Synthetic Studies towards the Calcium-Dependent Lipopeptide Antibiotic Cadaside B.

In the current global crisis of antimicrobial resistance, antimicrobial peptides represent a promising source of alternative antibiotics. Recently discovered cadaside B, a novel calcium-dependent antibiotic, exhibits potent antimicrobial activity towards Gram-positive pathogens including multi-drug resistant strains. These properties, coupled with a novel structure, non-cytotoxicity, and low likelihood of developing resistance render cadaside B an important synthetic target. Herein, a synthetic strategy towards cadaside B is reported with the key steps involving on-resin depsipeptide bond formation and solution-phase macrolactamization. Good agreement of the synthetic cadaside B MS/MS fragmentation pattern was observed with the natural product, but a different 1 H NMR spectrum and absence of antimicrobial activity suggest an undetected epimerization event took place during the synthesis. Herein the findings of our synthetic journey and suggestions for future directions are presented.

The tryptophan connection: cyclic peptide natural products linked via the tryptophan side chain.

Covering: from 1938 up to March 2021The electron-rich indole side chain of tryptophan is a versatile substrate for peptide modification. Upon the action of various cyclases, the tryptophan side chain may be linked to a nearby amino acid residue, opening the door to a diverse range of cyclic peptide natural products. These compounds exhibit a wide array of biological activity and possess fascinating molecular architectures, which have made them popular targets for total synthesis studies. This review examines the isolation and bioactivity of tryptophan-linked cyclic peptide natural products, along with a discussion of their first total synthesis, and biosynthesis where this has been studied.

A Concise Synthetic Strategy Towards the Novel Calcium-dependent Lipopeptide Antibiotic, Malacidin A and Analogues.

Malacidin A is a novel calcium-dependent lipopeptide antibiotic with excellent activity against Gram-positive pathogens. Herein, a concise and robust synthetic route toward malacidin A is reported, employing 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis of a linear precursor, including late-stage incorporation of the lipid tail, followed by solution-phase cyclization. The versatility of this synthetic strategy was further demonstrated by synthesis of a diastereomeric variant of malacidin A and a small library of simplified analogues with variation of the lipid moiety.

Folding and duplex formation in mixed sequence recognition-encoded m-phenylene ethynylene polymers.

Oligomers equipped with complementary recognition units have the potential to encode and express chemical information in the same way as nucleic acids. The supramolecular assembly properties of m-phenylene ethynylene polymers equipped with H-bond donor (D = phenol) and H-bond acceptor (A = phosphine oxide) side chains have been investigated in chloroform solution. Polymerisation of a bifunctional monomer in the presence of a monofunctional chain stopper was used for the one pot synthesis of families of m-phenylene ethynylene polymers with sequences ADnA or DAnD (n = 1-5), which were separated by chromatography. All of the oligomers self-associate due to intermolecular H-bonding interactions, but intramolecular folding of the monomeric single strands can be studied in dilute solution. NMR and fluorescence spectroscopy show that the 3-mers ADA and DAD do not fold, but there are intramolecular H-bonding interactions for all of the longer sequences. Nevertheless, 1 : 1 mixtures of sequence complementary oligomers all form stable duplexes. Duplex stability was quantified using DMSO denaturation experiments, which show that the association constant for duplex formation increases by an order of magnitude for every base-pairing interaction added to the chain, from 103 M-1 for ADA·DAD to 105 M-1 for ADDDA·DAAAD. Intramolecular folding is the major pathway that competes with duplex formation between recognition-encoded oligomers and limits the fidelity of sequence-selective assembly. The experimental approach described here provides a practical strategy for rapid evaluation of suitability for the development of programmable synthetic polymers.

H-Bonded Duplexes based on a Phenylacetylene Backbone.

Complementary phenylacetylene oligomers equipped with phenol and phosphine oxide recognition sites form stable multiply H-bonded duplexes in toluene solution. Oligomers were prepared by Sonogashira coupling of diiodobenzene and bis-acetylene building blocks in the presence of monoacetylene chain terminators. The product mixtures were separated by reverse phase preparative high-pressure liquid chromatography to give a series of pure oligomers up to seven recognition units in length. Duplex formation between length complementary homo-oligomers was demonstrated by 31P NMR denaturation experiments using dimethyl sulfoxide as a competing H-bond acceptor. The denaturation experiments were used to determine the association constants for duplex formation, which increase by nearly 2 orders of magnitude for every phenol-phosphine oxide base-pair added. These experiments show that the phenylacetylene backbone supports formation of extended duplexes with multiple cooperative intermolecular H-bonding interactions, and together with previous studies on the mixed sequence phenylacetylene 2-mer, suggest that this supramolecular architecture is a promising candidate for the development of synthetic information molecules that parallel the properties of nucleic acids.

H-Bond Self-Assembly: Folding versus Duplex Formation.

Linear oligomers equipped with complementary H-bond donor (D) and acceptor (A) sites can interact via intermolecular H-bonds to form duplexes or fold via intramolecular H-bonds. These competing equilibria have been quantified using NMR titration and dilution experiments for seven systems featuring different recognition sites and backbones. For all seven architectures, duplex formation is observed for homo-sequence 2-mers (AA·DD) where there are no competing folding equilibria. The corresponding hetero-sequence AD 2-mers also form duplexes, but the observed self-association constants are strongly affected by folding equilibria in the monomeric states. When the backbone is flexible (five or more rotatable bonds separating the recognition sites), intramolecular H-bonding is favored, and the folded state is highly populated. For these systems, the stability of the AD·AD duplex is 1-2 orders of magnitude lower than that of the corresponding AA·DD duplex. However, for three architectures which have more rigid backbones (fewer than five rotatable bonds), intramolecular interactions are not observed, and folding does not compete with duplex formation. These systems are promising candidates for the development of longer, mixed-sequence synthetic information molecules that show sequence-selective duplex formation.