Synthesis, photophysical properties, tumor uptake, and preliminary in vivo photosensitizing efficacy of a homologous series of 3-(1′-alkyloxy) ethyl-3-devinaylpurpurin-18-N-alkylimides with variable lipophilicity
Synthesis, photophysical properties, tumor uptake, and preliminary in vivo photosensitizing efficacy of a homologous series of 3-(1′-alkyloxy) ethyl-3-devinaylpurpurin-18-N-alkylimides with variable lipophilicity
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DOI：
10.1021/jm0005510
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发表时间：
2001-05-10
影响因子：
7.3
通讯作者：
Pandey, RK
中科院分区：
文献类型：
--
作者：
Zheng, G;Potter, WR;Pandey, RK
以脱镁叶绿酸-a甲酯为起始原料，合成了一系列在两个不同位置上含有烷基取代基的红嘌呤酰亚胺（3-（1（1）-O-烷基）和13（2）-N-烷基）。这些化合物具有可变的亲脂性（log P 5.32-16.44），在λ（max）700 nm附近（λ = 45 000，在二氯甲烷中）显示出长波长吸收，单线态;氧（O-1（2））产生在57- 60%的范围内。通过体内反射光谱法在携带RIF肿瘤的C3 H小鼠中测定这些化合物的体内吸收和肿瘤/皮肤吸收的变化。从一组具有相似亲脂性（log P 10.68-10.88）的光敏剂获得的结果表明，除了总体亲脂性之外，分子中烷基（O-烷基vs N-烷基）的存在和位置在肿瘤摄取、肿瘤选择性和体内PDT功效中起重要作用。目前，所有的purpurinimide类似物正在评估在不同的剂量，并正在进行实验，以建立一个定量的结构-活性关系的有限的一组化合物。1D和2D NMR和质谱分析证实了所需的红嘌呤酰亚胺和在各种反应条件下形成的副产物的结构。本文还讨论了在某些反应条件下生成12-甲酰基和12-羟甲基红嘌呤酰亚胺的机理。
Starting from methylpheophorbide-a, a homologous series of purpurinimides containing alkyl substituents at two different positions [as 3-(1(1)-O-alkyl) and 13(2)-N-alkyl] were synthesized. These compounds with variable lipophilicity (log P 5.32-16.44) exhibit long wavelength absorption near lambda (max)700 nm (epsilon: 45 000 in dichloromethane) with singlet; oxygen (O-1(2)) production in the range of 57-60%. The shifts in in vivo absorptions and tumor/skin uptake of these compounds were determined in C3H mice bearing RIF tumors by in vivo reflectance spectroscopy. The results obtained from a set of photosensitizers with similar lipophilicity (log P 10.68-10.88) indicate that besides the overall lipophilicity, the presence and position of the alkyl groups (O-alkyl vs N-alkyl) in a molecule play an important role in tumor uptake, tumor selectivity, and in vivo PDT efficacy. At present, all purpurinimide analogues are being evaluated at various doses, and experiments are underway to establish a quantitative structure-activity relationship on a limited set of compounds. The 1D and 2D NMR and mass spectrometry analyses confirmed the structures of the desired purpurinimides and the byproducts formed during various reaction conditions. The mechanisms of the formation of the unexpected 12-formyl-and 12-(hydroxymethyl)purpurinimides under certain reaction conditions are also discussed.