Photoredox-Catalyzed Reactions for Application in Medicinal Chemistry – A Novel Strategy for Difluoromethylation & Stable S–C(sp2) Linkers for Antibody-Drug Conjugates

光氧化还原催化反应在药物化学中的应用——二氟甲基化的新策略

• 批准号: 437535512
• 负责人: Dr. Alexander Lipp
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/437535512?language=en
• 关键词: Photoredox; Catalyzed; Reactions; Application; Medicinal

The objective of this work is the design of two photoredox-catalyzed transformations for application in medicinal chemistry. New strategies for the difluoromethylation of small molecules and for the construction of stable antibody-drug conjugates (ADCs) will be developed. Geminal difluorides are omnipresent in pharmaceuticals and agrochemicals. In the past years, many photoredox-catalyzed difluoromethylations were reported that rely on trapping of reductively generated difluoromethyl radicals with unsaturated substrates (e.g., alkynes, arenes, alkenes, isocyanides). In the first subproject, a complementary approach will be developed – trapping of oxidatively generated alkyl radicals with 1,1-difluoroethene. This new strategy will overcome previous limitations by enabling a radical difluoroalkylation using carboxylic acids, aldehydes (via dihydropyridines), alcohols (via oxalates) or alkyl trifluoroborates as radical precursors. However, since 1,1-difluoroethene is gaseous and prone to radical polymerization, a suitable surrogate is necessary. Vinylboronates, such as the commercially available vinyl-Bpin, appear to be promising candidates in this respect. Reaction of the latter with oxidatively generated alkyl radicals in the presence of Selectfluor with subsequent deboronation/fluorination should provide a one-pot access to the desired difluoroalkylated products. The utility of the devised method will be demonstrated in the synthesis of designed prostaglandin analogs from commercially available derivatives of Corey lactone. The second subproject aims at developing novel linkers for ADCs. Such immunoconjugates offer the chance to deliver a pharmaceutically active compound selectively to a specific cell type and are hence ideally suited for the harmful cytotoxins used in cancer therapy. In most cases, conjugation of the linker/cytotoxin unit to the antibody is accomplished through Michael reaction of cysteine side chains with maleimides. However, its reversibility limits the ADC’s circulation half-life and reduces the therapeutic window because of the systemic toxicity caused by released cytotoxins. In the course of this project, new linkers will be developed that enable the construction of stable S–C(sp2) conjugates through photoredox or nickel/photoredox dual catalysis. The reaction will be investigated using glutathione as cysteine-containing model substrate in combination with benzylamine and a short oligopeptide as cytotoxin-placeholders. The optimized conditions will then be applied to the functionalization of Trastuzumab, a commercially available antibody for targeting breast cancer cells. After fine-tuning the reaction conditions with an oligopeptide as cytotoxin-placeholder, a full ADC consisting of Trastuzumab and monomethyl auristatin E as cytotoxin will be assembled.

这项工作的目的是设计两个光氧化还原催化的转化在药物化学中的应用。小分子的二氟甲基化和构建稳定的抗体-药物结合物(ADC)的新策略将被开发出来。双氟化物在医药和农用化学品中无处不在。在过去的几年里，许多光氧化还原催化的二氟甲基化反应都依赖于不饱和底物(例如，炔烃、芳烃、烯烃、异氰化物)对还原生成的二氟甲基自由基的捕获。在第一个分项目中，将开发一种补充方法--用1，1-二氟乙烯捕获氧化生成的烷基自由基。这一新策略将克服以前的限制，使用羧酸、醛(通过二氢吡啶)、醇(通过草酸盐)或烷基三氟硼酸盐作为自由基前体进行自由基二氟烷基化。然而，由于1，1-二氟乙烯是气态的，容易发生自由基聚合，因此有必要选择合适的替代品。在这方面，乙烯基硼酸盐，如商业上可获得的乙烯基双宾，似乎是很有希望的候选者。后者在选择氟存在下与氧化生成的烷基反应，然后脱溴/氟化，应可一锅制得所需的二氟烷化产物。设计的方法的实用性将在从商业上可获得的Corey内酯的衍生物合成设计的前列腺素类似物中得到证明。第二个子项目旨在开发用于ADC的新型连接器。这种免疫结合物提供了选择性地将药物活性化合物输送到特定细胞类型的机会，因此非常适合于癌症治疗中使用的有害细胞毒素。在大多数情况下，接头/细胞毒素单元与抗体的结合是通过半胱氨酸侧链与马来酰亚胺的Michael反应完成的。然而，由于释放的细胞毒素引起的全身毒性，其可逆性限制了ADC的循环半衰期，并缩短了治疗窗口。在这个项目的过程中，将开发新的连接物，使其能够通过光氧化还原或镍/光氧化还原双重催化构建稳定的S-C(Sp2)共轭化合物。该反应将以谷胱甘肽作为含半胱氨酸的模型底物，结合苯甲胺和短寡肽作为细胞毒素占位符进行研究。然后，优化的条件将应用于曲妥珠单抗的功能化，曲妥珠单抗是一种用于靶向乳腺癌细胞的商用抗体。以寡肽为细胞毒素占位符，微调反应条件后，将组装成以曲妥珠单抗和单甲基金黄色E为细胞毒素的完整ADC。