PHOTOS.COM/M.MCEVOY, Structures courtesy of US FOOD AND DRUG ADMINISTRATION

Nucleoside analogs

Nucleoside analogs have provided a rich structural class for the design of novel anticancer and antiviral drugs. "Leustatin" (cladribine) by Ortho Biotech and "Fludara" (fludarabine phosphate), developed by Berlex Oncology and now owned by Bayer Healthcare (Leverkusen, Germany), are two members of that class that were evaluated as potential anticancer agents. "While these were exciting discoveries, there was some initial concern in the discovery community that the glycosidic bond of those agents might prove too labile for ultimate utility in the clinic," explains Stephen Munk, president and CEO of Ash Stevens (Detroit, MI). Ash Stevens is the contract manufacturer of fludarabine phosphate, the API in Fludara. While both of these agents were subsequently approved as drugs by various regulatory agencies, including the USFood and Drug Administration, that concern led scientists at the Southern Research Institute in Birmingham, Alabama, to consider analogs that would retain activity while affording a chemical structure with a glycosidic bond with enhanced stability, says Munk. Those studies led to the discovery by Secrist and Montgomery of a nucleoside analog now known as clofarabine (1).

Figure 1 ALL Figures Courtesy of US Food and Drug Administration

Clofarabine is a second-generation adenosine-related antimetabolite. The original synthesis of clofarabine involved chromatography and was not adequately cost-effective or scalable. The task for improving the synthesis was to develop a new process that would avoid chromatography, produce a drug substance of high purity, and improve the cost-effectiveness of the manufacturing process (2).

Workers at Ilex Oncology (now part of Genyzme) and Ash Stevens developed a very efficient process that proved quite scalable (2). That process involved preparing a suitably protected bromosugar and coupling with chloroadenine in the presence of potassium tert-butoxide to afford protected clofarabine that had excellent anomeric purity following crystallization, explains Munk. Subsequent deprotection and further crystallization afforded clofarabine drug substance with minimal α-anomer as an impurity. "The process proved scaleable and avoided chromatographic purification steps, which can be very costly at plant scale," says Munk. Ash Stevens successfully commercialized the process.

Lipoxins

Early this year, the Centre for Synthesis and Chemical Biology in Ireland reported progress in synthesizing novel lipoxin-based molecules that may be used as anti-inflammatory agents. The Centre for Synthesis and Chemical Biology is a collaboration in the chemical sciences between University College Dublin (UCD), Trinity College Dublin (TCD), and the Royal College of Surgeons in Ireland (RCSI). The UCD center forms part of the UCD Conway Institute of Biomolecular and Biomedical Research.

Lipoxins were first isolated in the 1980s. These molecules appear at the site of inflammation, leading researchers to believe that they are involved in the process and thus may have potential therapeutic applications. Some of the beneficial action ascribed to aspirin is now believed to be due to the formation of lipoxins. Both Lipoxin A4 and Lipoxin B4 have been detected in a variety of inflammatory conditions.

"Lipoxins have been shown to promote phagocytosis of the neutrophils," said Pat Guiry, professor of organic chemistry at the UCD School of Chemistry and Chemical Biology, in an April 2007 press release. Reducing the number of neutrophils reduces the inflammation. "However the therapeutic potential of lipoxins is limited by reactions with enzymes in our bodies which break them down."