In vitro structure/activity relationship studies of second generation derivatives of the translation initiation inhibitor desmethyl, desamino‐Pateamine A

Abstract

The natural product Pateamine A (PatA) from the marine sponge Mycale hentscheli has been found to be a highly potent antiproliferative agent with potential as a novel anti‐neoplastic agent. PatA binds to the eukaryotic translation initiation factor 4A (eIF4A) and prevents translation initiation. Previous structure/activity relationship (SAR) studies identified a rigid binding region on the molecule consisting of the “eastern” portion of the macrolide ring and a side chain terminating in a N,N‐dimethyl tertiary amine. The “western” portion of the macrolide serves as a flexible scaffold domain. Further SAR studies are presented here with a second generation of derivatives of the simplified Pateamine A analog desmethyl,desamino‐PatA (DMDA‐PatA). In vitro translation assays, and enzyme assays with purified recombinant eIF4AI were performed. The results presented here confirm the findings of the first SAR analysis and further clarify the structural requirements for activity. Rigidity of the binding domain was found to be critical for activity, and the tertiary amine found at the end of the side chain of the binding domain may serve as a potential site for future modifications to improve activity and specificity. Source of Funding, St. John's University.