Abstract
DNA is considered to be the primary target of platinum-based anticancer drugs which have gained great success in clinics, but DNA-targeted anticancer drugs cause serious side-effects and easily acquired drug resistance. This has stimulated the search for novel therapeutic targets. In the past few years, substantial research has demonstrated that zinc-containing metalloenzymes play a vital role in the occurrence and development of cancer, and they have been identified as alternative targets for metal-based anticancer agents. Metal complexes themselves have also exhibited a lot of appealing features for enzyme inhibition, such as: (i) the facile construction of 3D structures that can increase the enzyme-binding selectivity and affinity; (ii) the intriguing photophysical and photochemical properties, and redox activities of metal complexes can offer possibilities to design enzyme inhibitors with multiple modes of action. In this review, we discuss recent examples of zinc-containing metalloenzyme inhibition of metal-based anticancer agents, especially three zinc-containing metalloenzymes overexpressed in tumors, including histone deacetylases (HDACs), carbonic anhydrases (CAs), and matrix metalloproteinases (MMPs).
Highlights
The discovery of platinum-based drugs has promoted the development of metal-based anticancer agents
20 and 21 displayed significant cytotoxicity against both A2780 and A2780cisR cells. They exerted their antitumor activities in a dual threat manner, including DNA binding and histone deacetylases (HDACs) inhibition. These results suggested that the dual targeting strategy was a viable approach in the design of platinum agents that were more effective against cisplatin-resistant cancer types
We have classified and illustrated metal-based compounds with zinc-containing metalloenzymes inhibitory activity. As shown in these examples, most of them exhibit stronger biological activity than that of metal moiety or organic inhibitor alone, suggesting that the conjugation of known organic inhibitors to a metal center can result in a synergistic advantage
Summary
The discovery of platinum-based drugs has promoted the development of metal-based anticancer agents. Platinum-based drugs, such as cisplatin (1), carboplatin (2), and oxaliplatin (3) (Figure 1) are being used in the treatment of ∼50–70% of cancers (Bruno et al, 2017). The serious side-effects and acquired drug resistance in cancer chemotherapy of platinum-based drugs have hindered their development (Galluzzi et al, 2012). This has stimulated the exploitation of other types of novel metal chemotherapeutics, which work through different mechanisms of action and may obtain a higher therapeutic index. Some of them have already advanced to clinical trials, such as NAMI-A (4) (Rademaker-Lakhai et al, 2004), KP1019 (5) (Hartinger et al, 2008), and KP1339 (6) (the sodium salt of KP1019) (Kuhn et al, 2015) (Figure 1)
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