Chemical fast-track could speed up nitrile drug synthesis
The new synthetic pathway is based on the conversion of carbon-hydrogen bonds into nitriles and could make it possible to make bioactive molecules from "abundant organic molecules," say the researchers.
Nitrile-containing compounds are a staple of the pharma industry because they tend to be stable and have good biocompatibility, and the class includes some widely-used drugs including Novartis' Galvus (vildagliptin) for diabetes and generics such as prostate cancer drug bicalutamide and zaleplon for insomnia.
The new pathway - elucidated by Chinese and US scientists - focuses on the preparation of benzylic nitriles, which are precursors to broad classes of hormones, neurotransmitters, psychoactive and anti-inflammatory drugs
It will "help break the stranglehold of carbon-hydrogen bonds present in the chemical feedstocks used to make bioactive molecules," according to the scientists, who have published the research in Science. Exchanging hydrogen atoms in feedstock molecules for more useful elements is difficult without damaging or destroying the rest of the molecule, they note.
Shannon Stahl of the University of Wisconsin-Madison - who headed the US team - says that being able to selectively functionalise carbon-hydrogen bonds is "one of the holy grails of modern chemistry."
The US group and a team led by Guosheng Liu of the Shanghai Institute of Organic Chemistry (SIOC) note that current methods of making biologically-active molecules are often laborious and create a lot of waste, while the new method removes many intermediate steps.
The method - described as a a copper-catalyzed radical relay pathway - also makes it easier to create chiral molecules, according to the scientists.
Organic compounds tend to exist in chiral or mirror image forms, also known as optical enantiomers. Whether a compound is optically left or right 'handed' has a major impact in the pharmaceutical industry. Today the majority of new drugs being introduced are made in one chiral form.
"The three-dimensional shape and chirality of molecules often correlates with the efficacy or potency of a pharmaceutical," says Stahl.
