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The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The overexpression of the Bcl-2 family proteins likely play a major role in the apoptosis blockade in CLL, and has been an effective target of CLL therapy. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. We have previously reported the first total synthesis of PatA. Mechanistic studies suggested that binding of eIF4A to PatA caused the stalling of initiation complexes on mRNA, halting the translation initiation process. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino …