Developing a structure-function relationship for anionic porphyrazines exhibiting selective anti-tumor activity.
Developing a structure-function relationship for anionic porphyrazines exhibiting selective anti-tumor activity.
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建立具有选择性抗肿瘤活性的阴离子四氮杂卟啉的结构-功能关系。
DOI：
10.1016/j.jphotobiol.2005.11.006
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Radosevich,JamesA
中科院分区：
文献类型：
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作者：
Vesper,BenjaminJ;Lee,Sangwan;Hammer,NealD;Elseth,KimM;Barrett,AnthonyGM;Hoffman,BrianM;Radosevich,JamesA
卟啉类化合物(PZS)是一类作为光学显像剂和光动力疗法(PDT)抗肿瘤药物而被研究的卟啉类化合物。先前的一项研究表明，形式H2[PZ(An；B4−n)]的阴离子PZ，18-，其中A是[S(CH2)3CO2-]，B是稠合的β‘，β’-二异丙氧基苯并，其中n=2(反式)选择性地杀死肿瘤细胞，而类似的中性和正电PZs没有这种性质。在这份报告中，我们比较了一套三个H2[PZ(An；B4−n)]PZ的性质，它们的A和B基团与18相同，但它们的值不同：PZS4(n=4)和11(n=3)，以及18(n=2，TRAN)，由于羧酸盐，疏水/亲水性质之间的平衡，以及单线态氧量子产率(ΦΔ)：ΦΔ(18)>；ΦΔ(11)>；ΦΔ(4))的递进变化，我们比较了它们的性质。在人肺癌(A549)和SV40转化的胚胎(WI-38 VA13)细胞系中检测了PZS的生物活性。PZS-4和PZS-11对肿瘤细胞和正常细胞均有明显的毒性作用，而PZS-18具有剂量依赖性的选择性抗肿瘤细胞活性。随着净负电荷数的减少，化合物对正常细胞的毒性变小，并且这些化合物的杀伤作用不依赖于光。这些观察表明，毒性可能与单线态氧量子产率关系不大，而更多地依赖于PZ包含的负电荷净数量。本文报道的这项研究提供了一个例子，说明了如何容易地对卟嗪进行修饰以改变其生物学行为，并特别建议具有较低n(较少的羧基，较大的疏水核心)的阴离子卟嗪PZ是更特异的肿瘤杀伤剂，而那些具有更大的n(增加的净负电荷)的阴离子卟啉PZ是更有效的肿瘤杀伤剂。
The porphyrazines (pzs) are a class of porphyrin derivatives being studied for their use as optical imaging agents and photodynamic therapy (PDT) anti-tumor agents. A previous study revealed that the anionic pz, 18 – of the form H2[pz(An;B4−n)], where A is [S(CH2)3CO2-], B is a fused β′,β′-diisopropyloxy benzo group, with n=2 (trans)–selectively killed tumor cells, while analogous neutral and positively charged pzs lacked this property. In this report, we compare the properties of a suite of three H2[pz(An;B4−n)] pzs containing the same A and B groups as 18, but differing in their values of n: pzs 4 (n=4) and 11 (n=3), and 18 (n=2, trans) exhibit a progressive variation in charge due to the carboxylates, balance between hydrophobic/hydrophilic character, as well as a progressive variation in the singlet oxygen quantum yield (ΦΔ): ΦΔ(18)>ΦΔ(11)>ΦΔ(4). The biological activity of the pzs was tested in human lung carcinoma (A549) and SV40 transformed embryonic (WI-38 VA13) cell lines. Pzs 4 and 11 exhibited significant toxicity in both tumor and normal cells, while 18 showed selective anti-tumor cell activity in a dose-dependent manner. As the number of net negative charges decreased, the compounds became less toxic to normal cells, and the killing effect observed with these compounds was light independent. These observations indicate that the toxicity may have little to do with singlet oxygen quantum yields, but rather is more dependent on the net number of negative charges a pz contains. The study reported herein presents an example of how the porphyrazines can be easily modified to vary their biological behavior and specifically suggest that anionic porphyrazines pzs with lower n (fewer carboxylates, larger hydrophobic core) are more specific tumor killers, while those with larger n (increased net negative charge) are more potent tumor killers.