Engineers know that the most stable, rigid shape is a triangle. That’s why you see it in bridges, rooftops, geodesic domes – and as a backbone for new drug molecules.
To visualize the shape of molecules, chemists make three dimensional models by connecting balls with sticks. In these colorful sculptures, it seems as if each atom, or ball, is glued in place.
Actually, molecules are flexible. Some even bend and rotate like Olympic gymnasts. But this flexibility can be a problem. For example, drug molecules are designed to have a specific shape so that they can bind to “docking” sites within the body. If a drug molecule bends or twists, it may no longer bind properly to its target.
Michael Rubin, assistant professor at the Center for Environmentally Beneficial Catalysis (CEBC), is working on a solution to this problem. He creates new drug candidates by building on a rigid molecule called cyclopropane. The molecule is a cousin to propane, the fuel used to fire-up your outdoor grill. While propane has a chain of three carbon atoms, in the cyclopropane molecule, the chain is fixed into the shape of a triangle.
The three blackball carbons of cyclopropane shown above define a plane, or flat surface. Six chemical groups (white balls), three above the plane and three below, can be attached to the carbons in cyclopropane. “The rigid shape of the triangle controls the spatial distance between these added groups,” said Rubin.
Using a novel method (see below) and advanced catalysts, Rubin’s team can reliably make a wide-array of molecules with extremely well-defined three-dimensional structures. The central cyclopropane backbone simply holds everything in place. This helps these molecules retain their shape to fit the chemical’s target docking site.
The resulting molecules are screened for biological activity as medicines, pesticides, etc. The beauty of Rubin’s process is that it can create compounds that simulate the precise geometry of biological targets. This is why these compounds may have potent effects on diseases such as viral infections and malaria.
Rubin's method for modifying cyclopropane:
First, bromocyclopropane is converted into cyclopropene, a highly strained ring with a double bond between two of the carbons. This intermediate structure is full of potential energy, like a hand grenade. All this stored energy helps it more easily react with other chemical groups, as published in Alnasleh, BK; Sherrill, WM; Rubina, M; Banning, J; and Rubin, M. “Highly Diastereoselective Formal Nucleophilic Substitution of Bromocyclopropanes” J. Am. Chem. Soc. 2009 131, 6906–6907, http://pubs.acs.org/doi/pdf/10.1021/ja900634m.
Recently, Rubin’s group demonstrated that it could use a rhodium catalyst to attach a formyl group to cyclopropene. This exciting result is the “first catalytic hydroformylation of cyclopropenes,” said Rubin. The formyl group is famous for the manifold transformations it will undergo. This creates the potential for using the cyclopropane platform to build many new synthetic compounds (see previous news article).
-- Story by Claudia Bode