A new synthesis strategy accelerates the identification of simpler versions of a natural product
A new chemical synthesis strategy to gather the rich information contained in natural products - organic compounds isolated from natural sources - has led to the identification of new, simpler derivatives capable of selectively protecting neurons, important for neurodegenerative diseases such as Alzheimer's disease, or preventing the immune system from rejecting organ transplants, according to a study conducted by Baylor University.
The study is published in the journal Nature Chemistry.
The researchers warn that their research has only led to potential leads rather than drug discovery and that it will probably take many years before they can be applied and that pharmaceutical companies will have to develop them on a large scale. But research is important because the strategy to reach these drug leads has the potential to significantly reduce the time it takes to move from an initial complex natural product to simplified versions that are ripe for further development.
The pilot study of this new approach began with graciline A, a natural product derived from a sea sponge, which other researchers had discovered as having medicinal potential, but whose detailed structure and bioactivity relationships were lacking," said Daniel Romo, PhD, lead author, Professor of Schotts Chemistry at the College of Arts & Sciences in Baylor.
The simplified synthetic method known as "pharmacophore-directed retrosynthesis" (PDR) is "like the difference between the construction of an eight-storey building and that of a six or seven-storey building," Romo said. A pharmacophore is the minimum structure required for the activity of a bioactive molecule.
Romo compares his synthesis group to molecular engineers who build molecules rather than buildings.
"We said to ourselves:'Why not make a hypothesis about what could be essential for bioactivity, integrate this minimal structure into our first floor plans, then gradually build the rest of the natural product, floor by floor, while conducting biological studies on each floor up to the top floor?" Romo said.
The long-term objective is to identify more quickly the simpler versions of the natural product that maintain the bioactivity of interest. This can be done on the way to synthesizing the more complex target of natural products "by stopping and looking at what is on the fifth, sixth and seventh floors on the way to the top floor," Romo said.
This could significantly reduce the time required to identify useful compounds derived from natural products, which could also have an impact on drug costs.
Chemists from Baylor University, the University of Santiago de Compostela in Lugo, Spain, and the University of Aberdeen in Aberdeen, Scotland, have used PDR to identify several gracilin A derivatives which, unlike the natural product itself, selectively bind to one of the two closely bound proteins, cyclophilin A (CypA) and cyclophilin D (CypD).
CypA plays a role in the immune response, and inhibition of this target protein leads to immunosuppression, an essential activity to prevent organ transplant rejection. COPD is involved in aberrant cellular processes involved in neurodegenerative diseases, such as Alzheimer's disease and atherosclerosis.
Mr. Romo hopes that pharmaceutical companies will find the PDR strategy attractive and once again turn to natural products as avenues for drug discovery, in addition to the more traditional approaches currently in use.
"The RDP could alleviate some of the concerns related to the complexity of natural products, which has contributed to the decline of natural products as a starting point for drug discovery," said Mr. Romo.
