Development of chemical probes: Toward the mode of action of a methylene-linked di(aryl acetate) E1

• Published in: Bioorganic & medicinal chemistry 2010-07, Vol.18 (14), p.4917-4927
• Main Authors: Smith, Mark E.B., Gunn, Richard M., Rosivatz, Evelyn, Mak, Lok H., Woscholski, Rüdiger, Hailes, Helen C.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biotin conjugates; Breast Neoplasms - drug therapy; Cell Line, Tumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; General aspects; Humans; Medical sciences; Methylene-linked aryls; Molecular probes; Pharmacology. Drug treatments; Phenylacetates - chemical synthesis; Phenylacetates - chemistry; Phenylacetates - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3-K/PKB inhibitors; PKB/Akt; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.017

Preliminary SAR based on compound E1 was performed, and molecular probes designed and synthesized for applications in studies to identify the target of compound E1. Analogues of the novel inhibitor of the PI3-K/PKB pathway, 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate (E1), have been prepared and preliminary SAR performed. This established that at least one of the chloroethyl para-substituents could be removed or modified and the ability to inhibit PKB/Akt activation retained. Synthetic methodologies were then developed to methylene-linked aryl acetates for use as molecular probes to identify the target of compound E1.