Recent developments in the design of bioreductive drugs.
Recent developments in the design of bioreductive drugs.
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发表时间：
1996-07
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通讯作者：
W. A. Denny;William R. Wilson;M. Hay
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作者：
W. A. Denny;William R. Wilson;M. Hay
生物还原药物（bd）的开发源于早期对米索硝唑(1)和DNA烷基化剂丝裂霉素C(2)的研究，这两种药物都被证明对缺氧条件下培养的细胞具有选择性细胞毒性。这些化合物可能用于选择性地杀死肿瘤中耐辐射和耐化学的缺氧细胞，这一前景刺激了广泛的研究，并报道了来自许多不同化学类别的大量化合物。其中一些化合物，特别是替拉帕胺(3)（Brown, 1993）、EO-9 (4) （Verweij et al., 1994）和卟啉霉素(5)（Sartorelli, 1988）已经进入临床试验阶段，而RB 6145的r -对映体(6)预计很快就会进入临床试验阶段。BD作为一种以氧抑制方式激活的前药，选择性地杀死缺氧细胞，这一原始概念也得到了扩展。有人建议（Denny和Wilson， 1993）， BDs在激活时释放扩散性细胞毒素，理想地提供一种旁观者效应，以便利用大多数实体肿瘤中存在的一小部分完全缺氧细胞。现在也很清楚，在某些情况下，bd可以进行酶特异性有氧生物还原，为肿瘤细胞选择性提供了一种潜在的新机制（Adams和Stratford， 1994）。在这篇综述中，我们阐述了一些目前在bd设计中的概念。
The development of bioreductive drugs (BDs) arose from early work with misonidazole (1) and the DNA alkylator mitomycin C (2), both of which were shown to possess selective cytotoxicity towards cells cultured under hypoxic compared with aerobic conditions. The prospect that such compounds might be used to selectively kill radioresistant and chemoresistant hypoxic cells in tumours has since stimulated extensive investigation, and a large number of compounds from many different chemical classes have been reported. Several of these compounds, particularly tirapazamine (3) (Brown, 1993), EO-9 (4) (Verweij et al., 1994) and porfiromycin (5) (Sartorelli, 1988) have reached clinical trial, while the R-enantiomer (6) of RB 6145 is expected to do so shortly. There have also been extensions of the original concept of a BD as a prodrug activated in an oxygen-inhibited fashion to kill hypoxic cells selectively. It has been suggested (Denny and Wilson, 1993) that BDs would ideally provide a bystander effect, by releasing a diffusible cytotoxin on activation, in order to utilise the small proportion of fully hypoxic cells present in most solid tumours. It is also now clear that BDs can in some cases undergo enzyme-specific aerobic bioreduction, offering a potential new mechanism for tumour cell selectivity (Adams and Stratford, 1994). In this review we illustrate some current concepts in the design of BDs.