Chen Yu, Hu Longqin
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Med Res Rev. 2009 Jan;29(1):29-64. doi: 10.1002/med.20137.
Anticancer prodrugs designed to target specifically tumor cells should increase therapeutic effectiveness and decrease systemic side effects in the treatment of cancer. Over the last 20 years, significant advances have been made in the development of anticancer prodrugs through the incorporation of triggers for reductive activation. Reductively activated prodrugs have been designed to target hypoxic tumor tissues, which are known to overexpress several endogenous reductive enzymes. In addition, exogenous reductive enzymes can be delivered to tumor cells through fusion with tumor-specific antibodies or overexpressed in tumor cells through gene delivery approaches. Many anticancer prodrugs have been designed to use both the endogenous and exogenous reductive enzymes for target-specific activation and these prodrugs often contain functional groups such as quinones, nitroaromatics, N-oxides, and metal complexes. Although no new agents have been approved for clinical use, several reductively activated prodrugs are in various stages of clinical trial. This review mainly focuses on the medicinal chemistry aspects of various classes of reductively activated prodrugs including design principles, structure-activity relationships, and mechanisms of activation and release of active drug molecules.
旨在特异性靶向肿瘤细胞的抗癌前药应能提高癌症治疗的有效性并降低全身副作用。在过去20年中，通过引入还原激活触发剂，抗癌前药的开发取得了显著进展。还原激活前药已被设计用于靶向缺氧肿瘤组织，已知该组织会过度表达几种内源性还原酶。此外，外源性还原酶可通过与肿瘤特异性抗体融合递送至肿瘤细胞，或通过基因递送方法在肿瘤细胞中过表达。许多抗癌前药已被设计成利用内源性和外源性还原酶进行靶向特异性激活，这些前药通常含有醌、硝基芳烃、N-氧化物和金属配合物等官能团。尽管尚无新的药物获批用于临床，但几种还原激活前药正处于临床试验的不同阶段。本综述主要关注各类还原激活前药的药物化学方面，包括设计原则、构效关系以及活性药物分子的激活和释放机制。
