Photo courtesy of Jeff Fitlow
and Rice University
Researchers say they have streamlined synthesis of delta12-prostaglandin J3, a molecule that has been shown to kill leukemia cells.
Total synthesis of the molecule now requires only 6 steps from commercially available starting materials.
The researchers say this work sets the stage for large-scale synthesis of the molecule—a lipid found in nearly all animal tissues—and related compounds that can be produced as potential anticancer agents.
K.C. Nicolaou, PhD, of Rice University in Houston, Texas, and his colleagues described the work in Chemistry - A European Journal.
The prostaglandin the researchers synthesized had been isolated in 2011 as a secondary metabolite formed from eicosapentaenoic acid, which is found primarily in fish oil.
The team reported the first total synthesis of the molecule in 2014. That allowed them to confirm its structure.
Now, the researchers have established techniques to develop related disease-fighting compounds and ramp up bulk production if necessary.
Several such prostaglandin derivatives under consideration as preclinical drug candidates were detailed in a second paper published in the Journal of the American Chemical Society.
That publication described the synthesis of dozens of prostaglandin derivatives that were tested against a range of cancer cells by the National Cancer Institute.
One such derivative, macrolactone 11, is currently under evaluation as a preclinical drug candidate. Related compounds macrolactone 33 and 44 showed evidence of even higher potency against leukemia, lung cancer, colon cancer, melanoma, renal, and prostate cancer.
“The macrolactones are very good—better than the natural product—and now we’re following this lead to optimize the potency while minimizing toxicity,” Dr Nicolaou said. “It’s a balancing act.”
In addition, he and his colleagues are developing other drug candidates based on prostaglandin.
“In the process, we’ve developed a lot of nice chemistry, and we know a lot more about the biology of this compound,” Dr Nicolaou said. “We’ve advanced organic synthesis in general and also enriched the knowledge about how these kinds of molecules behave. We hope the papers provide some ideas and leads and inspiration for others to follow.”
