The pargamicins are a family of non-ribosomal piperizic acid (Piz)-containing hexapeptides isolated from a soil actinomycete strain. Pargamicin A (PrgA) was named for its ability to weakly inhibit poly-ADP ribose glycohydrolase (PARG) in vitro and was later found to potently inhibit the growth of drug-resistant bacteria including MRSA and VRE. In addition to D-Piz, PrgA contains the nonproteinogenic residues γ-OH-D-Piz, N-Me-β-OH-l-Val, and N-OH-L-Ile, resulting in 5 sequential N-substituted amide bonds. Upon isolation, the stereochemical configuration of the N-OH-Ile residue was not assigned. Here, we describe the first total synthesis and structure confirmation of PrgA, paving the way for initial structure-activity relationship studies. Incorporation of the D-Piz residues was achieved through a submonomer approach, where D-hydroxynorvaline derivatives are N-aminated, acylated, then cyclized at a late stage. This strategy proved critical for successful assembly of the sterically congested linear hexapeptide. Also reported is the solid-phase synthesis of a structurally simplified analogue (cyclo[Sar-D-Phe-Ile-D-Pip-L-N-Me-Val-D-Pip] in addition to congeners of PrgA obtained through late-stage modification. Finally, we present a preliminary investigation of biological activity, including bacterial/human cell viability and hemolysis of red blood cells. Our studies inform the design of more potent and selective PrgA analogues and enable the synthesis of other sterically congested Piz-containing natural products.

Synthesis of the non-ribosomal peptide antibiotic pargamicin A

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