2-DIMENSIONAL PARALLEL ARRAY TECHNOLOGY AS A NEW APPROACH TO AUTOMATED COMBINATORIAL SOLID-PHASE ORGANIC-SYNTHESIS

An automated, 96-well parallel array synthesizer for solid-phase organ ic synthesis has been designed and constructed. The instrument employs a unique reagent array delivery format, in which each reagent utilize d has a dedicated plumbing system. An inert atmosphere is maintained d uring all phases of a synthesis, and temperature can be controlled via a thermal transfer plate which holds the injection molded reaction bl ock. The reaction plate assembly slides in the X-axis direction, while eight nozzle blocks holding the reagent lines slide in the Y-axis dir ection, allowing for the extremely rapid delivery of any of 64 reagent s to 96 wells. In addition, there are six banks of fixed nozzle blocks , which deliver the same reagent or solvent to eight wells at once, fo r a total of 72 possible reagents. The instrument is controlled by sof tware which allows the straightforward programming of the synthesis of a larger number of compounds. This is accomplished by supplying a gen eral synthetic procedure in the form of a command file, which calls up on certain reagents to be added to specific wells via lookup in a sequ ence file. The bottle position, flow rate, and concentration of each r eagent is stored in a separate reagent table file. To demonstrate the utility of the parallel array synthesizer, a small combinatorial libra ry of hydroxamic acids was prepared in high throughput mode for biolog ical screening. Approximately 1300 compounds were prepared on a 10 mu mole scale (3-5 mg) in a few weeks. The resulting crude compounds were generally >80% pure, and were utilized directly for high throughput s creening in antibacterial assays. Several active wells were found, and the activity was verified by solution-phase synthesis of analytically pure material, indicating that the system described herein is an effi cient means for the parallel synthesis of compounds for lead discovery . (C) 1998 John Wiley & Sons, Inc.