Total Solid-Phase Synthesis of Dehydroxy Fengycin Derivatives.

A rapid and efficient solid-phase strategy for the synthesis of dehydroxy fengycins derivatives is described. This synthetic approach involved the linkage of a Tyr to a Wang resin via a Mitsunobu reaction and the elongation of the peptide sequence followed by subsequent acylation of the N-terminus of the resulting linear peptidyl resin, esterification of the phenol group of a Tyr with an Ile, and final macrolactamization. The amino acid composition as well as the presence of the N-terminal acyl group significantly influenced the stability of the macrolactone. Cyclic lipodepsipeptides with a l-Tyr3/d-Tyr9 configuration were more stable than those containing the Tyr residues with an opposite configuration. This work constitutes the first approach on the total solid-phase synthesis of dehydroxy fengycin derivatives.

Tryptophan-Containing Cyclic Decapeptides with Activity against Plant Pathogenic Bacteria.

A library of 66 cyclic decapeptides incorporating a Trp residue was synthesized on solid phase and screened against the phytopathogenic bacteria Pseudomonas syringae pv. syringae, Xanthomonas axonopodis pv. vesicatoria, and Erwinia amylovora. The hemolytic activity of these peptides was also evaluated. The results obtained were compared with those of a collection of Phe analogues previously reported. The analysis of the data showed that the presence of the Trp improved the antibacterial activity against these three pathogens. In particular, 40 to 46 Trp analogues displayed lower minimum inhibitory concentration (MIC) values than their corresponding Phe counterparts. Interestingly, 26 Trp-containing sequences exhibited MIC of 0.8 to 3.1 µM against X. axonopodis pv. vesicatoria, 21 peptides MIC of 1.6 to 6.2 µM against P. syringae pv. syringae and six peptides MIC of 6.2 to 12.5 µM against E. amylovora. Regarding the hemolysis, in general, Trp derivatives displayed a percentage of hemolysis comparable to that of their Phe analogues. Notably, 49 Trp-containing cyclic peptides showed a hemolysis ≤ 20% at 125 µM. The peptides with the best biological activity profile were c(LKKKLWKKLQ) (BPC086W) and c(LKKKKWLLKQ) (BPC108W), which displayed MIC values ranging from 0.8 to 12.5 µM and a hemolysis ≤ 8% at 125 µM. Therefore, it is evident that these Trp sequences constitute promising candidates for the development of new agents for use in plant protection.

Solid-Phase Synthesis of Cyclic Depsipeptides Containing a Tyrosine Phenyl Ester Bond.

The first solid-phase strategy for the synthesis of cyclic depsipeptides containing a phenyl ester linkage in their structure is described. The key steps of the synthesis were the formation of the phenyl ester bond and the on-resin head-to-side-chain cyclization. The amino acid configuration significantly influenced the formation and the stability of the cyclic depsipeptides. The presence of a l-Tyr(1) and a d-Tyr(7) led to the most stable sequences.

Antimicrobial cyclic decapeptides with anticancer activity.

Antimicrobial peptides have been considered as potential candidates for cancer therapy. We report here the cytotoxicity of a library of 66 antibacterial cyclodecapeptides on human carcinoma cell lines, and their effects on apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase (PARP)] and cell signaling proteins (p53 and ERK1/2) in cultured human cervical carcinoma cells. A design of experiments approach permitted to analyze the results of a subset of 16 peptides and define rules for high anticancer activity against MDA-MB-231 breast carcinoma cells. Eight peptides were identified with IC(50) values ranging from 18.5 to 57.5 µM against the five cell lines tested, being HeLa cells the most sensitive. Among these sequences, BPC88, BPC96, BPC98, and BPC194 displayed specificity and high cytotoxicity against HeLa cells (IC(50) of 22.5-38.5 µM), showed low hemolytic activity and low cytotoxicity to non-malignant fibroblasts, and were stable to proteases in human serum. Induction of apoptosis by these peptides was observed and the apoptotic effect of BPC88 and BPC96 caused a marked decrease on the activated form of ERK1/2 kinase and an induction of p53. We further showed that BPC96 at low doses synergized the cytotoxic effect of cisplatin. These findings suggest that cyclic decapeptides may represent novel anticancer agents providing a new strategy in cancer therapy.