Abstract
Platinum(II) terpyridine complexes has attracted increasing attention as they have displayed great potential as antitumor agents due to their high intercalation affinity with nucleic acids. Epidermal growth factor receptor (EGFR) is often overexpressed in various tumor cells, leading to uncontrolled growth of tumor, and is regarded as an important target for developing novel antitumor drugs. Herein, we report four platinum(II) terpyridine complexes bearing EGFR inhibiting 4-anilinoquinazoline derivatives as potent multi-targeting antiproliferation agents against a series of cancer cells. EGFR inhibition assay revealed that these complexes are highly potent EGFR inhibitors. But competitive DNA binding assay and docking simulations also suggested that these complexes exhibited multiple modes of DNA interaction, especially great affinity toward DNA minor groove. Finally, cellular uptake and distribution measurements by inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) demonstrated that both nucleus DNA and membrane proteins are important targets for their anticancer mechanisms. The complexes herein can therefore be regarded as promising multi-targeting anticancer agents.
Highlights
Since the approval of cisplatin as an anticancer agent in the late 1970s, it has been used worldwide in clinics as an important chemotherapeutic drug for the treatment of cancer (Hanif and Hartinger, 2018; Kenny and Marmion, 2019)
In the previous work of our group, we developed a panel of dual-targeting metal-based anticancer complexes using the “pharmacophore conjugation” strategy by coupling a ruthenium complex moiety with a gefitinib pharmacophore (Zheng et al, 2013; Ji et al, 2014; Du et al, 2015, 2016; Zhang et al, 2015)
T1 or T2 were reacted with PtII precursors such as K2PtCl4 or Pt(DMSO)2Cl2 to give rise to the intermediates P1 and P2 (Cummings, 2009b)
Summary
Since the approval of cisplatin as an anticancer agent in the late 1970s, it has been used worldwide in clinics as an important chemotherapeutic drug for the treatment of cancer (Hanif and Hartinger, 2018; Kenny and Marmion, 2019) This breakthrough advancement further inspired the development of other platinum anticancer agents, such as two worldwide-approved drugs, carboplatin, and oxaliplatin, to overcome the downsides of cisplatin. Multi-Targeted Anticancer Agents photoactive PtIV-azido anticancer complexes (Farrer et al, 2010; Shi et al, 2018, 2019; Wang et al, 2019) Another very important strategy is to change the geometry of the coordinated ligands around the PtII center, which has produced a panel of complexes with distinct activities with respect to cisplatin (Johnstone et al, 2016). Besides direct coordination of metal center to DNA, noncovalent interactions such as groove binding and intercalation by the terpyridine ligands play important roles in interactions with DNA (Keene et al, 2009), which indicates different mechanisms of action compared to cisplatin and its analogs
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