A leading Canadian scientist has developed a synthetic compound that appears to be capable of killing cancer cells while leaving healthy cells intact.
Brock University chemist Tomas Hudlicky has created and patented several variations of the compound pancratistatin, which has been tested on 20 different types of cancer cells by a research team at the University of Windsor. The team’s paper, “Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III,” appeared in the February issue of Scientific Reports.
Scientists have known for some time that pancratistatin (PST), a substance found in the spider lily, causes cancer cells to die. But the low rate of natural production (a kilogram of spider lily produces less than 2 mg of PST) is a major challenge to research and clinical advancement.
Hudlicky is the Tier 1 Canada Research Chair in biocatalysis — the use of biological methods to manufacture chemicals — and one of North America’s top organic researchers. His previous breakthroughs in green chemistry have led to more efficient and environmentally conscious ways to create synthetic versions of morphine and other natural drugs.
He has spent more than 25 years researching PST’s chemical structure and constructing molecules that had similar structures and functions.
“The aim is to make the new and active derivatives available for the manufacture of anti-cancer drugs,” says Hudlicky, a Professor of Chemistry at Brock.
A key part of the construction of new drugs involves manufacturing what are known as “unnatural derivatives” of natural compounds such as PST or narciclasine, a congener of PST that is more available from natural sources. These derivatives are available through chemical synthesis from Hudlicky’s laboratory. What Hudlicky and other chemists do is to artificially enhance a natural compound’s properties through synthesis of derivatives.
The Windsor research team found that Hudlicky’s PST derivatives target a cancer cell’s mitochondria, a structure within a cell responsible for respiration, energy production and cell apoptosis (or programed cell death). Current cancer treatments tend to attack DNA in both cancerous and healthy cells, but mitochondria is specific to each cell and can therefore be more precise as a target.
Hudlicky says it’s still not clear how and why PST brings about cell death, but said some of the new synthetic derivatives made in his laboratory “are actually more potent and more bioavailable than the natural compounds.”
‘Bioavailability’ measures how much of a substance such as a drug is absorbed into a living system and how quickly it is absorbed.
Hudlicky is continuing with research on discovering and manufacturing anti-cancer compounds that can be used in drugs to treat the disease. With funding from the Natural Sciences and Engineering Research Council and a Canadian pharmaceutical company, he is developing derivatives of Amaryllidaceae alkaloids, some of which are isolated from daffodils and snowdrops.
Hudlicky has also formed a partnership with McMaster University chemistry professor James McNulty to develop more compounds that can be used in effective cancer treatment, efficient pro-drug design, and other commercial uses.
McNulty has developed techniques for the isolation of naturally occurring compounds in high yield and also semi-synthesis from natural intermediates and total synthesis of selected alkaloids. In addition to the discovery of compounds that exhibit potent anticancer activity, the Amaryllidaceae framework has allowed the discovery of congeners with potent and selective antiviral activity, for example to herpes viruses (HSV-1 and VZV) and one of the most active compounds reported to date against the Zika virus.
McNulty and Hudlicky together have more than 50 years of experience in the isolation, synthesis and modification of Amaryllidaceae alkaloids. The discovery of other valuable biological activities is under active investigation including many other biomedical and agrochemical applications.