New synthesis strategy speeds identification of simpler versions of a natural product
Researchers are careful that their research has only led to potential drug prospects rather than drug discovery, and that possible applications would probably be many years and would require a in-depth development by pharmaceutical companies. But research is important because the strategy to reach these drug leads has the potential to drastically reduce the time it takes to move from an initial complex natural product to mature simplified versions for further development.
The pilot study for this new approach began with gracilin a, a natural product derived from a sea sponge, which other researchers had found to have medicinal potential, but lacked detailed structure and bioactivity relationships, said lead author Daniel Romo, Ph.d., Professor of chemistry at the Schotts at Baylor College of Arts & Sciences.
The streamlined synthetic method-called "Pharmacophore-led retrosynthesis" (PDR)--is "like the difference between building an eight-storey building when everything you need can be a six-or seven-storey building," a said Romo. A Pharmacophore is the minimum structure required for the activity of a bioactive molecule.
Romo compares his synthesis group with molecular engineers who build molecules rather than buildings.
"We thought," why not find a hypothesis about what might be essential for bioactivity, integrate this minimal structure into our first floor plans, and then gradually build the rest of the natural product, floor by floor, while carrying out biological activities studies on each floor on the way up to the upper floor? "Romo says.
The long-term goal is the faster identification of simpler versions of the natural product that conserve the bioactivity of interest. This can be done on the way to synthesize the more complex natural product target "by stopping and looking at what is on the fifth, sixth and seventh floors on your way up to the top floor," said Romo.
This could greatly reduce the time to identify useful compounds derived from natural products, which could also have an impact on the cost of drugs.
Chemists from Baylor University, the Universidad de Santiago de Compostela in Lugo, Spain, and the University of Aberdeen in Aberdeen, Scotland, have used the PDR to identify several derivatives of graciline A which, unlike the natural product itself, were found to selectively bind one of the two closely related proteins, cyclophilin A (CypA) and cyclophiline D (CyPh).
CypA is involved in the immune response, and inhibition of this target protein leads to immunosuppression, an essential activity to prevent organ transplant rejection. CyPh is involved in aberrant cellular processes that are involved in neurodegenerative diseases, such as Alzheimer's disease and atherosclerosis.
Romo said he hopes that pharmaceutical companies will find the PDR strategy attractive and once again look at natural products as tracks for drug discovery in addition to the more traditional approaches currently Practiced.
"The PDR could mitigate some of the concerns related to the complexity of natural products, which has contributed to the decline of natural products as starting points for drug discovery in the first place," said Mr. Romo.
This research was supported by a grant (MERIT Award R37 GM052964) from the Institute of General Medical Sciences of the national institutes of health.
