A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On-Resin Ozonolysis to Install the Kynurenine Residue.

A de novo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC100 =1.0 µg mL-1 ) against S. aureus, while five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3-methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.

Genome mining, isolation, chemical synthesis and biological evaluation of a novel lanthipeptide, tikitericin, from the extremophilic microorganism Thermogemmatispora strain T81.

Genome mining of the New Zealand extremophilic microorganism Thermogemmatispora strain T81 indicated the presence of biosynthetic machinery to produce several different peptidic natural products. Solid-phase culture of T81 led to the isolation of tikitericin 1, a new lanthipeptide characterised by four (methyl)lanthionine bridges. The mass-guided isolation and structural elucidation of tikitericin 1 is described together with its total synthesis via Fmoc-solid-phase peptide synthesis (SPPS). The key non-canonical (methyl)lanthionine residues were synthesised in solution phase via an improved synthetic route and subsequently assembled to construct the peptide backbone using Fmoc-SPPS. N-Terminal truncated analogues of tikitericin (2-5) were also prepared in order to evaluate the contribution of each sequential ring of the polycyclic lanthipeptide to the antibacterial activity.

Design, synthesis, and biological evaluation of 2-substituted ethenesulfonic acid ester derivatives as selective PTP1B inhibitors.

Fifteen 2-substituted ethenesulfonic acid ester derivatives were designed, synthesized, and evaluated for the inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and T-Cell protein tyrosine phosphatase (TCPTP). The structural activity relationship (SAR) of these compounds are discussed to clarify the impact of the linker and the optimized tail on the inhibitory activity of PTP1B and selectivity over TCPTP. Most of the compounds exhibit excellent inhibitory activities against PTP1B with IC50 values of 1.5-8.9 µM. SAR analysis reveal that the substituents at the hydrophobic tail significantly alter the inhibitory activity against PTP1 B and selectivity over TCPTP, e.g. compound 5d showed excellent inhibitory activity to PTP1B with IC50 = 7.8 µM, and -6-fold selectivity over TCPTP. Combined with our previous findings, we confirm that the linker length and the substituted hydrophobic tail have decisive influence on the PTP1B inhibitory activity and selectivity.