A team at Princeton University has conducted research that may lead to cheaper manufacturing of drugs. Their use of novel compounds as catalysts appears to overcome one of the fundamental problems in producing biologically active chemicals.
Biological systems are sensitive to the way a molecule is structured as well as what it is made of. To illustrate: hold up a hand and extend your thumb and create a loop with your index finger. Think of this as a molecule. Now rotate your hand so the thumb is on top. Although in the composition of our pretend molecule your hand and fingers are the same in either position, in the biological world, only one of those two positions could be a valid drug. The other position would be inactive, or maybe even harmful.
With current technology, synthesizing a drug results in a mixture of molecule orientations. Additional processing must be done to remove the molecules that are "pointed the wrong way" so as to increase the drug's biologic activity or specialized "asymmetric" catalysts must be used to produce the drug with only the correct orientation. These additional steps can be extremely expensive and hard to do since we have very few purification tools that can detect the orientation of a molecule.
The damage the wrong orientation can do was painfully demonstrated by the thalidomide birth defect tragedy of the 1960s. The correctly oriented version of the drug helped pregnant women overcome morning sickness, but its mirror image caused birth defects.
What the Princeton team of David MacMillan, Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong, and Kate Ashton have done is show that by using organic catalysts rather than the classic metal-based catalysts it is possible to synthesize molecules with a preponderance of molecules oriented in a single manner.
Since 2000, MacMillan's team at the Merck Center for Catalysis have been working with a new family of catalysts which produce drugs with the correct orientation in greater purity. These catalysts have proven desirable because they are based on organic substances, and are therefore not harmful either to patients or to the environment. Their work has yielded not merely better catalysts, but whole new types of chemical reactions previously unavailable.
"The big payoff here is that the discovery will allow new chemical reactions to be developed that are powerful yet unprecedented in the field of chemistry," MacMillan said. "They will allow access to correctly structured drugs, and they will do it using cheap, environmentally friendly small organic molecules as catalysts. It's a double whammy."
The paper, "Enantioselective Organocatalysis using SOMO Activation", which MacMillan cowrote with first author Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong and Kate Ashton, all members of his research group, appears in the March 29 issue of the journal Science.