Biotech profile: Novogen

Research into the potential of the plant polyphenols known as flavonoids has been ongoing for decades, particularly for the beneficial biochemical and antioxidant effects the compounds seem to confer.

One particular group within the flavonoid class, the phytoestrogen compounds known as isoflavones, are of particular interest as both nutritional supplements and in therapeutic applications.

Primarily derived from the legume family, there are several main isoflavones of interest to basic researchers and the pharmaceutical world, particularly genistein and daidzein, found in high concentrations in red clover and soya beans.

Not only do isoflavones have oestrogenic activity, and are therefore being used as a dietary supplement for menopausal women, but they seem to have quite pronounced anti-cancer and pro-cardiovascular effects.

Sydney company Novogen has taken a very close look at these compounds and has now developed a technology platform to produce synthetic molecules with highly predictive effects.

Using a quantitative structure activity relationship (QSAR) database, Novogen’s scientists are able to create new molecules by making subtle changes to the structure of their compounds, which result in subtle changes in activity.

When Novogen was set up in 1992, the idea was to use isoflavones in dietary supplements as a first step, with the main game being to manufacture them into therapeutic applications, the company’s director of research, Professor Alan Husband says.

That first step is a going concern: Novogen’s consumer business produces a number of dietary supplements, the lead product being Promensil, an adjunctive treatment for menopause. The consumer business is becoming self-sustaining while the rest of the company gets on with developing new therapeutic applications.

“These isoflavones have oestrogenic activity and therefore can help replace the missing oestrogen in menopause, but that’s only a very small part of what we are now doing,” Husband says.

“We discovered that the naturally occurring isoflavones also have very pronounced anti-cancer activity. If you add these isoflavones to cultures of cancer cells, we found the cancer cells were dying.”

“There is also improved cardiovascular health, and indication of anti-inflammatory activity, so the original proposition was that even though these dietary supplements might be useful, the real opportunity for us was to manufacture totally new flavonoid-type molecules that we’d deduced originally – and now we can actually predict – will have activities in cardiovascular, anti-inflammatory and anti-cancer areas.”

One of the first compounds with anti-cancer potential that Novogen developed was phenoxodiol, which seems to have quite remarkable properties. It works against a broad range of cancers in vitro – in fact, almost every cancer cell line the company tested it against was susceptible – but it has no effect on healthy cells, Husband says.

“We now understand in exquisite detail how that works: it targets the abnormal signal transduction which occurs in cancer cells. The whole hallmark of a cancer cell is that pro-survival mechanisms are upregulated and cell death mechanisms are switched off.

“We found that phenoxodiol and its downstream relatives like triphendiol and some others in the pipeline bind to a surface oxidase that is expressed in a different form on abnormally dividing cells.

“And it’s sufficiently different, both structurally and functionally, to enable us to target that specifically on cancer cells, but it’s not so strongly expressed on healthy cells.

“So this has given us a molecule that is not only very effective in producing an anti-cancer benefit, but it’s proven to be almost entirely safe in clinical use.

“It’s absolutely remarkable, because I think it’s the first time that there has been a relatively safe but apparently effective anti-cancer agent.”

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