Homogeneous Pharmacologic and Cell-based Screens Provide Diverse Strategies in Drug
Discovery: Somatostatin Antagonists as a Case Study. Pp. 171-184.
John R. Zysk and William R. Baumbach
[Abstract]
Solid Phase Synthesis of Heterocycles by Cyclization/Cleavage Methodologies. Pp. 185-214.
Jan H. van Maarseveen
[Abstract]
The Properties of Resin Supports and Their Effects on Solid-Phase Organic Synthesis. Pp. 215-229.
Bing Yan
[Abstract]
[Back to top] Homogeneous Pharmacologic and Cell-based Screens Provide Diverse Strategies in Drug Discovery: Somatostatin Antagonists as a Case Study. John R. Zysk and William R. Baumbach.
The development of high throughput, homogeneous pharmacologic and functional assays and their implementation in screening combinatorial libraries has increased the pace of stochastic drug discovery in recent years. New, noninvasive approaches involving radiometric proximity assays, an array of fluorescence-based technologies, and reporter gene constructs in mammalian and nonmammalian systems are providing more options for the selection of specific therapeutic targets. The increasing sophistication of homogeneous assay designs has also served as a springboard to better lead validation in drug discovery initiatives. This review examines these approaches in the context of new drug discovery strategies which combine a growing repertoire of high throughput screening techniques. The utility and importance of cell-based assays vis-à-vis pharmacologic (cell-free) assays is considered with specific reference given to yeast-based functional screens and homogeneous binding methodologies used to search for somatostatin antagonists and other potential growth hormone secretagogues. Also considered is the custom tailoring of specific chemical libraries which provide yet another level of target selectivity. The advantages and shortcomings of these various technologies are discussed in light of emerging trends toward higher throughput and nanoscale formats which are pushing the limits of measurable response at the cellular and molecular level.
[Back to top] Solid Phase Synthesis of Heterocycles by Cyclization/Cleavage Methodologies. Jan H. van Maarseveen.
For the solid phase preparation of various (pharmacologically important) heterocycles, cyclization/cleavage (C/C) or cyclorelease strategies proved to be superior. CC approaches take utmost advantage of the benefits of solid phase synthesis. Besides the practical benefits of solid phase reactions, cyclative release approaches are distinguished especially because of the generally found high purity of the final detached products, since only the anticipated structures cleave off the resin. Also cyclization/cleavage strategies are "traceless", as the obtained moiety after cyclization is part of the formed heterocycle. Over the last thirty years numerous approaches towards important heterocycle classes have been published. Among the successfully applied strategies are carbon-nitrogen (sulfur) bond, carbon-oxygen bond, sulfur-sulfur bond and carbon-carbon forming reactions in the final cyclorelease step.
[Back to top] The Properties of Resin Supports and Their Effects on Solid-Phase Organic Synthesis. Bing Yan.
Solvated resin supports are important carriers for solid-phase organic synthesis in combinatorial chemistry and high-throughput parallel synthesis. The physical properties of resin, resin swelling and dynamic solvation, effects of solvated supports on synthesis, kinetics, site interaction, and product purity are reviewed. Selective solvation of resin alters the local reactivity and accessibility of the bound substrate and the mobility of the entrapped reagent. Resin solvation changes during the course of the reaction when the attached substrate changes its polarity or other physicochemical properties. Selective adsorption determines the reaction kinetics and the action of a phase-transfer catalyst further improves the reaction on resin. Sites interact with each other in 1% DVB polystyrene resins to varying degrees depending on solvent, resin, and reactivity of the pendant groups. Total site isolation seems only achievable by controlling several factors simultaneously such as lower loading and steric hindrance. Through the proper selection of resin and solvent, alternating solvents to accommodate dynamic solvation of the resin, optimization of kinetics when changing solid supports and a careful control of resin impurities, solid-phase organic synthesis can lead to high quality combinatorial libraries.