We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMPactivated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK. KeywordsFragment-based drug design; FBDD; 5'-AMP-activated protein kinase; AMPK; compound C 5'-AMP-activated protein kinase (AMPK) is a major regulator of normal cellular energy metabolism [1]. AMPK activity is sensitive to the cellular AMP:ATP ratio, which is increased by physiological stresses such decreased oxygen and glucose concentrations (hypoxia and hypoglycemia). AMPK activity is also associated with the growth of solid tumors, which commonly contain regions of pathologic hypoxia and hypoglycemia [2]. AMPK cooperates with hypoxia-inducible factor-1 (HIF-1), the primary transcriptional regulator of the mammalian response to hypoxia and other metabolic stresses that lower cellular ATP levels, in pathophysiological tumor microenvironments [3,4]. Thus, in the context of microenvironmental stress, AMPK may represent a novel target for the treatment of solid tumors. The successful design of potent and selective inhibitors of AMPK that exhibit activity is an important first step toward establishing the proof-of-concept for the therapeutic value of AMPK inhibition in solid tumor microenvironments.This Letter describes our efforts to design a Type I inhibitor of AMPK with a superior biological profile than that of compound C (Figure 1), which is a commonly used experimental direct inhibitor of the enzyme [5], through the use of our proprietary fragmentbased drug design (FBDD) software [6][7][8][9] Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. We discuss the SAR of a series of pyrazolopyrimidine and aminooxazole analogues of compound C and present their general binding mode obtained through the use of homology modeling and Grand Canonical Monte Carlo (GCMC) fragment simulations [9]. A focused kinase selectivity profile for the most active subset of these compounds is presented, as well as the cellular AMPK inhibition data for the most promising pyrazolopyrimidine. NIH Public AccessWe generated a model of the catalytic α2 subunit of AMPK with the DFG-loop in the 'in' conformation using MOE [12]. The crystal structure of the AMPK α2 subunit (RCSB ID# 2H6D, ...

1,2-Disubstituted olefins bearing an acetamide group were found to undergo intramolecular Kulinkovich-de Meijere cyclopropanation in moderate yield but almost complete diastereoselectivity.

This article describes new examples of intramolecular Kulinkovich–de Meijere reactions applied to carboxylic amides bearing an olefin moiety and an aromatic ring at a suitable position. Upon heating, the aminocyclopropanes thus obtained undergo intramolecular aromatic electrophilic substitution to afford polycyclic systems. Among the various starting materials prepared, best results are obtained from indole and phenol derivatives. In each case, a benzylic quaternary centre is introduced at the newly‐formed ring junction. On one example, the efficiency of the cyclisation has been dramatically improved using a catalytic amount of para‐toluenesulfonic acid. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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