Design, synthesis, and spectroscopic investigation of zinc dodecakis(trifluoroethoxy)phthalocyanines conjugated with deoxyribonucleosides.
Design, synthesis, and spectroscopic investigation of zinc dodecakis(trifluoroethoxy)phthalocyanines conjugated with deoxyribonucleosides.
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DOI：
10.1002/anie.200603590
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发表时间：
2006-12
影响因子：
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通讯作者：
M. R. Reddy;N. Shibata;Yuki Kondo;Shuichi Nakamura;T. Toru
中科院分区：
文献类型：
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作者：
M. R. Reddy;N. Shibata;Yuki Kondo;Shuichi Nakamura;T. Toru
设计和合成一种有效的药物载体，以促进药物输送已成为药物开发，特别是癌症治疗的主要挑战。[1]在新的载体中，如脂质体气溶胶和富勒烯，设计用于在特定位点与肿瘤细胞相互作用，[2]我们对卟啉和酞菁染料感兴趣。[3]两者都在现代光动力疗法（PDT）癌症的深入研究中。[4]众所周知，这些染料在肿瘤细胞中积累，并在可见光激发下引起局部细胞损伤;因此，它们充当有效的药物载体和光引发的癌症药物。用于这种目的的特别有吸引力的目标是酞菁。[5]虽然卟啉的主要吸收在400 nm附近，但酞菁在600-700 nm处显示出强烈的吸收。这是特别有利的，因为在PDT中，染料应该被630 nm处的可用红光有效地活化。酞菁的另一个好处是亲脂性、亲水性和自聚集性质可以通过改变酞菁核周围的取代基来偏置。作为我们正在进行的研究计划的一部分，旨在开发一种新的方法，导致官能化的酞菁[6]和含氟生物活性化合物的合成[7]，我们在此描述了含氟酞菁-脱氧核糖核苷缀合物1和2对PDT试剂的设计，合成和光谱研究。酞菁侧链中的12个外围三氟乙氧基取代改善了酞菁作为光治疗剂的性质，使得它们没有聚集性质、更高的亲油性、在长波长处的强吸收带和可接受的光敏性。在1和2的苯单元之一处的核苷附件将在DNA识别位点处的结合中发挥关键作用，这有助于辐射下肿瘤细胞中DNA链的自由基诱导的选择性切割。目标缀合物十二烷基-（三氟乙氧基）酞菁锌/乙炔基尿苷（Zn-CF 3-Pc-U，1）和十二烷基-（三氟乙氧基）酞菁锌/乙炔基腺苷（Zn-CF 3-Pc-Ad，2）的结构示于方案1中。除了在药物化学中使用三氟甲基化官能团的高度特定原因之外，[8]基于19 F NMR技术，氟化缀合物将是有前途的体内报告分子。虽然全（三氟乙氧基）酞菁的独特性质已经被揭示[9]，但没有报道过与生物分子缀合的全（三氟乙氧基）酞菁的例子。因此，我们考虑将核苷引入全（三氟乙氧基）酞菁。核苷部分应增强水溶性并潜在地改善对肿瘤细胞的敏感性。由于肿瘤细胞通常比正常细胞分裂得更快，它们需要更多的核苷。因此，与酞菁缀合的核苷将是负责摄取天然核苷的核苷转运蛋白的良好底物，[10]并且它们可能被肿瘤细胞摄取。脱氧核糖核苷单元通过乙炔基接头与酞菁环连接，因为1）乙炔基嘌呤和嘧啶核苷，特别是将乙炔基部分连接到嘌呤核苷中的C8位和嘧啶核苷中的C6位的那些，由于其潜在的生物活性而受到极大的关注，[11]和2）乙炔基刚性杆系统将是一种有用的方式来加强…
The design and synthesis of an efficient drug carrier that facilitates drug delivery has become a major challenge in drug development, especially for cancer treatment.[1] Among the novel carriers, such as liposome aerosol and fullerene, designed to interact with the tumor cell at specific sites,[2] we are interested in the dyes porphyrins and phthalocyanines.[3] Both are under intensive study in the modern photodynamic therapy (PDT) for cancer.[4] It is well known that these dyes accumulate in the tumor cells and cause localized cellular damage on excitation by visible light; as a result, they act as efficient drug carriers and photoinitiated cancer drugs. A particularly attractive target for such a purpose is phthalocyanines.[5] Although the main absorption of porphyrins is around 400 nm, phthalocyanines display an intense absorption at 600–700 nm. This is particularly favorable because the dyes should be effectively activated by available red light at 630 nm in PDT. Another benefit of phthalocyanines is that the lipophilicity, hydrophilicity, and self-aggregation properties can be biased by altering the substituents on the periphery of the phthalocyanine core. As part of our ongoing research programs directed to the development of a new methodology leading to functionalized phthalocyanines [6] and the synthesis of fluorine-containing biologically active compounds,[7] we describe herein the design, synthesis, and spectroscopic investigations of fluorine-containing phthalocyanine–deoxyribonucleoside conjugates 1 and 2 towards PDT agents. The twelve peripheral trifluoroethoxy substitutions in the phthalocyanine side chains improve the properties of phthalocyanines as phototherapeutic agents such that they have no aggregation properties, higher lipophilicity, a strong absorption band at long wavelength, and acceptable photosensitivity. The nucleoside appendage at one of the benzene units of 1 and 2 would play a key role in binding at the DNA recognition site, which assists radical-induced selective cleavage of the DNA strand in the tumor cell under irradiation. The structures of the target conjugates, zinc dodecakis-(trifluoroethoxy) phthalocyanines/ethynyluridine(Zn-CF3-Pc-U, 1) and zinc dodecakis (trifluoroethoxy) phthalocyanines/ethynyladenosine (Zn-CF3-Pc-Ad, 2), are shown in Scheme 1. In addition to the highly specific reasons to make use of trifluoromethylated functional groups in medicinal chemistry,[8] the fluorinated conjugates would be promising reporter molecules in vivo based on an 19F NMR technique. Although unique properties of per (trifluoroethoxy) phthalocyanines have been revealed,[9] no example of per (trifluoroethoxy) phthalocyanines conjugated with biomolecules has been reported. We therefore considered the introduction of a nucleoside to per (trifluoroethoxy) phthalocyanines. The nucleoside moieties should enhance water solubility and potentially improve the sensitivity towards tumor cells. As tumor cells generally divide faster than normal cells, they require more of the nucleosides. Therefore, the nucleosides conjugated with phthalocyanines would be good substrates for nucleoside transporter proteins responsible for the uptake of natural nucleosides,[10] and they could likely be taken into tumor cells. A deoxyribonucleoside unit is connected with the phthalocyanine ring by an ethynyl linker because 1) ethynylpurine and pyrimidine nucleosides, in particular those tethering the ethynyl moiety to the C8 position in purine nucleosides and the C6 position in pyrimidine nucleosides, are of great interest in view of their potential biological activities,[11] and 2) an ethynyl rigid-rod system would represent a useful way to strengthen the …