Guiry's research group synthesized novel lipoxin-based molecules. The belief was that an analog could be synthesized with the potency of the lipoxins, but with improved chemical stability. "The challenge is to protect the molecules from the enzymes without altering their biological activity," he explained.

With this goal, the group identified the region of the molecule essential for its biological function and tailored the nonessential region to make it evade enzymatic degradation. The strategy was that the novel molecules would retain the functions of Lipoxin A4 and Lipoxin B4, while the metabolic reactions that break the molecule down would be blocked, according to the release.

The research team used Sharpless epoxidation, Heck coupling, and diastereoselective reduction to synthesize a new set of lipoxin analogs. The analogs maintained the active carboxyl and hydroxy region of the lipoxins, but contain an aromatic ring in the part responsible for the metabolic activity (3, 4).

Further modification may increase the potency of the analogs by blocking other metabolic pathways. "Work is underway on the synthesis of other analogs and their subsequent biological evaluation. "Several chronic inflammatory conditions may be amenable to therapeutic intervention by stable synthetic lipoxin analogs," he said.

Bayer Schering Pharma (Berlin, Germany), for example, has a lipoxin molecule in early-stage clinical development to treat inflammatory bowel disease.

Antibiotics

Earlier this year, researchers at the Scripps Institution of Oceanography at the University of California at San Diego and the Skaggs School of Pharmacy and Pharmaceutical Sciences reported success in synthesizing an antibiotic. Natural product sources typically have complex molecular structures that make them difficult to synthesize. The research focused on taking the enzymes that produce these chemicals inside cells and mimicking this process outside of a cell. The research carries the potential to develop new drugs by combining certain natural enzymes to produce new molecules that typically cannot be found in nature.

Qian Cheng and Bradley Moore of Scripps were able to synthesize an antibiotic that is naturally produced by a Hawaiian sea-sediment bacterium, according to a September 2007 press release. Specifically, the researchers reported the multienzyme total synthesis of the Streptomyces maritimus enterocin and Wailupemycin bacteriostatic agents in a single reaction vessel from benzoate and malonate substrates. The researchers believe that their results represent the first in vitro assembly of a complete Type II polyketide synthase enzymatic pathway to synthesize natural products (5).

"This study may signal the start of a new era in how drugs are synthesized," said Moore, a professor in the Center for Marine Biotechnology and Biomedicine at Scripps. "Assembling all the enzymes together in a single reaction vessel is a different way to make a complex molecule."

The antibiotic synthesized, enterocin, was assembled in approximately two hours. Such a compound would normally take months if not a year to prepare chemically, according to Moore.

Asymmetric synthesis

Asymmetric chemocatalytic methods, such as asymmetric hydrogenation, is an important tool to synthesize single enantiomer compounds. There are in excess of 3000 ligands known for asymmetric hydrogenation processes, although only a portion are truly available on a kilogram scale within a reasonable time frame (6). Several drugs recently approved by FDA are reported to use asymmetric hydrogenation in their manufacture. These include "Rozerem" (ramelteon) and "Aptivus" (tipranavir), both approved in 2005, "Januvia" (sitagliptin), approved in 2006, and "Tekturna" (aliskiren), approved in 2007 (6).