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.

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.

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.

An efficient, high-yielding strategy has been developed for the asymmetric total synthesis of seven norditerpenoid dilactones known for their diverse biological properties. The three key steps employed to obtain a tricyclic lactone intermediate involved a Morita-Baylis-Hillman reaction, the stereocontrolled construction of a gamma-lactone through bromolactonization, and an efficient catalytic Reformatsky-type reaction. Access to CJ-14,445, LL-Z1271gamma, oidiolactones A, B, C, and D, and nagilactone F was possible from a common intermediate. Structures and stereochemistry were determined by X-ray analysis.

The first total synthesis of the enantiomer of the indolizidine alkaloid, cyclizidine, was accomplished from readily available d-serine as the starting chiron. The relevant key reactions involve the stereocontrolled construction of the indolizidine ring system with the required functionality and further elaboration to install the cyclopropyl dienyl side chain. With this total synthesis, the absolute configuration of the natural product based on a redetermination of its X-ray structure has been confirmed.