Copper Complex Entangles DNA, Kills Cancer Cells

Cisplatin is a widely used anticancer drug that works through the DNA-binding ability of its single platinum center. A new study suggests that when it comes to anticancer treatments, two metal centers may be better than one. Chemists designed a molecule with two coppers that bind to neighboring phosphates in the DNA backbone, which in turn inhibits DNA synthesis and kills cancer cells (Inorg. Chem. 2015, DOI: 10.1021/ic5028465).

Although cisplatin is widely used, researchers want to design new cisplatin-like compounds to treat types of cancer that cisplatin is ineffective against and to combat resistance in cancers the drug already targets. “Much of the research for anticancer drugs focuses on modifying cisplatin,” says Thorsten Glaser of Bielefeld University, in Germany. “We wanted something new, with a different mechanism.”

The platinum in cisplatin binds to nitrogens on adjacent DNA bases. This gnarls the DNA, which disrupts normal cell functions such as replication and leads to cell death.

Glaser’s team decided to target DNA’s phosphates instead of its bases. As a starting point, the researchers selected a compound with a phenolic ligand and a copper center known to bind phosphate. However, the phosphate binding was weak. Glaser’s solution was to add more copper. “If you bind two phosphates at the same time, the binding constant is greater,” he says. Using an old-school molecular modeling kit, the researchers built a model of a new molecule that essentially doubled the existing one, adding a second copper site, and expanded the phenol into a naphthalenediol. The distance between the two coppers is 6 to 7 Å, which matches the distance between two phosphates in the DNA backbone.

The researchers developed a synthesis for the molecule and then checked its ability to bind DNA. In atomic force microscopy images, DNA strands without the new compound remain separate and relatively straight. But adding the copper agent caused the DNA to become visibly gnarled. The researchers suspect that hydrophobic interactions between naphthalenediols on separate DNA-bound copper complexes pull the strands together, leading to the DNA entanglements.

To check whether the copper complex disrupts DNA replication as cisplatin does, the researchers performed polymerase chain reaction with and without the molecule. At a concentration of 10 μM, the copper compound halts DNA amplification, while cisplatin levels need to reach 50 μM to produce the same level of inhibition. As a final test, the researchers added the agents to cultures of cancer cells, finding that most of the cells died at 10 μM of the copper complex versus 20 μM of cisplatin.

“Targeting the phosphate groups is a very creative idea,” says Shiladitya Sengupta of Harvard Medical School. “I love it.” But, he says, “just because it’s potent doesn’t mean it’s a cancer drug.” Sengupta wants to see experiments that demonstrate that the copper complex selectively targets cancer cells over healthy ones. Glaser agrees; however, he first wants to optimize the molecule’s potency through a better understanding of how it binds DNA and kills cells.