Among the plethora of microbial secondary metabolites produced by the soil bacterium of the Streptomyces family is pactamycin, a structurally unique member of aminocyclopentitol-containing natural products (Scheme 1).Pactamycin was isolated in 1961 from a fermentation broth of Streptomyces pactum var pactum by scientists at the former Upjohn Company.[1] It exhibits activity against Grampositive and Gram-negative bacteria, in addition to potent in vitro and in vivo cytotoxic effects.[2] Its further development as a chemotherapeutic agent was curtailed owing to its toxicity. The potent protein synthesis inhibitory activity of pactamycin is attributed to the stage of translocation from the A and P sites to the P and E sites during formation of certain m-RNA-t-RNA complexes in prokaryotes as well as in eukaryotes.[3] Pioneering X-ray crystallographic studies [4] involving binding to the 30S site of Thermus thermophilus show unique interactions, whereby pactamycin adopts a spatial orientation so as to mimic an RNA nucleotide. The two aromatic moieties stack against each other like consecutive RNA bases, while the core cyclopentane motif mimics the RNA sugar-phosphate backbone, which results in an intricate network of hydrogen-bonded interactions within the 30S site of the ribosome. Recent elegant studies on the biosynthesis of pactamycin by Mahmud and coworkers [5a] revealed a gene cluster which also produced pactamycate, de-6-MSA-pactamycin and de-6-MSA-pactamycate, the natural congeners lacking the 6-methyl salicylic acid moiety.
This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues.
Biosynthetically and chemically derived analogs of the antibiotic pactamycin and de-6-methylsalicylyl (MSA)-pactamycin have attracted recent interest as potential antiprotozoal and antitumor drugs. Here, we report a 3.1-Å crystal structure of de-6-MSA-pactamycin bound to its target site on the Thermus thermophilus 30S ribosomal subunit. Although de-6-MSA-pactamycin lacks the MSA moiety, it shares the same binding site as pactamycin and induces a displacement of nucleic acid template bound at the E-site of the 30S. The structure highlights unique interactions between this pactamycin analog and the ribosome, which paves the way for therapeutic development of related compounds.
Among the plethora of microbial secondary metabolites produced by the soil bacterium of the Streptomyces family is pactamycin, a structurally unique member of aminocyclopentitol-containing natural products (Scheme 1).Pactamycin was isolated in 1961 from a fermentation broth of Streptomyces pactum var pactum by scientists at the former Upjohn Company.[1] It exhibits activity against Grampositive and Gram-negative bacteria, in addition to potent in vitro and in vivo cytotoxic effects.[2] Its further development as a chemotherapeutic agent was curtailed owing to its toxicity. The potent protein synthesis inhibitory activity of pactamycin is attributed to the stage of translocation from the A and P sites to the P and E sites during formation of certain m-RNA-t-RNA complexes in prokaryotes as well as in eukaryotes.[3] Pioneering X-ray crystallographic studies [4] involving binding to the 30S site of Thermus thermophilus show unique interactions, whereby pactamycin adopts a spatial orientation so as to mimic an RNA nucleotide. The two aromatic moieties stack against each other like consecutive RNA bases, while the core cyclopentane motif mimics the RNA sugar-phosphate backbone, which results in an intricate network of hydrogen-bonded interactions within the 30S site of the ribosome. Recent elegant studies on the biosynthesis of pactamycin by Mahmud and coworkers [5a] revealed a gene cluster which also produced pactamycate, de-6-MSA-pactamycin and de-6-MSA-pactamycate, the natural congeners lacking the 6-methyl salicylic acid moiety.
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