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NEWS OF THE WEEK
COMBINATORIAL CHEMISTRY
March 18, 2002
Volume 80, Number 11
CENEAR 80 11 p. 11
ISSN 0009-2347
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ALL-IN-ONE LIBRARY EVALUATIONS
Identity, purity, and concentration determined in a single experiment

STU BORMAN

A new system has been developed for evaluating, in a single experiment, the identity, purity, and concentration of combinatorial library compounds made by parallel synthesis.

In the system, high-performance liquid chromatography (HPLC) separates components of synthetic samples that are arrayed on microtiter plates. The eluent is first analyzed by a UV-visible photodiode array (PDA) detector and is then directed to three other analyzers--an evaporative light-scattering detector (ELSD), a chemiluminescent nitrogen detector (CLND), and a time-of-flight mass spectrometry (TOFMS) unit.

The approach was developed by analytical chemists David A. Yurek and Ming-Shang Kuo and information scientist Derek L. Branch of the Discovery Technologies unit at Pharmacia Corp. [J. Comb. Chem., 4, 138 (2002)].

It was devised to solve a common parallel synthesis problem: Target compounds are produced in a range of yields and purities, making it difficult to screen them for biological activity.

Scientists generally address this problem by purifying samples before screening or by characterizing "hits" after screening. But both approaches can be time-consuming and inefficient. The Pharmacia technique identifies library compounds and determines their purity and concentration in one procedure, potentially speeding combinatorial studies.

One of its advantages is that TOFMS has high mass accuracy, making it possible to rigorously confirm a library compound's exact molecular formula and to identify synthetic impurities and side products mixed in with it. And CLND can determine the concentration of any nitrogen-containing compound, without any need for comparison with primary standards, if the compound's molecular formula is known from the TOFMS step.

"Parameters like identity, purity, and concentration are crucial to define the quality of a combinatorial library, and the quality of a library is absolutely essential for the success of biological screening," comments Bing Yan, director of analytical sciences at the ChemRx division of Discovery Partners International. The Pharmacia system "has streamlined the processes of obtaining all these important parameters into a single measurement. This technology and any modified and derivative versions will make a great impact on the advance of combinatorial synthesis."

Several other groups have developed quantitative HPLC detector systems for combinatorial applications. For instance, analytical chemist Eric W. Taylor and coworkers at Chiron Corp. devised a technique for characterizing libraries using HPLC with CLND, UV-Vis, and ion-trap MS detection [Anal. Chem., 70, 3339 (1998)]. And a group including Nikhil Shah and William L. Fitch at Affymax Research Institute reported a similar approach for characterizing combinatorial libraries [J. Comb. Chem., 2, 453 (2000)]. However, the system reported by Kuo's group "is the most comprehensive one so far," Yan says.

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