从安曲霉素到含吡咯苯并二氮䓬（PBD）的抗体药物偶联物（ADC）。
From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs).
机构信息
Institute of Pharmaceutical Science, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, and Femtogenix Ltd, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
Professor of Drug Discovery, King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
出版信息
Angew Chem Int Ed Engl. 2017 Jan 9;56(2):462-488. doi: 10.1002/anie.201510610. Epub 2016 Nov 15.
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their C11-position and the C2-NH groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG-136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor-targeting antibodies to create antibody-drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre-clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD-containing ADCs, and explores both structure-activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.
吡咯并[2,1-c][1,4]苯并二氮杂卓（PBDs）是一组序列选择性 DNA 小沟结合剂，它们在其 C11 位和鸟嘌呤碱基的 C2-NH 基团之间形成共价亚胺键。第一个 PBD 单体，天然产物蒽环霉素，于 20 世纪 60 年代被发现，而最著名的 PBD 二聚体 SJG-136（也称为 SG2000、NSC 694501 或 BN2629）于 20 世纪 90 年代合成，并于最近在白血病和卵巢癌患者中完成了 II 期临床试验。最近，PBD 二聚体类似物被连接到肿瘤靶向抗体上，以创建抗体药物偶联物（ADC），其中一些目前正在临床试验中，还有许多正在临床前开发中。这篇综述从蒽环霉素到第一个 PBD 二聚体，再到含有 PBD 的 ADC，探讨了 PBD 的结构-活性关系（SAR）和生物学，并探讨了将它们用作 ADC 有效载荷的策略。
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