High throughput solid phase chemical synthesis utilizing thin cylindrical reaction vessels useable for biological assay

Abstract

A high throughput chemical synthesis system utilizing cylindrical reaction vessels is disclosed. Reaction vessels are utilized which include a tubular member adapted for placement of electronically readable identifying indicia thereon. The identifying indicia are representative of reaction conditions within the tubular member and of one or more reagents utilized in a reaction within the tubular members. A method of performing chemical synthesis on solid phase reactive material within a plurality of reaction vessels using a plurality of reaction stages resulting in final products and employing identifying indicia representing the reaction stages is also disclosed. The method includes reading the identifying indicia located on the reaction vessels, reacting one or more reagents within the reaction vessels under particular reaction conditions which may be determined by reading the identifying indicia, thereby synthesizing chemical compounds within the reaction vessels. The method allows chemical synthesis to occur according to a predetermined set of reactions and also allows for combinatorial chemistry to be performed utilizing random mix and split techniques. The final synthesized products may be tested for chemical or biological activity. The chemical structures of desired end products may be obtained by reading recorded information wherein the reaction conditions and reagents of reaction steps have been recorded, preferably in conjunction with the identifying indicia.

Description

FIELD OF THE INVENTIONThis invention relates to the field of combinatorial chemistry and, more particularly, to a technique for performing combinatorial chemistry using high throughput solid phase chemical synthesis within a plurality of thin elongate reaction vessels.DESCRIPTION OF RELATED ARTCombinatorial chemistry involves the synthesis of a large variety of chemical compounds from a series of reactions or "chemical recipes". Various combinatorial chemistry techniques have been used to create a large number or library of compounds and these large numbers of compounds can then be screened for various possible biological activities for pharmaceutical, agricultural or other purposes. Typically such a synthesis occurs in successive stages, each of which involves a chemical modification of the then existing molecules.Geysen, in PCT Patent Appln. No., WO 90 / 09395 describes an approach to high-throughput synthesis of peptide oligomers by synthesizing these structures as they are attache...

AI Technical Summary

Benefits of technology

The present invention also has the advantage of providing a convenient means to facilitate delivery of chemical samples to typical testing formats (e.g. 96-well or higher density arrays of vessels used in bio-tech laboratories).

The present invention also provides convenient and reliable means to track the identity of each compound during the synthesis, sampling and testing process to facilitate detailed studies of chemical structure vs. biological activity relationships (QSAR). Improved tracking and control of samples during synthesis also increases the flexibility in designing such "combinatorial libraries."

The present invention also facilitates the testing of synthesized compounds for biological or chemical activity. The tested compounds are synthesized during multiple reaction stages on solid phase reactive material contained within the reaction vessel prior to any testing. The testing may include transferring synthesized compounds from the tubular reaction vessels into a testing medium, the reaction vessels comprising electronically readable identifying indicia thereon representing reaction conditions which have occurred within the tubular reaction vessels. The synthesized compounds are then tested for a desired biological or chemical activity. By electronically reading the identifying indicia on the reaction vessel wherein was synthesized a compound having the desired biological or chemical activity, the method of synthesis of such compound (and, consequently, the structure of such compound) may be determined by looking up recorded information wherein specific identifying indicia correspond with specific reaction histories.

Problems solved by technology

However, using this approach, quantities of synthesized compounds are limited.

Again, using these techniques, yields are limited, typically to subpicomoles, chemistries are also limited by the lithographic technique, and biological activities must be assessed on the lithographic array.

However, the quantity available on each bead is generally less than 1 nanomole and the process of identifying compounds involves PCR or some other tedious chemical method.

However, these systems are somewhat awkward to use, require that the beads be agitated, require many fluid-tight seals that must allow removal and insertion and may require physically large layout areas for a reasonable number of distinct compounds.

In addition, detachment of compounds and delivery to bioassays would be cumbersome for large numbers of compounds.

However, these systems are essentially serial in nature and do not enjoy the enormous advantages of the split synthesis methods described above.

Operation is generally limited to hundreds or thousands of compounds, and the automation can add extra constraints on the choices or efficiencies of the synthetic reaction steps used.

However, the methods described by Beattie et al. and Frank et al. are specific to oligomers, and the disk support structures do not provide a convenient interface to standard bioassays such as 96-well-plate-based tests.

Compounds in solutions extracted from these disks are not easily loaded into standard 96-well plates.

The sorting and loading methods for the disks may also be inadequate if the numbers of different structures desired reaches 100,000 or more.

Moreover, the mesh-like solid supports described by Beattie et al. and Frank et al. may not be applicable to non-oligomeric chemistries.

Therefore, none of these methods is ideal for synthesizing greater than milligram quantities of non-oligomeric chemical compounds in combinatorial or otherwise large libraries in such a way that sampling such libraries into 96-well plates or other standard bio-assay formats is easily achieved.

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