Using chemical probes to investigate the sub-inhibitory effects of azithromycin.

The antibacterial drug azithromycin has clinically beneficial effects at sub-inhibitory concentrations for the treatment of conditions characterized by chronic Pseudomonas aeruginosa infection, such as cystic fibrosis. These effects are, in part, the result of inhibition of bacterial biofilm formation. Herein, the efficient synthesis of azithromycin in 4 steps from erythromycin and validation of the drug's ability to inhibit biofilm formation at sub-MIC (minimum inhibitory concentration) values are reported. Furthermore, the synthesis of immobilized and biotin-tagged azithromycin analogues is described. These chemical probes were used in pull-down assays in an effort to identify azithromycin's binding partners in vivo. Results from these assays revealed, as expected, mainly ribosomal-related protein binding partners, suggesting that this is the primary target of the drug. This was further confirmed by studies using a P. aeruginosa strain containing plasmid-encoded ermC, which expresses a protein that modifies 23S rRNA and so blocks macrolide entry to the ribosome. In this strain, no biofilm inhibition was observed. This work supports the hypothesis that the sub-inhibitory effects of azithromycin are mediated through the ribosome. Moreover, the synthesis of these chemical probes, and proof of their utility, is of value in global target identification in P. aeruginosa and other species.

Exploiting domino enyne metathesis mechanisms for skeletal diversity generation.

In the context of diversity-oriented synthesis, the exploration and optimization of the domino metathesis of decorated norbornenes allowed complex polycyclic architectures to be generated in a highly efficient and atom-economical process.

Gemmacin B: bringing diversity back into focus.

Through the synthesis of a focused library and SAR investigations, a more potent analogue of gemmacin (discovered in a previous diversity-oriented synthesis (DOS) campaign), gemmacin B, was discovered.

Diversity-oriented synthesis.

Diversity-oriented synthesis (DOS), which describes the synthesis of structurally diverse collections of small molecules, was developed, in part, to address combinatorial chemistry's shortfalls. In this paper, we hope to give an indication of what can be achieved using the DOS approach to library generation. We describe some of the most successful strategies utilized in DOS, with special focus on our own area of interest; DOS from simple, pluripotent starting materials.

Total synthesis of sanguiin H-5.

Using an atropdiastereoselective oxidative biaryl coupling as the key step, the total synthesis of the ellagitannin natural product sanguiin H-5 is reported. Both organomagnesium and organozinc based metalation methodologies were used to efficiently construct the strained medium-ring core of the natural product.

Diversity-oriented synthesis; a spectrum of approaches and results.

Since our emerging area article, diversity-oriented synthesis (DOS), which aims to prepare efficiently collections of skeletally diverse small molecules, has developed in the synthetic approaches it employs. This article describes three general strategies, highlighting some successful examples. The utility of DOS, in the interrogation of chemical space and in the identification of novel biologically active lead compounds, is also discussed.