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Researchers at Stanford University have discovered a rapid, sustainable way to synthesize a promising cancer-fighting compound
in the lab.
The compound's use is limited because the only known natural source is a plant that grows only in a small rainforest region in
northeast Australia.
The compound, named EBC-46 and technically known as tegilanotigate, works
by promoting a local immune response to tumors.
This reaction ruptures the tumor's blood vessels, eventually killing the tumor's cancer cells
.
EBC-46 recently entered human clinical trials because of its extremely high success rate
in treating one type of cancer in dogs.
However, given the complex structure of EBC-46, it seems impossible to synthesize, meaning that there does not seem to be a viable way
to actually produce it in the laboratory.
However, thanks to an ingenious process, researchers at Stanford University demonstrated for the first time how to chemically convert a rich plant-based starting substance into EBC-46
.
As a bonus, this process could produce EBC-46 "analogues"—chemically similar compounds, but it could prove more effective and have the potential to treat a surprising
wide range of other serious diseases.
These diseases, including AIDS, multiple sclerosis and Alzheimer's disease, share a common biological pathway and are influenced by EBC-46's target, a key enzyme
called protein kinase C (PKC).
"We are very excited to report the first scalable synthesis of EBC-46," said Paul Wind, professor of chemistry and professor of chemistry and systems biology at Stanford University and professor of chemistry and systems biology in the College of Humanities and Sciences
.
"Being able to make EBC-46 in the lab really opens up tremendous research and clinical opportunities
.
"
The study's co-authors are Zachary Gentry, David Fanelli, Owen McAteer and Edward Njoo, all doctoral students in Wende's lab, and former member Quang Luu-Nguyen
.
Wende expressed the team's great satisfaction with the breakthrough in the synthesis of EBC-46
.
"If you visit the lab in the first few weeks after their success," Winder says, "you'll see my wonderful colleagues smiling out loud
.
" They are able to do things that
many people think are impossible.
”
Tigilanol tiglate was first discovered through QBiotics' automated drug candidate screening process
.
In nature, this compound appears in
the seeds of the pink fruit of the mahogany tree (Fontainea picrosperma).
Marsupials such as musk kangaroos eat mahogany fruit and avoid seeds rich in tiger squal alcohol, which can cause vomiting and diarrhea
when ingested.
Injecting small doses of EBC-46 directly into some solid tumors can alter the cell signaling
of PKC.
Specifically, EBC-46 is thought to activate certain forms of PKC, which in turn affect the activity of various proteins in cancer cells, causing an immune response
from the host body.
The resulting inflammation leaks the tumor's blood vessels, and this bleeding causes the tumor to grow and die
.
In the case of external, cutaneous malignancies, the tumor crusts and falls off, while the method of delivery of EBC-46 to the internal tumor is being studied
.
In 2020, both the European Medicines Agency and the U.
S.
Food and Drug Administration approved an EBC-46-based drug for sale under the brand name Stelfonta for the treatment of mast cell carcinoma
, the most common skin tumor in dogs.
One study showed a cure rate of 75% for a single injection and 88%
for a second injection.
Since then, clinical trials have begun
for human skin, head and neck and soft tissue cancers.
Based on these emerging research and clinical needs, coupled with the geographical limitations of sourced seeds, the scientists considered establishing dedicated plantations
for redwood trees.
But doing so brings its own set of problems
.
First, the trees need to be pollinated, which means there must be the right kinds of pollinators on hand, and the trees must be planted at the right density and distance to aid pollination
.
In addition, changes in seasons and climate can affect trees, as well as pathogens
.
Leaving aside land for rosewood further creates land use problems
.
"In order to produce EBC-46 sustainably and reliably in the quantities we need, we really need to go the synthetic route
," Winder said.
Wende and his colleagues realized that a good starting point for making EBC-46 was the plant-derived compound phorbol
.
More than 7,000 plants worldwide produce xyloxyl derivatives, and seeds rich in dichoxyl are commercially cheap
.
The researchers chose Barodong, commonly known as Epsom Barodong, an herb
used in traditional Chinese medicine.
Windle explained that the first step in preparing EBC-46 is consistent
with everyday experience.
Winder said, "You buy a bag of these seeds, it's
like making coffee in the morning.
" "You grind the seeds, pass them through them with some hot solvent, extract the active ingredient," in this case, a phosphorus-rich oil
.
After processing the oil into phorbol, the researchers had to figure out how to overcome the previously insurmountable challenge of carefully placing oxygen atoms
on a part of the molecule called the B-ring.
This is necessary
for EBC-46 to interact with PKC and modify enzyme activity in cells.
To guide their chemistry and biology research, the researchers rely on the Stanford Neuroscience Microscopy Service, the Stanford Cancer Institute Shared Proteomics/Mass Spectrometry Resource, and the Stanford Sherlock Cluster of Computer Modeling Instruments
.
With this guidance, the team succeeded in adding additional oxygen atoms to Phorbol's B-ring, first under flow conditions through a so-called ene (pronounced "een") reaction, in which the reactants are mixed
in a pipeline.
The team then introduced other B-ring groups in a step-by-step, controlled manner to obtain the desired atomic spatial arrangement
.
In general, obtaining an analogue of EBC-46 requires only 4 to 6 steps, and obtaining EBC-46 itself requires 12 steps
.
Wende hopes that the broader range of EBC-46 and its close cousins that affect pkc provided by this breakthrough approach will accelerate research
into potentially revolutionary new therapies.
"As we learn more about cell function, we also learn more about how to control that function
," Winder said.
"This control of function is especially important
when dealing with cells that are out of control in diseases ranging from cancer to Alzheimer's.
"
Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues
