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.

Peptide Lipidation - A Synthetic Strategy to Afford Peptide Based Therapeutics.

Peptide and protein aberrant lipidation patterns are often involved in many diseases including cancer and neurological disorders. Peptide lipidation is also a promising strategy to improve pharmacokinetic and pharmacodynamic profiles of peptide-based drugs. Self-adjuvanting peptide-based vaccines commonly utilise the powerful TLR2 agonist PamnCys lipid to stimulate adjuvant activity. The chemical synthesis of lipidated peptides can be challenging hence efficient, flexible and straightforward synthetic routes to access homogeneous lipid-tagged peptides are in high demand. A new technique coined Cysteine Lipidation on a Peptide or Amino acid (CLipPA) uses a 'thiol-ene' reaction between a cysteine and a vinyl ester and offers great promise due to its simplicity, functional group compatibility and selectivity. Herein a brief review of various synthetic strategies to access lipidated peptides, focusing on synthetic methods to incorporate a PamnCys motif into peptides, is provided.

Alcanivorax gelatiniphagus sp. nov., a marine bacterium isolated from tidal flat sediments enriched with crude oil.

A Gram-reaction-negative, rod-shaped marine bacterium, designated MEBiC08158(T), was isolated from sediments collected from Taean County, Korea, near the Hebei Spirit tanker oil spill accident. 16S rRNA gene sequence analysis revealed that strain MEBiC08158(T) was closely related to Alcanivorax marinus R8-12(T) (99.5% similarity) but was distinguishable from other members of the genus Alcanivorax (93.7-97.1%). The DNA-DNA hybridization value between strain MEBiC08158(T) and A. marinus R8-12(T) was 58.4%. Growth of strain MEBiC08158(T) was observed at 15-43 °C (optimum 37-40 °C), at pH 6.0-9.5 (optimum pH 7.0-8.0) and with 0.5-16% NaCl (optimum 1.5-3.0%). The dominant fatty acids were C16 : 0, C19 : 0 cyclo ω8c, C12 : 0, C18 : 1ω7c, C12 : 0 3-OH and summed feature 3 (comprising C15 : 0 2-OH and/or C16 : 1ω7c). Several phenotypic characteristics differentiate strain MEBiC08158(T) from phylogenetically close members of the genus Alcanivorax. Therefore, strain MEBiC08158(T) should be classified as representing a novel species of the genus Alcanivorax, for which the name Alcanivorax gelatiniphagus sp. nov. is proposed. The type strain is MEBiC08158(T) ( = KCCM 42990(T) = JCM 18425(T)).

Plant antimicrobial peptides snakin-1 and snakin-2: chemical synthesis and insights into the disulfide connectivity.

Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine-rich snakin-1 and -2 antimicrobial peptides by using a combination of solid-phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40-50 % yield. By comparative evaluation of mass spectrometry, HPLC, biological data and trypsin digest mapping of folded synthetic snakin-2 compared to natural snakin-2, we demonstrated that synthetic snakin-2 possesses full antifungal activity and displayed similar chromatographic behaviour to natural snakin-2. Trypsin digest analysis allowed tentative assignment of three of the purported six disulfide bonds.

A phase II study of docetaxel and oxaliplatin combination in recurrent gastric cancer patients after fluoropyrimidine and/or cisplatin adjuvant treatment: a Korean Cancer Study Group Protocol ST06-02.

BACKGROUND: Surgery alone is no longer an adequate standard of care for patients with resectable gastric cancer. Thus, research efforts should focus on which regimens are the most effective for patients with recurrent gastric cancer after combined treatment with surgery and perioperative or adjuvant chemotherapy. METHODS: Patients with histologically confirmed and measurable advanced gastric cancer who showed a relapse even after fluoropyrimidine and/or cisplatin-based adjuvant chemotherapy received docetaxel (35 mg/m(2)) intravenously on day 1 and 8 plus oxaliplatin (100 mg/m(2)) intravenously on day 1 every 3 weeks until disease progression or unacceptable toxicity. RESULTS: A total of 34 patients with relapsed advanced gastric cancer who had received adjuvant chemotherapy with fluoropyrimidine and/or cisplatin for a median of 6 months (range, 1-48 months) were enrolled in this trial; 22 (64.7 %) patients had been exposed to both agents. Their median age was 58 years (range, 50-68 years). The overall response rate was 55.9 % (95 % confidence interval (CI), 38.3-73.5 %), including 1 complete response and 18 partial responses. At a median follow-up duration of 28.5 months (range, 9.2-50.7 months), the median progression-free survival for all patients was 5.3 months (95 % CI, 4.4-6.1 months) and the median overall survival was 13.8 months (95 % CI, 11.1-16.4 months). The most common grade 3 or 4 hematologic and nonhematologic toxicities were neutropenia (47.1 %) and diarrhea (17.6 %), respectively. Five patients (14.7 %) experienced febrile neutropenia. CONCLUSIONS: Docetaxel and oxaliplatin combination chemotherapy was active and tolerable in patients with recurrent gastric cancer after fluoropyrimidine and/or cisplatin-based adjuvant chemotherapy.