Synthesis of hydrophilic conjugated porphyrin dimers for one-photon and two-photon photodynamic therapy at NIR wavelengths
Synthesis of hydrophilic conjugated porphyrin dimers for one-photon and two-photon photodynamic therapy at NIR wavelengths
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DOI：
10.1039/b814789b
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发表时间：
2009-01-01
影响因子：
3.2
通讯作者：
Anderson, Harry L.
中科院分区：
文献类型：
--
作者：
Balaz, Milan;Collins, Hazel A.;Anderson, Harry L.
我们报道了一系列亲水性丁二炔偶联卟啉锌二聚体（1-7）的合成，设计为光动力治疗（PDT）剂。这些卟啉二聚体具有非常高的双光子吸收截面（δ (max)接近8,000-17,000 GM）和红移线性吸收光谱（λ (max)接近700-800 nm），使其成为单光子和双光子激发光动力治疗的理想候选者。四个极性三乙二醇取代基位于每个二聚体的两侧，但是，就其本身而言，这些TEG链在水生理介质中不具有足够的溶解度，无法再现地传递到活细胞中。在卟啉二聚体的介位上，采用了三种不同的合成策略：1)Suzuki偶联、2)Sonogashira偶联和3)亲核圣基芳基化，分别将带电荷的阳离子（甲基吡啶和三甲基铵）和阴离子（磺酸盐和羧酸盐）取代基附加在卟啉二聚体的介位上。方法1和方法3都允许芳香取代基直接连接到卟啉的中间位。方法2提供了一种亲水性卟啉二聚体的途径，在卟啉和极性芳香取代基之间有乙烯连接。钯催化方法1和2允许合成范围更广的中端卟啉，因为有许多芳基卤化物可用。然而，合成这些路线所需的中间体需要一个统计反应步骤，这降低了总收率。另一方面，圣芳基化提供了高度区域选择性的亲核芳香取代，并且比其他途径具有更高的总产率。所有这些带电二聚体在极性溶剂（如甲醇）和含水溶剂混合物（含水DMSO或DMF）中表现出良好的溶解度。
We report the synthesis of a series of hydrophilic butadiyne-linked conjugated zinc porphyrin dimers (1-7), designed as photodynamic therapy (PDT) agents. These porphyrin dimers exhibit exceptionally high two-photon absorption cross sections (delta(max) approximate to 8,000-17,000 GM) and red-shifted linear absorption spectra (lambda(max) approximate to 700-800 nm) making them ideal candidates for one-photon and two-photon excited photodynamic therapy. Four polar triethyleneglycol substituents are positioned along the sides of each dimer, but, on their own, these TEG chains do not confer sufficient solubility in aqueous physiological media for reproducible delivery into live cells. Charged cationic (methylpyridinium and trimethylammonium) and anionic (sulfonate and carboxylate) substituents have been appended to the meso-positions of porphyrin dimers using three synthetic strategies: 1) Suzuki coupling, 2) Sonogashira coupling, and 3) nucleophilic Senge arylation. Approaches 1 and 3 both allow attachment of aromatic substituents directly to the meso-positions of porphyrins. Approach 2 provides a route to hydrophilic porphyrin dimers with an ethyne link between the porphyrin and the polar aromatic substituent. The palladium-catalysed approaches 1 and 2 allow the synthesis of a broader range of meso-capped porphyrins, as many aryl halides are available. However the synthesis of the intermediate required for these routes necessitates a statistical reaction step, which decreases the overall yield. On the other hand, Senge-arylation provides highly regioselective nucleophilic aromatic substitution, and offers higher overall yield than the other routes. All these charged dimers exhibit good solubility in polar solvents (e. g. methanol) and aqueous solvent mixtures (aqueous DMSO or DMF).