School of Physical, Environmental and Mathematical Sciences, University College, University of New South Wales, Australian Defence Force Academy, Northcott Drive, Campbell, ACT 2600, Australia.
Org Biomol Chem. 2010 Jul 21;8(14):3328-37. doi: 10.1039/c003732j. Epub 2010 Jun 4.
The albendazole derivatives (2-methoxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (MEABZ), N1-(2-methoxyethoxycarbonyl)-2-amino-5-propylthiobenzimidazole and N1-(2-methoxyethoxycarbonyl)-2-amino-6-propylthiobenzimidazole (MEABZ isomers A and B) and (2-hydroxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (HEABZ) have been synthesised. The cytotoxicity of these compounds was evaluated against a human colorectal cancer cell line (HT-29) and a human prostate cancer cell line (PC-3). The results demonstrate MEABZ, a new benzimidazole, is up to ten times more cytotoxic than the parent drug albendazole, whereas the MEABZ isomers A and B and HEABZ show no activity. A comparison of the cytotoxicity of these compounds, relative to ABZ, provides structure-activity data for this important class of anticancer agents. The aqueous solubilities of MEABZ encapsulated in Q[n] have been determined by (1)H NMR spectroscopy. The aqueous solubility of MEABZ at a physiologically relevant pH increased by 1200-fold by encapsulation in Q[8], from 8 microM to 9.4 mM, while Q[6,7] encapsulation substantially increased the solubility to more than 2 mM. Encapsulation in Q[7] and Q[8] induced significant upfield shifts for the MEABZ propyl and benzimidazole resonances. The upfield shifts indicate that the propyl and benzimidazole protons are located within the Q[7] and Q[8] cavity upon encapsulation. By contrast, encapsulation in Q[6] induced large upfield shifts for the (1)H resonances from the carbamate functional group, indicating that MEABZ associates with Q[6] at its portals, with only the carbamate group binding within the cavity.
阿苯达唑衍生物（2-甲氧基乙基）5-丙基硫代-1H-苯并咪唑-2-基氨基甲酸酯（MEABZ）、N1-（2-甲氧基乙氧基羰基）-2-氨基-5-丙基硫代苯并咪唑和 N1-（2-甲氧基乙氧基羰基）-2-氨基-6-丙基硫代苯并咪唑（MEABZ 异构体 A 和 B）和（2-羟乙基）5-丙基硫代-1H-苯并咪唑-2-基氨基甲酸酯（HEABZ）已被合成。这些化合物的细胞毒性已针对人结肠直肠癌细胞系（HT-29）和人前列腺癌细胞系（PC-3）进行了评估。结果表明，新型苯并咪唑 MEABZ 的细胞毒性比母体药物阿苯达唑高 10 倍，而 MEABZ 异构体 A 和 B 以及 HEABZ 则没有活性。这些化合物的细胞毒性与 ABZ 的比较为这一类重要的抗癌药物提供了结构活性数据。通过（1）H NMR 光谱法测定了 MEABZ 包封在 Q[n]中的水溶解度。在生理相关 pH 下，MEABZ 的水溶解度通过包封在 Q[8]中增加了 1200 倍，从 8 μM 增加到 9.4 mM，而 Q[6,7]包封则将溶解度大大提高到 2 mM 以上。在 Q[7]和 Q[8]中包封导致 MEABZ 丙基和苯并咪唑共振的向上场位移。向上场位移表明，在包封后，丙基和苯并咪唑质子位于 Q[7]和 Q[8]腔中。相比之下，在 Q[6]中包封会导致氨基甲酸酯官能团的（1）H 共振发生大的向上场位移，表明 MEABZ 与其门户处的 Q[6]缔合，只有氨基甲酸酯基团结合在腔体内。
