10,20-二萘基卟啉2(b))和三硝化产物(5,10,15-三(4-硝基萘基)-20-单萘基卟啉3)。研究了硝化反应的规律,发现TNP的硝化是分步进行的,反应先生成单硝化TNP,进一步反应生成二硝化TNP,最后生成三硝化TNP。而目前还没有TNP选择性硝化的报道。
通过C=N键将大的共轭性基团引入卟啉母体是一种好的合成PDT药物的方法。首先,通过还原单硝化产物1,合成了5-(4-氨基萘基)-10,15,20-三萘基卟啉4,再通过三种不同的醛和氨基卟啉反应合成了5-N-(4-氨基萘基-缩-2-羟基-1-萘醛)-10,15,20-三萘基卟啉5,5-N-(4-氨基萘基-缩-水杨醛)-10,15,20-三萘基卟啉6,5-N-(4-氨基萘基-缩-2-噻吩醛)-10,15,20-三萘基卟啉7。并选择多萘基产物6合成了相应的Zn(Ⅱ)、Cu(Ⅱ)、Co(Ⅱ)三种金属配合物8、9、10,同时进行了4-10化合物针对人体白血病细胞K562的光动力学研究。研究发现,5-N-(4-氨基萘基-缩-水杨醛)-10,15,20-三萘基卟啉6和5-N-(4-氨基萘基-缩-噻吩醛)-10,15,20-三萘基卟啉7表现出明显的抗肿瘤活性并且几乎没有暗毒性。
所有合成的卟啉衍生物都进行了紫外,核磁,红外,质谱,元素分析等表征。
Numerous studies have been focused on the search of new adequate synthetic routes of the asymmetrical functionalized porphyrins and their potential applications.Nitroporphyrins are very important not only because there are few sustitutional reaction of the porphyrin framework but also because nitro-and the reduction products amino-substituted porphyrins are useful synthetic precursors to biological active molecules.In the present paper,the selective nitration of the tetranaphthylporphyrin(TNP) and the photodynamic study(PDT) were processed.PDT is one of the most promising applications of porphyrins in the detection and cure of tumors.With the 65%HNO_3 as the nitration agent,the selective nitration of the tetranaphthylporphyrins was investigated in details.The reaction leads to exquisite regioselectivity in favor of the mononitroporphyrin(5-(4-nitronaphthyl)-10,15, 20-trinaphthylporphyrin 1),dinitroporphyrin(5,10-di(4-nitronaphthyl)-15, 20-dinaphthylporphyrin 2(a),5,15-di(4-nitronaphthyl)-10,20-dinaphthylporphyrin 2(b)) and trinitroporphyrin(5,10,15-tri(4-nitronaphthyl)-20-naphthyl porphyrin 3) over 80%yield.It was concluded that the nitration was conducted stepwisely at the para position of the naphthyl group and the work in the field of synthesizing asymmetrically functionalized porphyrins through selective nitration of TNP is blank.
Porphyrin bearing large conjugated groups through the linker of the schiff base structure C=N could appear as promising candidates for an application in PDT.First, monoaminoporphyrin(5-(4-aminonaphthyl)-10,15,20-trinaphthylporphyrin 4) was synthesized through the reduction of the mononitroporphyrin 1. 5-N-(4-aminonaphthyl-2-hydroxy-1-naphthaldehyde)-10,15,20-trinaphthylporphyrin 5, 5-N-(4-aminonaphthyl-salicylaldehyd)-10,15,20-trinaphthylporphyrin 6 and 5-N-(4-aminonaphthyl-thiophene-2-carboxaldehyde)-10,15,20-trinaphthylporphyrin 7 were obtained through reaction of three different aromatic aldehydes with the aminoporphyrin 4 through the linker C=N.The PDT study of the resulting Schiff base-substituted porphyrins and the complexes of 5-N-(4-aminonaphthyl-2-hydroxy-1-naphthaldehyde)-10,15, 20-trinaphthylporphyrin(Zn 8,Cu 9,Co 10) were tested.Two Schiff base-substituted porphyrins 5 and 7 showed obvious antitumor activities and nearly no dark photocytotoxicities.
All the porphyrins synthesized were characterized by UV-vis,~1HNMR,Elemental analyses, FT-IR,and MS.
