Solid‐phase synthesis of fusaricidin/li‐f class of cyclic lipopeptides: Guanidinylation of resin‐bound peptidyl amines

Abstract

Fusaricidins/LI-Fs and related cyclic lipopeptides represent an interesting new class of antibacterial peptides with the potential to meet the challenge of antibiotic resistance in bacteria. Our previous study (N. Bionda et al. ChemMedChem 2012, 7, 871-882) revealed the significance of the guanidinium group located at the termini of the lipidic tails of these cyclic lipopeptides for their antibacterial activities. Therefore, devising a synthetic strategy that will allow incorporation of guanidinium functionality into their structure is of particular practical importance. Since appropriately protected guanidino fatty acid building blocks are not commercially available, our strategy toward guanidinylated fusaricidin/LI-F analogs include solid-phase synthesis of a cyclic lipopeptide precursor possessing a lipidic tail with a terminal amino group followed by its conversion into corresponding guanidine. To find the optimal method for this conversion, we have examined commonly used guanidinylation reagents under the conditions compatible with standard solid-phase peptide synthesis. Described experimental results demonstrated superiority of N,N′-di-Boc-N″-triflylguanidine in solid-phase preparation of fusaricidin/LI-F class of cyclic lipopeptides. The triflylguanidine reagent gave a single monoguanidinylated product in excellent yield independently of the type of solid-support.

Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities

“…The cyclic lipopeptide synthetic combinatorial library was generated by the process of divide, couple and recombine (tea bag“ method) using a previously developed Fmoc SPPS chemistry. [34, 41, 42] In brief, our synthetic strategy included attachment of the C -terminal amino acid Fmoc-D-Asp 5 -OAllyl to a PEG-based amide resin via the side chain, use of a combination of orthogonal protecting groups, stepwise solid-phase assembly of a linear precursor, attachment of a lipidic tail followed by coupling of the N -terminal Fmoc-Dap 1 (Mtt)-OH and on-resin cyclization. To maintain the same order of D- and L-amino acids as they appear in the sequences of the fusaricidin/LI-F natural products in the synthesized cyclic lipopeptides, D-Val 2 , D-Thr 4 , and D-Ala 6 were replaced with D-amino acid mixtures, whereas L-Val 3 was similarly replaced with an L-amino acid mixture.…”

“…The conversion of the lipid tail amino group into the desired guanidino group was achieved by removal of the Fmoc protecting group using standard piperidine deprotection protocol and treatment of the peptidyl-resin with N,N ′-di-Boc- N ″-triflylguanidine (5 eq) and triethylamine (5 eq) in DCM as described previously. [62] The final purity of synthesized peptides 1 – 13 was confirmed by analytical RP-HPLC, LC ESI MS and MALDI TOF MS, and was ≥ 95% in all cases.…”

Pyrrolopyrimidine vs Imidazole-Phenyl-Thiazole Scaffolds in Nonpeptidic Dimerization Inhibitors of Leishmania infantum Trypanothione Reductase

“…-pyrrolo [2,3-d] After washing and swelling the resin, Alloc deprotection was performed by treatment of the resin with Pd(PPh 3 ) 4 (92 mg, 0.08 mmol) and PhSiH 3 (0.95 mL, 7.68 mmol) in dry DCM at room temperature (2 x 1 h). Once the amino group was deprotected, the guanilidation reaction was carried out by reaction of the resin with 1,3-Di-Boc-2-(trifluoromethylsulfonyl)guanidine (626 mg, 1.6 mmol) and TEA (0.22 mL, 1.6 mmol) in dry DCM at room temperature for 5 h. 46 After thorough washing (DMF/DCM/DMF/DCM) the final pyrrolopyrimidine 2i was cleaved from the resin using an acidolitic cleavage cocktail (TFA:TIPS:H 2 O 95:2.5:2.5) for 2 h at room temperature. The filtrate was precipitated from cold diethylether (50 mL), centrifuged at 5000 rpm (3 x 10 min) and lyophilized.…”

A Comparative Study of Antimicrobial Profile Having Broad Spectrum Bacteriocins Against Antibiotics

“…AMP-JSa-9 are a group of cyclic lipodesipeptide antibiotics which are composed of a peptide ring that consists of a six amino acid residues and a 15-guanidino-3-hydroxypentadecanoic acid moiety and exhibit a broad antimicrobial spectrum with particularly high potency against Gram-positive bacteria and fungi [42,43]. Earlier studies suggested that the positively charged guanidinium group at the end of the 12-carbon lipidic tail and the presence of hydrophobic amino acids in the depsipeptide sequence of LI-Fs are important for the antibacterial activity [44].…”