In Search of Bioactive Shapes

Natural products are classic inspirations for, and indeed sources of, therapeutic agents, but they are scarce and often painstaking to make by synthetic means. At the American Chemical Society national meeting this week in Washington, D.C., Eric Meggers of the University of Pennsylvania demonstrated that simple metal complexes could replicate the unique activities of natural products.

The key to a natural product’s bioactivity often is a defined shape complementing the pocket of a protein, Meggers said. Rigid, defined shapes, he showed, are easily achieved with complexes built from a central metal core. Several ruthenium complexes his group has designed to mimic the shape of staurosporine have proven to be potent and selective inhibitors of protein kinases, including glycogen synthase kinase 3.

GSK-3 is part of a signaling pathway that is involved in the formation of the body axis in frog embryos, Meggers explained. A second body axis develops when GSK-3 is inhibited. Indeed, when the GSK-3-inhibiting ruthenium complex was injected into a developing frog embryo, it developed into a two-headed tadpole, he said.

That experiment, Meggers noted, verifies that the metal complex works in a biological environment with no obvious effect on cells or organisms other than what is expected when it hits its intended target. This point is important, he told C&EN, because metal-containing compounds for therapeutics are perceived to be high risk. Although Meggers is not necessarily looking for therapeutic agents, he believes that metal complexes with defined shapes have therapeutic potential.

Meggers said his approach of “morphing natural products into metal complexes” is validated by its inclusion in Penn’s Center for Molecular Discovery, part of the National Institutes of Health’s initiative to support discovery of molecular probes. At the moment, his group participates by taking initial hits from the screening of organic-compound libraries and improving their properties by transforming them into rigid metal complexes.