A-228839

The antitumor compound ABT-839 was synthesized in eight steps from com. available starting materials.The synthesis was carried out with a single purification prior to final salt isolation.The key sequence is an efficient bromination and a novel bis-coupling strategy that transforms the bi-aryl core to the penultimate ester in a single operation with no isolation in 94% yield.After bisulfate salt formation, the product was isolated as a crystalline solid.The synthesis was carried out on kilogram scale and gave an overall yield of 43%.

Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed.