This paper describes a novel supported Weinreb amide resin that facilitates parallel synthesis of aldehydes and ketones on a scale useful for chemical library synthesis. This new resin makes it possible to produce custom aldehydes and ketones from a wide range of carboxylic acids, including N-BOC-amino acids. A variety of commercially unavailable aldehydes are easily synthesized in parallel and obtained in high purity via a simple filtration workup, thus facilitating parallel synthesis of lead optimization libraries that typically require custom synthesis of aldehyde intermediates for development of structure-activity relationships. To demonstrate the utility of this method, we synthesized a small library based on a supported Horner-Emmons reagent. This is the first time it has been shown that aldehydes generated via a supported Weinreb amide could be used directly as reagents in chemical library synthesis employing moisture-sensitive reactions. The analogous solution reaction is not suited for parallel synthesis because of the laborious extractive workup procedure necessary and, at times, the instability of these reactive intermediates.

A new tetrafluorophenol activated resin that facilitates the use of 19F NMR to quantitate loading is presented. This new resin provides a useful tool for acylation, and a novel activated polymeric sulfonate ester to generate sulfonamides. This activated resin reacts with a wide scope of N-nucleophiles including primary and secondary amines, and anilines. This new activated resin methodology provides a powerful tool for pure single-compound library synthesis.

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The synthesis, cell growth-inhibitory activity, in vivo antileukemic activity, and extent of DNA binding of the alpha- and beta-anomeric 7-O-(3-amino-3,5-dideoxy-D-ribofuranosyl)daunomycinones and their trifluoroacetamides are described. These compounds are unique in that they are the first reported furanoside analogues of the antitumor antibiotics daunorubicin and adriamycin. Continuing analysis of structure-activity relationships amongst natural and semisynthetic anthracyclines fails to reveal a predictable relationship between in vivo antitumor activity and the in vitro properties of DNA complexation and cell growth inhibition.

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.