Synthesis of 1,4-Oxazepane-2,5-diones via Cyclization of Rotationally Restricted Amino Acid Precursors and Structural Reassignment of Serratin.

Several natural products containing a 1,4-oxazepane-2,5-dione-core are known. One example is serratin, isolated from Serratia marcescens. Because of the presence of a carboxylic amide, which has a preference for a trans-conformation, and the presence of a labile lactone in this core, many synthetic methodologies commonly used for the cyclization toward medium-sized heterocycles cannot be applied. As N-acyl amino acids lacking a third substituent at nitrogen failed to undergo ring-closure, several N-protecting groups were evaluated. With the use of the removable PMB-group, an N-unsubstituted 1,4-oxazepane-2,5-dione was synthesized. Via the application of pseudoprolines (i.e. serine-derived oxazolidines as another type of protecting group), a compound with the presumed structure of the natural product serratin was obtained. As a result of the differences in spectral data, the incorrect structural assignment of the natural product serratin was identified. Instead of the predicted seven-membered heterocycle, a symmetrical serratamolide analogue is proposed to be the correct structure of serratin.

Haloperoxidase mediated quorum quenching by Nitzschia cf pellucida: study of the metabolization of N-acyl homoserine lactones by a benthic diatom.

Diatoms are known to produce a variety of halogenated compounds, which were recently shown to have a role in allelopathic interactions between competing species. The production of these compounds is linked to haloperoxidase activity. This research, has shown that this system may also be involved in diatom-bacteria interactions via the H2O2 dependent inactivation of a type of quorum sensing (QS) molecule, i.e., N-ß-ketoacylated homoserine lactones (AHLs), by a natural haloperoxidase system from the benthic diatom Nitzschia cf pellucida. The AHL degradation pathway towards corresponding halogenated derivatives was elucidated via HPLC-MS analysis and the synthesis of a broad series of novel halogenated AHL analogues as reference compounds. Furthermore, their biological activity as quorum sensing modulators was directly compared and evaluated against a series of naturally occurring ß-keto-AHLs. It has been demonstrated that the loss of the QS activity results from the final cleavage of the halogenated N-acyl chain of the signal molecules.

Synthesis and biological evaluation of novel N-α-haloacylated homoserine lactones as quorum sensing modulators.

Novel N-α-haloacylated homoserine lactones, in which a halogen atom was introduced at the α-position of the carbonyl function of the N-acyl chain, have been studied as quorum sensing (QS) modulators and compared with a library of natural N-acylated homoserine lactones (AHLs). The series of novel analogues consists of α-chloro, α-bromo and α-iodo AHL analogues. Furthermore, the biological QS activity of the synthetic AHL analogues compared to the natural AHLs was evaluated. Halogenated analogues demonstrated a reduced activity in the Escherichia coli JB523 bioassay, with the α-iodo lactones being the less active ones and the α-chloro AHLs the most potent QS agonists. Most of the α-haloacylated analogues did not exhibit a significant reduction when tested in the QS inhibition test. Therefore, these novel analogues could be utilized as chemical probes for QS structure-activity studies.

N-Acyl Homoserine Lactone Derived Tetramic Acids Impair Photosynthesis in Phaeodactylum tricornutum.

Marine bacteria contribute substantially to nutrient cycling in the oceans and can engage in close interactions with microalgae. Many microalgae harbor characteristic satellite bacteria, many of which participate in N-acyl homoserine lactone (AHL) mediated quorum sensing. In the diffusion-controlled phycosphere, AHLs can reach high local concentrations, with some of them transforming into tetramic acids, compounds with a broad bioactivity. We tested a representative AHL, N-(3-oxododecanoyl) homoserine lactone, and its tetramic acid rearrangement product on the diatom Phaeodactylum tricornutum. While cell growth and photosynthetic efficiency of photosystem II were barely affected by the AHL, exposure to its tetramic acid rearrangement product had a negative effect on photosynthetic efficiency and led to growth inhibition and cell death in the long term, with a minimum inhibitory concentration between 20 and 50 µΜ. These results strengthen the view that AHLs may play an important role in shaping the outcome of microalgae-bacteria interactions.