开发具有生物活性的轴配体的镀铂（IV）络合物，具有单一疗法和药物联合疗法所没有的优势，是改善铂（II）类药物的临床缺陷的有效策略。本文合成并评估了一系列4-氨基喹唑啉基团（已广泛研究的EGFR抑制剂的特权药效团）配位的镀铂（IV）络合物的抗癌活性。其中，17b复合物对被测肺癌细胞（包括CDDP耐药的A549/CDDP细胞）表现出更高的细胞毒性，而对人正常细胞的细胞毒性却比奥沙利铂（Oxa）或顺铂（CDDP）低。机械调查表明，17b的增强细胞内摄取有效地提高了反应性氧种类水平，比Oxa高6.1倍。详细的克服CDDP抵抗的机制揭示，17b通过诱导严重的DNA损伤、扰乱线粒体跨膜电位、有效地扰乱EGFR-PI3K-Akt信号传导和激活线粒体依赖的凋亡通路，显著诱导凋亡。此外，17b显著抑制了A549/CDDP细胞的迁移和侵袭。体内实验表明，17b在A549/CDDP移植瘤中获得了卓越的抗肿瘤效果，并减轻了系统毒性。所有这些结果强调了17b的抗肿瘤作用与传统的铂（II）类药物不同，并提供了一种克服CDDP抵抗的肺癌的新型实用方法。版权所有© 2023 Elsevier Inc. 保留所有权利。

Developing bioactive axial ligands ligated platinum(IV) complexes with advantages over monotherapy and drug combinations is an efficient strategy to ameliorate the clinical defects of platinum(II) drugs. In this article, a series of 4-amino-quinazoline moieties (privileged pharmacophores of well-studied EGFR inhhibitors) ligated platinum(IV) were synthesized and evaluated for their anticancer activities. Among the complex, 17b demonstrated higher cytotoxicity against the tested lung cancer cells (including CDDP-resistant A549/CDDP cells) while lower cytotoxicity toward human normal cells than Oxaliplatin (Oxa) or cisplatin (CDDP). Mechanistic investigation demonstrated that the enhanced intracellular uptake of 17b efficiently elevated the of reactive oxygen species levels by 6.1 times more than Oxa. Detailed mechanisms of overcoming CDDP resistance revealed that 17b significantly induced apoptosis via inducing severe DNA damage, disturbing mitochondrial transmembrane potentials, efficiently disturbing EGFR-PI3K-Akt signaling transduction and activating a mitochondria-dependent apoptosis pathway. Besides, 17b significantly inhibited migration and invasion in A549/CDDP cells. In vivo tests exhibited that 17b obtained superior antitumor effect and attenuated systemic toxicity in A549/CDDP xenografts. All these results emphasized that the antitumor action of 17b differed from that of. classical platinum(II) drugs and provided a novel practical method to overcome CDDP resistance in lung cancer.Copyright © 2023 Elsevier Inc. All rights reserved.