Synthesis, Anticancer Activity, and Genome Profiling of Thiazolo Arene Ruthenium Complexes

Sixteen
hydrazinyl-thiazolo arene ruthenium complexes of the general
formula [(η6-p-cymene)­Ru­(N,N′-hydrazinyl-thiazolo)­Cl]Cl were synthesized.
All complexes were tested in vitro for their antiproliferative
activity on three tumor cell lines (HeLa, A2780, and A2780cisR) and
on a noncancerous cell line (HFL-1). A superior cytotoxic activity
of the ruthenium complexes as compared to cisplatin and oxaliplatin,
on both cisplatin-sensitive and cisplatin resistant ovarian cancer
cells, was observed. In addition, the biological activity of two selected
derivatives was evaluated using microarray gene expression assay and
ingenuity pathway analysis. p53 signaling was identified as an important
pathway modulated by both arene ruthenium compounds. New activated
molecules such as FAS, ZMAT3, PRMT2, BBC3/PUMA, and PDCD4, whose overexpressions
are correlated with overcoming resistance to cisplatin therapy, were
also identified as potential targets. Moreover, the arene ruthenium
complexes can be used in association with cisplatin to prevent cisplatin
resistance development and synergistically to induce cell death in
ovarian cancer cells.

本文合成了通式为[(η6-p-cymene)­Ru­(N,N′-hydrazinyl-thiazolo)­Cl]Cl的十六种水合亚胺基噻唑杂芳烃钌配合物。在体外实验中，这些配合物对三种肿瘤细胞系（HeLa、A2780和A2780cisR）以及一种非癌性细胞系（HFL-1）的抗增殖活性进行了测试。与顺铂和奥沙利铂相比，钌配合物在顺铂敏感性和顺铂耐药的卵巢癌细胞中均表现出优异的细胞毒性。此外，通过微阵列基因表达分析和Ingenuity通路分析，对两种选定的衍生物的生物活性进行了评估。芳香族钌化合物被确定为调节p53信号通路的重要途径。同时，新发现的激活分子如FAS、ZMAT3、PRMT2、BBC3/PUMA和PDCD4，这些分子的过表达与克服顺铂治疗耐药性相关，也被认定为潜在的靶点。此外，芳香族钌配合物可用于与顺铂联合使用，以预防顺铂耐药性的发生，并协同诱导卵巢癌细胞死亡。