Using an ancient Chinese folk remedy as a model,
researchers at Johns Hopkins 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 announced their successful results last
week 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. "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
pharmacology at the 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
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 said. "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.