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Open Access Publications from the University of California

Utilization of the beta-Lactam Core Towards the Preparation of Chiral Ring-Fused Lactams and Preparation and Application of Synthetic Peptide Libraries Toward the Discovery and Understanding of Membrane-Permeable Macrocycles

  • Author(s): Hewitt, William Merton
  • Advisor(s): Konopelski, Joseph P
  • Lokey, Robert S
  • et al.

The beta-lactam synthon method is an established technique utilizing beta-lactams in natural product synthesis. Through application of our previously described novel beta-lactam preparation, we describe the C3 functionalization and application of previously described and novel β-lactams towards the synthesis of pactamycin--a densely functionalized cyclopentane natural product--and non-natural analogs of salinosporamide A--a proteasome inhibitor currently in clinical trials for treatment of multiple myeloma.

Additionally, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds towards development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.

Finally, we report the application of this "split-pool" synthetic library approach towards the extension of known physical models of passive membrane permeation--in particular, the barrier domain model--to larger molecular weight chemical space. We show that the membrane permeability of macrocycles is governed by lipophilicity and solubility and that the window between the two narrows with increasing molecular size. We recognize this brings into question again the origin of intrinsic permeability of natural membrane-permeable macrocycles such as cyclosporin A.

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