Hilmey David G, Abe Masako, Nelen Marina I, Stilts Corey E, Baker Gary A, Baker Sheila N, Bright Frank V, Davies Sherry R, Gollnick Sandra O, Oseroff Allan R, Gibson Scott L, Hilf Russell, Detty Michael R
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, USA.
J Med Chem. 2002 Jan 17;45(2):449-61. doi: 10.1021/jm0103662.
Water-soluble, core-modified porphyrins were prepared and evaluated as sensitizers for photodynamic therapy (PDT). The addition of an aromatic aldehyde to 2,5-dilithiothiophene or -selenophene gave diol 3 as a nearly equimolar mixture of meso and d,l diastereomers, which gave a single diastereomer following careful recrystallization. The condensation of pyrrole with a diol 3 using catalytic BF(3)-etherate gave bispyrrolochalcogenophenes (4). Condensation of a diol 3 with 4 in the presence BF(3)-etherate gave 21,23-dichalcogenaporphyrins (5). 21-Thiaporphyrins (6) were prepared by condensation of a diol 3 with excess pyrrole and benzaldehyde in the presence of tetrachlorobenzoquinone and catalytic BF(3)-etherate. Sulfonation of 5 and 6 with concentrated sulfuric acid at 100 degrees C gave sulfonated derivatives 7-15. Bis-4-methoxy-21,23-dithiaporphyrins 5h and 5l were demethylated with BBr(3), and the resulting phenols were alkylated with ethyl bromoacetate. Saponification gave 21,23-dithiaporphyrin dicarboxylate salts 16 and 17. The 21,23-core-modified porphyrins gave band I absorption maxima (lambda(max) of 689-717 nm) at longer wavelengths than band I for the corresponding 21-core-modified porphyrins, but both classes had band I maxima at longer wavelengths than either TPPS(4) or Photofrin (lambda(max) of 630 nm for both). The core heteroatoms had little effect on either absorption maxima or quantum yields of singlet oxygen generation in 7-17. The meso substituents had a greater impact on absorption maxima. Compounds 7-17 were evaluated for phototoxicity against Colo-26 cells in culture using 4 J cm(-2) of 570-800 nm light. Compounds 8-12, 14, 16, and 17 gave a 50% cell kill in vitro at a lower concentration than Photofrin [5.7 mg (9 micromol)/kg]. Compounds 14, 16, and 17 gave a 50% cell kill with 4 J cm(-2) of light and submicromolar concentrations of sensitizer. Sensitizers 8 and 11 showed no toxicity or side effects in BALB/c mice observed for 90 days following a single intravenous injection of 10 mg/kg of sensitizer. Distribution studies show that sensitizer 8 accumulates in the tumors of BALB/c mice. PDT with 8 at 0.125 mg (0.13 micromol)/kg or 11 at 2.5 mg (2.5 micromol)/kg and 135 J cm(-2) of 694 nm light was comparable to PDT with Photofrin at 2.5 mg (4 micromol)/kg and 135 J cm(-2) of 630 nm light against Colo-26 tumors in BALB/c mice.
制备了水溶性、核心修饰的卟啉，并将其作为光动力疗法（PDT）的敏化剂进行评估。向2,5 - 二锂噻吩或 - 硒吩中加入芳香醛得到二醇3，它是内消旋体和d，l非对映异构体的近等摩尔混合物，经过仔细重结晶后得到单一非对映异构体。使用催化量的三氟化硼乙醚络合物使吡咯与二醇3缩合得到双吡咯并硫族苯并菲（4）。在三氟化硼乙醚络合物存在下，二醇3与4缩合得到21,23 - 二硫族卟啉（5）。21 - 硫代卟啉（6）通过在四氯苯醌和催化量的三氟化硼乙醚络合物存在下，使二醇3与过量吡咯和苯甲醛缩合制备。在100℃下用浓硫酸对5和6进行磺化得到磺化衍生物7 - 15。用三溴化硼使双 - 4 - 甲氧基 - 21,23 - 二硫代卟啉5h和5l脱甲基，所得酚用溴乙酸乙酯烷基化。皂化得到21,23 - 二硫代卟啉二羧酸盐16和17。与相应的21 - 核心修饰的卟啉相比，21,23 - 核心修饰的卟啉在更长波长处给出I带吸收最大值（λmax为689 - 717nm），但这两类卟啉的I带最大值都比四磺基苯基卟啉（TPPS(4)）或血卟啉衍生物（Photofrin）（两者的λmax均为630nm）的波长更长。核心杂原子对7 - 17中单线态氧生成的吸收最大值或量子产率影响很小。中位取代基对吸收最大值有更大影响。使用570 - 800nm光的4J/cm²对培养的Colo - 26细胞评估化合物7 - 17的光毒性。化合物8 - 12、14、16和17在体外以低于血卟啉衍生物[5.7mg（9μmol）/kg]的浓度实现50%的细胞杀伤。化合物14、16和17在4J/cm²的光和亚微摩尔浓度的敏化剂作用下实现50%的细胞杀伤。敏化剂8和11在单次静脉注射10mg/kg敏化剂后观察90天的BALB/c小鼠中未显示毒性或副作用。分布研究表明敏化剂8在BALB/c小鼠的肿瘤中积累。在BALB/c小鼠中，用0.125mg（0.13μmol）/kg的8或2.5mg（2.5μmol）/kg的11以及135J/cm²的694nm光进行光动力疗法，与用2.5mg（4μmol）/kg的血卟啉衍生物和135J/cm²的630nm光对BALB/c小鼠的Colo - 26肿瘤进行光动力疗法相当。
