David J. Hunter

Polymer discs — An alternative support format for solid phase synthesis

Abstract Monolithic crosslinked polymer rods (∼10 mm × 50 mm) have been prepared by polymerisation of styrene with divinylbenzene, poly(ethylene glycol) (PEG)400 diacrylate or PEG1000 diacrylate as crosslinker dissolved in a suitable solvent. Adjustment of the reaction composition allows soft but mechanically strong rods to be produced which can be readily cut into discs of 1–2.5 mm thickness. Discs with good swelling characteristics in toluene, DCM, MeOH and water, and which resist osmotic shock, have been prepared. Analogous vinylbenzyl chloride-based discs crosslinked either with divinylbenzene or with PEG1000 di-4-vinylbenzyl ether have also been produced. These have been chemically modified by reaction with NMe3, and also used in a two stage solid phase synthesis. Discs of individual mass up to 0.25g capable of yielding up to 0.5 mmole of a single compound in a solid phase synthesis have been used and demonstrated to be viable supports. This almost certainly does not represent the upper limit.

Techniques for analysis and purification in high-throughput chemistry

The success of combinatorial chemistry, and the increased emphasis on single well-characterised compounds of high purity, has had a significant impact on analytical and purification technologies. The requirement for ever-increasing throughput has led to the automation and parallelisation of these techniques. Advances have also been made in developing faster methods to augment throughput further.

Life in the fast lane: High-throughput chemistry for lead generation and optimisation

The pharmaceutical industry has come under increasing pressure due to regulatory restrictions on the marketing and pricing of drugs, competition, and the escalating costs of developing new drugs. These forces can be addressed by the identification of novel targets, reductions in the development time of new drugs, and increased productivity. Emphasis has been placed on identifying and validating new targets and on lead generation: the response from industry has been very evident in genomics and high throughput screening, where new technologies have been applied, usually coupled with a high degree of automation. The combination of numerous new potential biological targets and the ability to screen large numbers of compounds against many of these targets has generated the need for large diverse compound collections. To address this requirement, high‐throughput chemistry has become an integral part of the drug discovery process. J. Cell. Biochem. Suppl. 37: 22–27, 2001.

Inhibitors of human collagenase: dipeptide mimetics with lactam and azalactam moieties at the P2′P3′ position

Abstract A series of thiol-, aminophosphonic acid-, and hydroxamic acid-containing collagenase inhibitors, with lactam and azalactam P 2′ P 3′ substituents has been prepared and evaluated in vitro as inhibitors of human fibroblast collagenase. The most potent inhibitor was the hydroxamic acid 17a (IC50 12 nM). Introduction of a basic amino function into the lactam ring had little effect on potency, but greatly enhanced aqueous solubility.