Solid-phase synthesis of cyclic hexapeptides wollamides A, B and desotamide B

Abstract

Solid-phase synthesis of antibacterial cyclohexapeptides including wollamides A, B and desotamide B has been developed. Briefly, the protected linear hexapeptides were assembled on 2-chlorotrityl chloride resin using standard Fmoc chemistry and diisopropylcarbodiimide/hydroxybenzotriazole coupling reagents, cleaved off-resin with hexafluoroisopropanol/dichloromethane to keep side-chain protecting groups intact, and cyclized in solution. Final global removal of all protecting groups using a cocktail of trifluoroacetic acid/triisopropylsilane/dichloromethane afforded the desired cyclic hexapeptides, which were characterized by 1H, 13C NMR, and HRMS. Subsequent investigation of macrocyclization parameters such as terminal residues, coupling reagents, and cyclization concentration revealed the optimized conditions for the synthesis of this class of cyclic hexapeptides.

Structure-Activity Relationships of Wollamide Cyclic Hexapeptides with Activity against Drug-Resistant and Intracellular Mycobacterium tuberculosis

“…Wollamide-producing Streptomyces species are exceptionally rare and to the best of our knowledge cannot be sourced from existing repositories (i.e., the ATCC). Our initial identification of the synthetically accessible antimycobacterial cyclic hexapeptide wollamides (8) have led to reports on the chemical synthesis of wollamides (9,11,12) and SAR investigations against M. tuberculosis H37Rv (11,12). The present study assessed 36 new synthetic wollamides and compared their structure-activity relationships to those of 46 known cyclic peptide wollamide derivatives.…”

“…Preliminary structure-activity relationship (SAR) studies, comparing the naturally produced wollamides and desotamides, highlighted the importance of amino acid residue VI (i.e., D-Orn over Gly) and suggested that compound 2 held promise. The solid-phase synthesis of compound 2 was subsequently described (9,10), as were SAR studies for some synthetic wollamides, assessing in vitro growth-inhibitory activity against M. tuberculosis H37Rv (11,12). Here, we report the synthesis and antimycobacterial activity of 36 new wollamide analogues and compare their antimycobacterial activity with that of 46 known wollamides.…”

Recent Reports of Solid-Phase Cyclohexapeptide Synthesis and Applications

“…In 2017, our group reported the total synthesis of the natural products wollamides A ( 48 ) and B ( 42 ) and desotamide B ( 49 ) ( Figure 9 ) using SPPS of linear hexapeptide precursors followed by cleavage and solution-phase cyclization [ 45 ]. A representative synthesis that was used to access wollamide B ( 42 ) is highlighted in Scheme 9 .…”

“…An optimization study investigated the efficiency of the macrocyclization step occurring at each of the six peptide bond sites. This determined that macrocyclization of the linear hexapeptide precursor between terminal L-Leu and D-Leu residues provided the most efficient macrocyclization without any detectable epimerization [ 45 ].…”

“…In 2018, our group reported the antitubercular and antibacterial activities of wollamides A ( 48 ) and B ( 42 ) and desotamide B ( 49 ) as well as structural analogues thereof [ 46 ]. The optimized synthetic route to access these compounds was described previously [ 45 ]. The 27 peptides’ library was screened against a panel of Gram-positive and -negative bacterial pathogens, which discovered that wollamides A ( 48 ) and B ( 42 ) and the position-II L-Ile analogue 52 exhibited promising antibacterial activity against Mycobacterium tuberculosis , with MIC values of 1.56 µg/mL and favorable selectivity indexes (SIs) of >100 ( Figure 10 ) [ 46 ].…”