Zhang Wen-Ying, Banerjee Samya, Imberti Cinzia, Clarkson Guy J, Wang Qian, Zhong Qian, Young Lawrence S, Romero-Canelón Isolda, Zeng Musheng, Habtemariam Abraha, Sadler Peter J
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-Sen University Cancer Centre, Guangzhou 510060, China.
Inorganica Chim Acta. 2019 Dec 23;503:119396. doi: 10.1016/j.ica.2019.119396. eCollection 2020 Apr 1.
We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.
我们报道了新型五甲基环戊二烯基（Cp*）铱（III）配合物[(Cp*)Ir(4-甲基-4'-羧基-2,2'-联吡啶)Cl]PF6（Ir-I）、Ir-I与二苯并环辛炔胺进行酰胺偶联的产物（Ir-II）及其与环状九肽c(CRWYDENAC)的共轭物（Ir-CP）的合成与表征。配合物Ir-I常见的三脚“钢琴凳”构型通过其单晶X射线结构得以证实。重要的是，已开发出无铜点击策略，用于将母体配合物Ir-I位点特异性共轭到肿瘤靶向性九环肽上。该方法包括两个步骤：（i）配合物Ir-I中联吡啶配体的羧酸基团首先通过酰胺形成连接到胺官能化的二苯并环辛炔基团上，生成配合物Ir-II；（ii）配合物Ir-II中二苯并环辛炔的炔键随后与修饰肽的叠氮基团发生应变促进的无铜环加成反应。有趣的是，虽然配合物Ir-I对A2780人卵巢癌细胞无活性，但配合物Ir-II表现出中等的细胞毒性活性。诸如Ir-CP之类的靶向配合物为这类抗癌配合物增强活性和选择性提供了空间。
