Y. scientists improve drug synthesis

A team of Brigham Young University researchers has come up with a more efficient way to synthesize the drug cladribine, the treatment of choice for certain "hairy cell" leukemias and a drug that is about to be tested as a possible treatment for multiple sclerosis.

The finding was published this fall in the Journal of Organic Chemistry.

It's a process that has a satisfying full-circle quality to it for the professor who led the effort to make the compound more efficiently. Morris J. Robins, the J. Rex Goates Professor of Chemistry at BYU, was the first individual to make the cladribine compound, back in the 1960s when he was a graduate student. But testing at the time by the National Cancer Institute and others "didn't find enough promise," and the compound languished for at least a decade until a doctor at Scripps Institute in San Diego discovered that the drug, used in very small doses, had potent activity against several leukemias and lymphomas, in some cases even prompting remissions. A quarter-century ago, one of Robins' second cousins, a BYU professor named Roland K. Robins, came up with an improved way to make cladribine.

The new manufacturing process marks a further refinement. Only this time, says Robins, they can make the compound without creating a lot of the extraneous by-product that had to be separated and disposed of as worthless.

Besides treating some cancers, cladribine has been tried in various ways, says Robins — including recently gaining "fast-track" approval by the Food and Drug Administration for Serono to test its new oral cladribine treatment for MS.

"It would be very exciting if they have found ways to treat MS patients, because it's such a debilitating condition," Robins says. MS affects about 2 million people worldwide.

Using the new process developed by Robins and graduate student Minghong Zhong and postdoctoral fellow Ireneusz Nowak, the BYU team has been able to "make the starting material for the cladribine synthesis simply, from readily available materials," Robins says. There are two parts to the molecule, one a heterocyclic base, the other the sugar. To make cladribine, the two have to be coupled together. But if the two parts are not perfectly positioned, useless compounds are also created. And the better the positioning of the two, the more pure the cladribine production, without all that useless excess. BYU researchers can now attach the heterocyclic base to the sugar at least 98 percent in the correct manner, while the attachment of the sugar to the base is perfect. Under the old method BYU had licensed to pharmaceutical companies, 10-15 percent of the positioning was wrong, leading to the need to separate out the cladribine and dispose of everything else that was created.

University of Utah professor of medicinal chemistry and associate dean for research Arthur D. Broom hailed the new process as "a novel, relatively inexpensive and highly specific way" to eliminate production of the by-products, helping keep drug-production costs reasonable.

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