Development of a reduction-responsive amino acid that induces peptide bond cleavage in hypoxic cells
Development of a reduction-responsive amino acid that induces peptide bond cleavage in hypoxic cells
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开发一种还原反应性氨基酸，可在缺氧细胞中诱导肽键裂解
DOI：
10.1002/cbic.201200141
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发表时间：
2012
期刊：
影响因子：
3.2
通讯作者：
et al.
中科院分区：
文献类型：
--
作者：
Shigenaga;A.;et al.
硝基生物还原为胺或羟胺是抗肿瘤前药最有吸引力的触发反应之一。[1，2]前药1具有硝基芳基甲基，可在活细胞中酶促还原为相应的硝基阴离子自由基2（图1）。然而，在需氧非恶性细胞中，阴离子自由基2通常被ROS（活性氧物质）氧化以再生母体前药1。相反，在缺氧的实体瘤中，由于缺氧细胞中的分子氧浓度低于非恶性细胞中的分子氧浓度，所以硝基自由基2的氧化受到抑制。因此，自由基阴离子2可以通过进一步还原，然后去除肿瘤细胞中特异性的芳基甲基而转化为细胞毒性药物3。[2]另一方面，抗体导向的酶前体药物治疗（ADEPT）和基因导向的酶前体药物治疗（GDEPT）在癌症治疗中引起了极大的临床兴趣，并且它们也利用具有硝基芳基甲基保护基的前体药物。[2，3]对于ADEPT或GDEPT，细菌硝基还原酶通过与肿瘤特异性抗体缀合而组装在肿瘤上，或通过使用肿瘤特异性基因载体而在肿瘤细胞中表达，以分别实现细胞毒素3的肿瘤特异性释放。考虑到这些，我们决定开发一种NO2还原响应性氨基酸，其在硝基还原后诱导肽键裂解，因为它可能有助于制备低氧响应性肽基前药和生物探针。
Bioreduction of a nitro group to an amine or a hydroxylamine is among the most attractive triggering reactions of antitumor prodrugs.[1, 2] Prodrug 1, possessing a nitroarylmethyl group, can be enzymatically reduced to corresponding nitro anion radical 2 in living cells (Figure 1). However, anion radical 2 is usually oxidized by ROS (reactive oxygen species) to regenerate parent prodrug 1 in aerobic non-malignant cells. On the contrary, the oxidation of nitro radical 2 is suppressed in hyopxic solid tumor, because concentration of molecular oxygen in hypoxic cells is lower than that in non-malignant cells. Therefore, radical anion 2 can be converted to cytotoxic drug 3 via further reduction followed by removal of the arylmethyl group specifically in tumor cells.[2] On the other hand, antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) evoke a great clinical interest for cancer therapy, and they also utilize prodrugs with the nitroarylmethyl protective group.[2, 3] For ADEPT or GDEPT, a bacterial nitroreductase is assembled on a tumor by conjugating to a tumor-specific antibody or is expressed in tumor cells by use of a tumor-specific gene vector to achieve a tumor-specific release of cytotoxin 3, respectively. With these in mind, we decided to develop an NO2 reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group, because it would potentially facilitate preparation of hypoxia-responsive peptidyl prodrugs and bioprobes.