Scaling the Amphiphilic Character and Antimicrobial Activity of Gramicidin S by Dihydroxylation or Ketal Formation

Abstract

The acid lability of aliphatic ketals, which often serve as protection groups for 1,2-diols, is influenced by their local structural environment. The acetonide of the protected amino acid cis-dihydroxyproline (Dyp) is a typical protecting group cleavable by traces of TFA. The tricyclic acetonide of the dipeptide d-Hot═Tap is resistant to TFA and thus can serve as a bioorthogonal modification of bioactive peptides. With the aim of improving antimicrobial activity and hemolytic properties, we use these reactivity differences to scale the membrane affinity of the decapeptide Gramicidin S cyclo(d-Phe-Pro-Val-Orn-Leu-) (GS). The cis-dihydroxylated amino acids are used to increase the polarity of GS or obversely decrease the polarity by stereoselective ketal formation with an aliphatic ketone. While Dyp (GS mimetic 15) has only minimal influence on the biological properties of GS, d-Hot═Tap at the position of d-Phe1-Pro2 eradicates the biological activity (GS mimetic 16). The acid-stable ketals 17-19 are bioorthogonal modifications which reconstitute the biological activity of GS. We describe an improved synthesis of orthogonally protected Fmoc-Dyp-acetonide (9) and of several Fmoc-d-Hot═Tap-ketals for solid-phase peptide synthesis.

Synthesis and Conformational Properties of 3,4-Difluoro-l-prolines

“…Dihydroxylation of Cbz-protected been reported to be high-yielding and very stereoselective, leading to the 2,3-trans-2,4-trans-diol 19d as the major isomer. 44,45,54 A similar result was observed when these conditions were applied to 25a (Table 2, entry 1). Interestingly, starting from the Boc-protected 25a with the osmate ester (entry 2), no all-cis-diol 41a was observed.…”

“…Furthermore, in contrast to base-mediated elimination reactions, it was found that direct Grieco elimination of (4 R )-4-hydroxyproline could also be performed with an N -Fmoc-protecting group ( 26c ) in a very good yield. This procedure is an improvement over the previously reported two-step elimination via 4-SePh intermediates, which are typically prepared from the corresponding 4-OMs or 4-OTs derivatives. − …”

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

“…Alternatively, the β-turn region could be successfully replaced by dipeptide surrogates, provided that the mimics have an aromatic/hydrophobic character and an adequate geometry. In some cases, the antimicrobial and hemolytic activities of GS analogues were shown to be dissociated after the introduction of peptidomimetics. , …”

Synergistic Catalysis of Se and Cu for the Activation of α‐H of Methyl Ketones with Molecular Oxygen/Alcohol to Produce α‐Keto Acetals†

“…Acetal moieties widely exist in polymers and functional materials. [ 8 ] However, the present methods to prepare acetals suffer from the tedious steps or low product yields, resulting in low synthetic efficiency, generation of wastes from the chemical oxidants, some of which are very toxic, or use highly irritant reagents (Scheme 1). [ 9 ] Synthesizing α ‐keto acetals from methyl ketones directly is a practical route for the high atom utilization ratio.…”