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New Compounds Show Promise in Fighting Malaria and Cancer


Using an ancient Chinese folk remedy as a model, researchers at The Johns Hopkins University in Baltimore have designed several new compounds that, in early testing, promise to be both safer and more effective in fighting malaria and some forms of cancer than the current “gold standard” drug treatments.

Scientists will announce their successful results in late August at the American Chemical Society’s annual summer meeting, held this year in Philadelphia. Some of the results also appeared in the January 2004 issue of the Journal of Medicinal Chemistry. “Preliminary data show that our laboratory-synthesized compounds have a therapeutic index – the measure of a drug’s safety and efficacy – that is better, in some cases, many times better, in rodents than the drugs currently considered the gold standard for chemotherapy of both malaria and prostate cancer,” said Gary Posner, Scowe Professor of Chemistry in the Krieger School of Arts and Sciences at Johns Hopkins. “These results are preliminary, but exciting, and certainly worth pursuing.”

Malaria afflicts between 300 million and 500 million people a year, killing between 1.5 million and 3 million of them – mostly children. Spread by female mosquitos feeding on human blood, the most commonly fatal strain of the malaria parasite began showing formidable resistance to current treatments decades ago, making the development of new and more effective drugs a worldwide priority.

With support from the National Institutes of Health since 1994, Posner’s research team, which also includes Theresa Shapiro, professor of clinical pharmacology at the Johns Hopkins School of Medicine, tackled that challenge by designing a series of compounds called trioxanes. These compounds are aimed at mimicking the mechanism of action of artemisinin, the active agent in the Artemisia annua plant, which has been used in China as an herbal remedy for malaria and other fevers for thousands of years.

Posner’s research and that of other laboratories revealed that the peroxide (oxygen-oxygen) unit within artemisinin and within other antimalarial trioxane drugs causes the malaria parasites to self-destruct. “We know that the malaria parasites digest hemoglobin in order to get nutrients, and in the process they release heme,” Posner explained. “When the heme encounters the peroxide bond, a chemical reaction occurs. Powerful chemical species such as carbon-free radicals and oxidizing agents are produced, harming and eventually killing the parasites.”

In the laboratory, several of the Posner trioxane compounds were compared against sodium artesunate – the gold standard for malaria treatment – in rodents. Administered intravenously, two of the new compounds outperformed the gold standard. “One was six or seven times better, and the other was three or four times more effective, which is substantial,” Posner said. “What’s more, when the trioxanes were administered orally, it was found that one of ours is four times more effective. That’s significant.”

Lab testing also revealed that at least one of the trioxane compounds – known as compound 7 – seems to be even safer than sodium artesunate. Testing of the Johns Hopkins trioxanes in rodent models for human prostate cancer in collaboration with the Roswell Park Cancer Institute in Buffalo, N.Y., was equally encouraging to the researchers, who are promoting the compounds as dual-use drug candidates.

In that laboratory, researchers pitted the potency of the trioxane compounds against two gold standard anticancer drugs, Gemzar and Adriamycin. They found that while trioxane compound 6 was comparable to the cancer-fighting action of Adriamycin, compound 5 appears to be nearly three times more powerful than that drug. “Our learning from this is that trioxane dimers 5 and 6, and especially 6, are exciting not just for their antimalarial potential, but also for their anticancer potential,” Posner said.

| newswise
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