Team leader Karl Scheidt, assistant professor of chemistry at the Weinberg College of Arts and Sciences, has already started evaluating compounds based on these so-called flavonones in cell cultures and mice, with the goal of developing targeted therapies for prostate cancer.

While the potential health benefits of flavonoids, a large family of polyphenolic compounds found in plants, have been much discussed, more easily synthesised forms such as isoflavones are "devoid of stereochemistry" and hence more limited in their therapeutic scope, Scheidt explains.

"With complexity comes opportunities," he notes.

Flavonones are chiral molecules but organic chemists have struggled for years to develop a means of asymmetric synthesis that will produce a 'one-handed' or single-enantiomer version. At the same time, the trend in oncology in particular has been towards either combination therapies or more selective compounds that bind more effectively to their target and avoid potentially toxic effects on healthy cells.

Since the body itself is chiral, there is a strong rationale for developing molecules that can be programmed "to fit a single space", Scheidt comments. Moreover, he adds, the US Food and Drug Administration (FDA) now requires a single-isomer version of a molecule if it comes in chiral form.

Flavonoids in general have only "modest activity", Scheidt says, yet previous efforts to produce more effective analogues have been "cumbersome and circuitous", with "many, many steps" on the road to synthesis.

After trying out some 30 to 40 chiral catalysts under different conditions over a period of six months, Scheidt and his team hit on a quinine-based catalyst that, through hydrogen bonding, can isolate single-isomer flavonones from natural sources such as milk thistle, soy, grapefruit and kosam, a root used in traditional Korean medicine.

The work is described in the April issue of the Journal of the American Chemical Society (JACS). The research team used a bifunctional quinine-derived thiourea catalyst to activate a ß-ketoester alkylidene substrate and promote the conjugate addition of a phenol to deliver enantioenriched flavonones and chromanones.

"Our preliminary understanding of this reaction invokes hydrogen bonding between the ß-ketoester substrate and chiral thiourea," the authors commented. "The interaction between the quinuclidine nitrogen and phenol then promotes the selective intramolecular conjugate addition. Importantly, tertiary amine and thiourea functional groups together in a single catalyst deliver high selectivity."

The Northwestern University team synthesised 10 different types of flavonone and Scheidt is now investigating them as potential anticancer compounds in collaboration with Raymond Bergan, associate professor of haematology and oncology at the university's Feinberg School of Medicine. While the flavonones have many other potential applications beyond oncology, such as asthma, the near-term target is prostate cancer, the number two cause of cancer-related deaths in men in the US after lung cancer.

For the next year or two the researchers will be focusing on developing the effective compounds in the laboratory, but in two to five years "we may know how we can run with it", Scheidt commented.