Vol 8. Issue 17 / May 19, 2008
Team Devises Innovative Method to Produce Highly Sought-After Drug
By Mark Schrope
A team of Scripps Research Institute scientists has developed an inexpensive and in many ways astonishing new method for economically producing a promising pharmaceutical steroid. The molecule, called cortistatin A, which was isolated in 2006 from a marine sponge discovered over 100 years ago, has shown huge promise for treating conditions ranging from macular degeneration to cancer.
This achievement, reported May 14 by a team led by Scripps Research chemist Phil Baran in an advanced, online issue of the Journal of the American Chemical Society, marks the finish line in a race that saw numerous research laboratories working to accomplish the feat. As with all potential pharmaceuticals, an efficient and economic means of producing cortistatin A is needed to enable research into the drug's effectiveness as a disease treatment, as well as to open the possibility of eventual commercial production.
"Its nice to see that a potentially huge application exists for science that was developed with the sole intention of conducting basic research at the core of organic chemistry," says Baran.
At least 20 other research groups around the world have been developing methods for synthesizing cortistatin A, in part because it has shown strong pharmaceutical potential, but also because its structure is especially challenging to recreate.
From the outset, Baran and his team decided that modifying the commonly available steroid prednisone, which has certain similarities to cortistatin A, would be the best route for synthesis. Baran says prednisone, commonly used as an immunosuppressive drug and to treat inflammation associated with allergies, was attractive not only because it is inexpensive and readily available. He also liked the idea of transforming one of the most abundant steroids on the planet, which was discovered on land, into an exceedingly rare marine-derived steroid.
The team accomplished the remarkable transformation from prednisone to cortistatin-A in just 15 steps. Though this may sound complex, it is exceedingly simple in relative terms for a field in which 30 or more expensive, complex steps are sometimes used to create commercially available drugs. The technique yields a healthy three grams of cortistatin-A from every 100 grams of prednisone, and Baran believes that optimization triple this efficiency will be possible.
"The whole point of this was to study fundamental organic chemistry and really provide some innovative new methods," says Baran, a goal the team has clearly accomplished. At one intermediate step in the prednisone transformation, by forcing the molecule to reversibly bond with itself at certain points, the researchers were able to achieve a critical reaction that makes the later steps yielding cortistatin-A possible. "It has a contorted form at that point that doesn't bear a lot of resemblance to the final product, but the molecule is literally protecting itself," Baran notes.
That protection is a key point, because complex chemical syntheses normally demand the addition of extra molecules called protecting groups that bond to and protect certain sections of the molecule being synthesized from reacting in undesirable ways. This adds not only complexity and time, but also cost to the production of a drug.
Causing the intermediate molecule in the cortistatin-A to protect itself is one way Baran avoided the overuse of protecting groups, allowing him to resort only minimally to this technique in the synthesis.
A cascade of reactions follows the self-protection trick, leading to an intermediate molecule that is just one change away from cortistatin A. The overall synthesis culminates with a precisely targeted conversion of a single hydrocarbon bond on that late intermediate molecule that manages to leave a number of vulnerable components unchanged. This was achieved through the careful selection of chemical reagents and solvents added in a way that exploits slower reaction times with those vulnerable components so that the necessary conversion is done before any unwanted reactions occur. "That part of the synthesis is unique and counterintuitive," says Baran.
Baran is currently focusing on further exploration of related chemistry. The methods he and his team devised for the new synthesis may aid in the development of production methods for a host of other steroids, but Baran is most interested in creating new molecules similar to cortistatin-A, or analogs, that may show useful new biological activity for potential development into new drugs.
Baran says producing a library of analogs should now be relatively straightforward, because one of the intermediate steps in the cortistatin-A synthesis, dubbed cortistatinone, is especially amenable to the addition of a huge range of chemical components. Each such addition could lead to its own pharmaceutically interesting activity. "Adding those other pieces," says Baran, "will be just like putting Legos® together."
In addition to Baran, authors of the paper, "Synthesis of Cortistatin A" are Ryan Shenvi, Carolos Guerrero, Jun Shi, and Chuang-Chuang Li. The work was supported by Amgen, the Beckman Foundation, Bristol-Myers Squibb, DuPont, Merck, Roche, the Searle Scholarship Fund, a Department of Defense pre-doctoral fellowship, and a National Institutes of Health pre-doctoral fellowship. See http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja8023466.html.
The paper is dedicated to Harvard University Professor and Nobel laureate E. J. Corey on the occasion of his 80th birthday.
Send comments to: mikaono[at]scripps.edu
"Its nice to see that a potentially huge application exists for science that was developed with the sole intention of conducting basic research at the core of organic chemistry."