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Linker design for the modular assembly of multifunctional and targeted platinum(II)-containing anticancer agents

机译：用于多功能和目标化的含铂（II）抗癌剂模块化组装的接头设计

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摘要

A versatile and efficient modular synthetic platform was developed for assembling multifunctional conjugates and targeted forms of platinum–(benz)acridines, a class of highly cytotoxic DNA-targeted hybrid agents. The synthetic strategy involved amide coupling beween succinyl ester-modified platinum compounds (>P1, >P2) and a set of 11 biologically relevant primary and secondary amines (>N1–>N11). To demonstrate the feasibility and versatility of the approach, a structurally and functionally diverse range of amines was introduced. These include biologically active molecules, such as rucaparib (a PARP inhibitor), E/Z-endoxifen (an estrogen receptor antagonist), and a quinazoline-based thyrosine kinase inhibitor. Micro-scale reactions in Eppendorf tubes or on 96-well plates were used to screen for optimal coupling conditions in DMF solution with carbodiimide-, uronium-, and phosphonium-based compounds, as well as other common coupling reagents. Reactions with the phosphonium-based coupling reagent PyBOP produced the highest yields and gave the cleanest conversions. Furthermore, it was demonstrated that the chemistry can also be performed in aqueous media and is amenable to parallel synthesis based on multiple consecutive reactions in DMF in a “one-tube” format. In-line LC-MS was used to assess the stability of the conjugates in physiologically relevant buffers. Hydrolysis of the conjugates occurs at the ester moiety and is facilitated by the aquated metal moiety under low-chloride ion conditions. The rate of ester cleavage greatly depends on the nature of the amine component. Potential applications of the linker technology are discussed.
机译：开发了一种通用且高效的模块化合成平台，用于组装多功能结合物和靶向形式的铂-（苯）ac啶类药物，一类高度细胞毒性的DNA靶向杂合剂。合成策略涉及在琥珀酸酯改性的铂化合物（> P1 ，> P2 ）与11种生物学上相关的伯胺和仲胺（> N1 – > N11 ）。为了证明该方法的可行性和多功能性，引入了结构和功能上不同的胺类。这些包括生物活性分子，例如rucaparib（PARP抑制剂），E / Z-endoxifen（雌激素受体拮抗剂）和基于喹唑啉的酪氨酸激酶抑制剂。使用Eppendorf管或96孔板上的微量反应，以DMF溶液中基于碳二亚胺，铀和and的化合物以及其他常见的偶联剂筛选最佳偶联条件。与基于-的偶联剂PyBOP的反应收率最高，转化率最干净。此外，已经证明该化学反应也可以在水性介质中进行，并且可以基于“单管”形式的DMF中的多个连续反应进行平行合成。在线LC-MS被用于评估缀合物在生理学相关缓冲液中的稳定性。结合物的水解发生在酯部分，并且在低氯离子条件下被水合金属部分促进。酯的裂解速率很大程度上取决于胺组分的性质。讨论了链接器技术的潜在应用。

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    S. Ding; U. Bierbach;

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  • 年(卷),期 -1(45),33
  • 年度 -1
  • 页码 13104–13113
  • 总页数 21
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