Researchers from Purdue University and the Scripps Research Institute have successfully synthesized a compound known as curcusone D. The compound is the first known BRAT1 protein inhibitor, which regulates DNA damage response and repair in cancer cells. However, the compound is found in nature at very low concentrations, limiting the therapeutic research around it and subsequent pharmaceutical manufacturing into a commercially available drug.
Occurring naturally in Jatropha curcas, a shrub common in tropical and sub-tropical climates, curcusone D has been found to be highly efficacious in breast cancer, but has the potential to be effective against brain, colorectal, prostate, lung and liver cancers as well.
“Our compound can not only kill these cancer cells, it can stop their migration,” Dai said. “If we can keep the cancer from metastasizing, the patient can live longer,” explains Mingji Dai, professor of chemistry, Purdue University Center for Cancer Research. “In nature, the plant doesn’t produce a lot of this compound,” Dai said. “You would need maybe as much as 100 pounds of the plant’s dry roots to get just about a quarter teaspoon of the substance — a 0.002% yield. “That’s why a new synthesis is so important,” Dai continues. “We can use the synthesis to produce more compounds in a purer form for biological study, allowing us to advance the field. From there, we can make analogues of the compound to improve its potency and decrease the potential for side effects.”
Further testing is required to determine if the compound has manageable toxicities in humans, although researchers are optimistic as the shrub that the compound is found naturally in has been used medicinally in various cultures. “Many of our most successful cancer drugs have come from nature,” Dai says. “A lot of the low-hanging fruit, the compounds that are easy to isolate or synthesize, have already been screened and picked over. We are looking for things no one has thought about before. Once we have the chemistry, we can build the molecules we’re interested in and study their biological function.”
Cui C et al., Total Synthesis and Target Identification of the Curcusone Diterpenes. J Am Cem Soc. 2021; 143(11): 4379-4386.