Cancer Research Horizons Therapeutic Innovation, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
Cancer Research Horizons Therapeutic Innovation, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Paul O'Gorman Building, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K.
J Med Chem. 2023 Sep 14;66(17):12324-12341. doi: 10.1021/acs.jmedchem.3c00845. Epub 2023 Aug 30.
A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.
细胞毒性化疗的一个主要缺点是缺乏对非癌细胞的选择性。将细胞毒性药物靶向递送至肿瘤细胞是癌症研究中的一个长期目标。我们提出，通过共价结合促进的加成-消除机制，可将迈克尔受体的β-位连接的细胞毒剂共价连接，从而将其适用于细胞毒药物的靶向递送。在模型系统中的研究表明，在相关时间范围内，通过硫醇加成可释放共轭 5-氟尿嘧啶（5FU）。合成了一系列作为其 5FU 衍生物的共价表皮生长因子受体（EGFR）抑制剂。证明了实现所需的 5FU 释放取决于化合物的电子和几何形状。质谱和 NMR 研究表明，与 EGFR 结合的苯胺基喹唑啉丙烯酰胺酯缀合物释放了 5FU。这项工作确立了丙烯酸盐可用于在与蛋白质共价结合时释放共轭分子，并且可用于开发靶向治疗药物。
