Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA.
Med Res Rev. 2012 Mar;32(2):254-93. doi: 10.1002/med.20212. Epub 2010 Jun 13.
Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA-binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently, the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. This review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, chemical synthesis of PBDs, mechanism of DNA alkylation, and DNA-binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.
吡咯并苯二氮䓬类化合物（PBDs）是一种具有显著抗肿瘤活性的序列选择性 DNA 烷化剂。它们要么是放线菌天然产生的，要么是人工合成的。天然产生的 PBDs 具有显著的广谱活性，这促使人们合成了几种 PBDs，包括二聚体和杂合 PBDs，从而提高了 DNA 结合序列特异性和这类化合物的效力。然而，化学合成的局限性限制了对最有效 PBD 之一——西博霉素（sibiromycin）的测试，西博霉素是一种天然产生的糖基化 PBD。直到最近，PBD 的生物合成基因簇才被鉴定出来，这为通过突变合成和生物合成工程生产糖基化 PBD 打开了大门。这篇综述描述了天然产生的吡咯并苯二氮䓬类化合物生物合成的最新研究进展。此外，还概述了天然产生的 PBD 的分离和表征、PBD 的化学合成、DNA 烷化作用机制以及天然产生和合成的吡咯并苯二氮䓬类化合物的 DNA 结合亲和力和细胞毒性特性。