通过C=N键将大的共轭性基团引入卟啉母体是一种好的合成PDT药物的方法。首先,通过还原单硝化产物1,合成了5-(4-氨基萘基)-10,15,20-三萘基卟啉4,再通过三种不同的醛和氨基卟啉反应合成了5-N-(4-氨基萘基-缩-2-羟基-1-萘醛)-10,15,20-三萘基卟啉5,5-N-(4-氨基萘基-缩-水杨醛)-10,15,20-三萘基卟啉6,5-N-(4-氨基萘基-缩-2-噻吩醛)-10,15,20-三萘基卟啉7。并选择多萘基产物6合成了相应的Zn(Ⅱ)、Cu(Ⅱ)、Co(Ⅱ)三种金属配合物8、9、10,同时进行了4-10化合物针对人体白血病细胞K562的光动力学研究。研究发现,5-N-(4-氨基萘基-缩-水杨醛)-10,15,20-三萘基卟啉6和5-N-(4-氨基萘基-缩-噻吩醛)-10,15,20-三萘基卟啉7表现出明显的抗肿瘤活性并且几乎没有暗毒性。
所有合成的卟啉衍生物都进行了紫外,核磁,红外,质谱,元素分析等表征。
Numerous studies have been focused on the search of new adequate synthetic routes of the asymmetrical functionalized porphyrins and their potential applications.Nitroporphyrins are very important not only because there are few sustitutional reaction of the porphyrin framework but also because nitro-and the reduction products amino-substituted porphyrins are useful synthetic precursors to biological active molecules.In the present paper,the selective nitration of the tetranaphthylporphyrin(TNP) and the photodynamic study(PDT) were processed.PDT is one of the most promising applications of porphyrins in the detection and cure of tumors.With the 65%HNO_3 as the nitration agent,the selective nitration of the tetranaphthylporphyrins was investigated in details.The reaction leads to exquisite regioselectivity in favor of the mononitroporphyrin(5-(4-nitronaphthyl)-10,15, 20-trinaphthylporphyrin 1),dinitroporphyrin(5,10-di(4-nitronaphthyl)-15, 20-dinaphthylporphyrin 2(a),5,15-di(4-nitronaphthyl)-10,20-dinaphthylporphyrin 2(b)) and trinitroporphyrin(5,10,15-tri(4-nitronaphthyl)-20-naphthyl porphyrin 3) over 80%yield.It was concluded that the nitration was conducted stepwisely at the para position of the naphthyl group and the work in the field of synthesizing asymmetrically functionalized porphyrins through selective nitration of TNP is blank.
Porphyrin bearing large conjugated groups through the linker of the schiff base structure C=N could appear as promising candidates for an application in PDT.First, monoaminoporphyrin(5-(4-aminonaphthyl)-10,15,20-trinaphthylporphyrin 4) was synthesized through the reduction of the mononitroporphyrin 1. 5-N-(4-aminonaphthyl-2-hydroxy-1-naphthaldehyde)-10,15,20-trinaphthylporphyrin 5, 5-N-(4-aminonaphthyl-salicylaldehyd)-10,15,20-trinaphthylporphyrin 6 and 5-N-(4-aminonaphthyl-thiophene-2-carboxaldehyde)-10,15,20-trinaphthylporphyrin 7 were obtained through reaction of three different aromatic aldehydes with the aminoporphyrin 4 through the linker C=N.The PDT study of the resulting Schiff base-substituted porphyrins and the complexes of 5-N-(4-aminonaphthyl-2-hydroxy-1-naphthaldehyde)-10,15, 20-trinaphthylporphyrin(Zn 8,Cu 9,Co 10) were tested.Two Schiff base-substituted porphyrins 5 and 7 showed obvious antitumor activities and nearly no dark photocytotoxicities.
All the porphyrins synthesized were characterized by UV-vis,~1HNMR,Elemental analyses, FT-IR,and MS.
引文
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[1] Lipstman S., Muniappan S., Goldberg I., Supramolecular Reactivity of Porphyrins with Mixed Iodophenyl and Pyridyl meso-Substituents[J]. Cryst. Growth Des.,2008, V8 (5): 1682-1688
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[6] Lipstman, S., Muniappan, S., George, S., et al. Framework coordination polymers of tetra(4-carboxyphenyl)porphyrin and lanthanide ions in crystalline solids[J]. Dalton Trans., 2007,V30: 3273-3281
[7] Spence J.D. , Lash T.D.. Porphyrins with Exocyclic Rings. 14.~1 Synthesis of Tetraacenaphthoporphyrins, a New Family of Highly Conjugated Porphyrins with Record-Breaking Long-Wavelength Electronic Absorptions[J]. J. Org. Chem., 2000, V65:1530-1539
[8] Xu H.J., Shen Z., Okujima T., et al. Synthesis and spectroscopic characterization of meso-tetraarylporphyrins with fused phenanthrene rings[J]. Tetrahedron Lett., 2006, V47:931-934
[9] Pushpan S.K., Srinivasan A., Narayanan S. J., et al. Meso Aryl Heptaphyrins: The First 30π Aromatic Expanded Porphyrins with an Inverted Structure[J]. Organic Lett., 2000, V2(24):3829-3832
[10] Schmitt F., Govindaswamy P., Suss-Fink G., et al. Ruthenium Porphyrin Compounds for Photodynamic Therapy of Cancer[J]. J. Med. Chem., 2008, V51(6): 1811-1816
[11] Lottner C., Bart K.C., Bernhardt G., et al. Hematoporphyrin-Derived Soluble Porphyrin-Platinum Conjugates with Combined Cytotoxic and Phototoxic Antitumor Activity[J]. J. Med. Chem.,2002, V45(10):2064-2078