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Design and synthesis of a folate-receptor targeted diazepine-ring-opened pyrrolobenzodiazepine prodrug conjugate.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-01-27 , DOI: 10.1016/j.bmcl.2020.126987 Iontcho R Vlahov 1 , Longwu Qi 1 , Hari Krishna R Santhapuram 1 , Albert Felten 1 , Garth L Parham 1 , Ning Zou 1 , Kevin Wang 1 , Fei You 1 , Jeremy F Vaughn 1 , Spencer J Hahn 1 , Hanna F Klein 1 , Paul J Kleindl 1 , Joe Reddy 1 , Dan Reno 1 , Jeff Nicoson 1 , Christopher P Leamon 1
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-01-27 , DOI: 10.1016/j.bmcl.2020.126987 Iontcho R Vlahov 1 , Longwu Qi 1 , Hari Krishna R Santhapuram 1 , Albert Felten 1 , Garth L Parham 1 , Ning Zou 1 , Kevin Wang 1 , Fei You 1 , Jeremy F Vaughn 1 , Spencer J Hahn 1 , Hanna F Klein 1 , Paul J Kleindl 1 , Joe Reddy 1 , Dan Reno 1 , Jeff Nicoson 1 , Christopher P Leamon 1
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Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.
中文翻译：
叶酸受体靶向的二氮杂环开环的吡咯并苯并二氮杂pine前药缀合物的设计和合成。
吡咯并二氮杂卓（PBD）及其二聚体（bis-PBD）已作为一些最有效的化学治疗化合物出现，目前正在开发为抗体-药物偶联物（ADC）中的新型有效负载。但是，当用作独立疗法或小分子药物偶联物（SMDC）的战斗部时，经常会观察到剂量限制的毒性。作为解决这一固有问题的理想解决方案，我们设计并合成了缺乏在相应的游离bis-PBD中发现的两个亚胺基团之一的二氮杂苯环开环的bis-PBD前体药物（pro-PBD-PBD）叶酸共轭物。进入靶细胞后，接头系统的裂解，包括恶唑烷部分的水解，导致形成具有新形成的醛以及芳族胺的反应性中间体。随后发生快速和自发的分子内闭环反应，这是因为芳族胺加到醛中而失去了水，从而产生了亚胺，因此形成了二氮杂ring环，从而将bis-PBD递送至靶细胞。已经在叶酸受体阳性KB细胞上评估了该结合物的体外和体内活性。已经观察到亚纳摩尔活性具有良好的特异性和高治愈率且毒性最小。
更新日期：2020-01-27
中文翻译：
叶酸受体靶向的二氮杂环开环的吡咯并苯并二氮杂pine前药缀合物的设计和合成。
吡咯并二氮杂卓（PBD）及其二聚体（bis-PBD）已作为一些最有效的化学治疗化合物出现，目前正在开发为抗体-药物偶联物（ADC）中的新型有效负载。但是，当用作独立疗法或小分子药物偶联物（SMDC）的战斗部时，经常会观察到剂量限制的毒性。作为解决这一固有问题的理想解决方案，我们设计并合成了缺乏在相应的游离bis-PBD中发现的两个亚胺基团之一的二氮杂苯环开环的bis-PBD前体药物（pro-PBD-PBD）叶酸共轭物。进入靶细胞后，接头系统的裂解，包括恶唑烷部分的水解，导致形成具有新形成的醛以及芳族胺的反应性中间体。随后发生快速和自发的分子内闭环反应，这是因为芳族胺加到醛中而失去了水，从而产生了亚胺，因此形成了二氮杂ring环，从而将bis-PBD递送至靶细胞。已经在叶酸受体阳性KB细胞上评估了该结合物的体外和体内活性。已经观察到亚纳摩尔活性具有良好的特异性和高治愈率且毒性最小。
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