Pateamine A (PatA), a marine metabolite from Mycale sp., is a potent inhibitor of the intracellular signal transduction pathway emanating from the T-cell receptor leading to the transcription of cytokines such as interleukin-2 (IL-2). On the basis of the structure of PatA and initial biological results, a hypothesis was developed regarding the presence of distinct binding and scaffolding domains in the PatA structure with respect to interactions with its putative cellular receptor(s). Employing a highly convergent approach involving a Hantzsch coupling strategy, we probed this hypothesis by preparing a simplified PatA derivative (desmethyl, desamino PatA, DMDAPatA, 3). This derivative was prepared in 10 fewer synthetic steps relative to PatA and was indeed found to exhibit equal to greater potency (IC50 0.81 +/- 0.27 nM) in inhibition of IL-2 production relative to PatA (IC50 4.01 +/- 0.94 nM) thus providing support for the binding/scaffolding domain hypothesis. In addition, as a means to find more stable derivatives and gain further insights into structure-activity relationships, several PatA derivatives were synthesized and assayed in the IL-2 reporter gene assay. Several of these derivatives displayed lower potency but marked stability relative to the natural product and provide further insights into the nature of the binding domain required for activity.