A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alterations to the C19-C22 Z,E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells. (C) 2013 Elsevier Ltd. All rights reserved.
Efficient synthesis of diverse hetero-bis-metallated alkenes as modular reagents towards highly conjugated and isolated olefinic systems
作者:Mario Altendorfer、Dirk Menche
DOI:10.1039/c2cc34052f
日期:——
An efficient synthesis of diverse hetero-bis-metallated alkenes with conjugated and isolated olefin subunits is reported. Relying on those useful tin/boron reagents a convergent, palladium-catalyzed fragment coupling strategy has been developed as an elegant methodology to construct highly conjugated polyenes and stabilized olefinic analogues thereof. The utility of these reagents was further demonstrated in a concise and modular construction of extended polyene side chains of the potent polyketide antibiotic etnangien.