Search

Kahalalide F (KF) is a natural product currently under phase II clinical trials. Here, we report the solid phase synthesis of 132 novel analogues of kahalalide F and their in vitro activity on a panel of up to 14 cancer cell lines. The structure-activity relationship of these analogues revealed that KF is highly sensitive to backbone stereotopical modification but not to side chain size modification. These observations suggest that this compound has a defined conformational structure and also that it interacts with chiral compounds through its backbone and not through its side chains. The N-terminal aliphatic acid appears to be a hydrophobic buoy in a membrane-like environment. Moreover, significant improvement of the in vitro activity was achieved.

Amino acid sequences and linear or head-to-tail cyclopeptides can be represented conveniently in one-line text formulae using the three-letter symbols. However, other – but nonetheless important – topologies of peptides are ‘side chain-to-head (or tail)’, ‘backbone-to-backbone’, ‘side chain-to-side chain’ cyclopeptides, ‘side chain-to-side chain’ connected peptide strands, and branched peptides (like peptide dendrimers). In general, such structures cannot be described using the three-letter symbols in one-line text: a chemical structure editor is required for symbolic representations according to the IUPAC-IUBMB recommendations. The aim of this contribution is to offer an unambiguous and general nomenclature system that enables researchers to represent all cyclic and branched homo- and hetero-detic peptides in a coherent manner in one-line text – as long as their as constituents can be represented in (three)-letter codes. The application of this new nomenclature would overcome the existing difficulties and provide a way to express complex situations in the shortest way in order to highlight more clearly the salient points in a given scientific communication.

[reaction: see text] A solid-phase method for the synthesis of tentoxin has been developed. Two key steps-dehydration and N-alkylation-are carried out while the peptide is anchored to the resin. The method, which has been validated by the preparation of a library of tentoxin analogues, should be applicable to the generation of further libraries that have the tentoxin scaffold structure, as well as other structures containing N-alkylated didehydroamino acids.

An optimized solid-phase strategy for the preparation of the cyclic lipononadepsipeptide [N-Mst(L-Ser1), D-Ser4, L-Thr6, L-Asp8, L-Thr9]syringotoxin is reported. The strategy is based on the use of a mild orthogonal protection scheme and the incorporation of the nonproteinogenic amino acid (Z)-Dhb into the peptide chain as the dipeptide Fmoc-Thr(tBu)-(Z)-Dhb-OH. The didehydrodipeptide was synthesized by a water-soluble carbodiimide-induced beta-elimination of a protected dipeptide containing a residue of Thr with its free hydroxy side chain unprotected.

α, β-Didehydroamino acids, which are key components of both natural andde novo peptides, are frequently encountered in naturally occurring peptides — mostly of microbial and fungal origin and/or from marine organisms. Herein, we report on a reappraisal of the use of the water-soluble carbodiimide/CuCl method for the preparation of this kind of peptide in both solution and solid-phase modes and describe some side reactions encountered during the process.

Kahalalide F, the only member of the family of peptides called kahalalides, isolated from the sacoglossan mollusc Elysia rufescens and the green alga Bryopsis sp., with important bioactivity, is in clinical trials for treatment of prostate cancer. An efficient solid-phase synthetic approach is reported. Kahalalide F presents several synthetic difficulties: (i) an ester bond between two beta-branched and sterically hindered amino acids; (ii) a didehydroamino acid; and (iii) a rather hydrophobic sequence with two fragments containing several beta-branched amino acids in a row, one of them terminated with a saturated aliphatic acid. The cornerstones of our strategy were (i) a quasiorthogonal protecting system with allyl, tert-butyl, fluorenyl, and trityl-based groups, (ii) azabenzotriazole coupling reagents, (iii) formation of the didehydroamino acid residue on the solid phase, and (iv) cyclization and final purification in solution. HPLC, high-field NMR, and biological activity studies showed that the correct stereochemistry of the natural product is that proposed by Rinehart et al. whereas the stereochemistry proposed by Scheuer et al. is that of a biologically less active diastereoisomer.

α,β-Didehydroamino acids are frequently encountered in natural peptides with important biological activity. Herein, we report a mild and convenient method for the preparation of peptides containing α,β-didehydroamino acids, where solid-phase techniques are used both for elongation of the peptide chain and formation of the double bond. This bond is formed through a β-elimination reaction, using a water soluble carbodiimide as the activating reagent of the hydroxyl function, and catalyzed by CuCl.

A suitable combination of soluble and polymeric protecting groups and coupling reagents has allowed the first synthesis of the natural cyclodepsipeptide of marine origin Kahalalide B to be carried out.

A suitable combination of soluble and polymeric protecting groups and coupling reagents has allowed the first synthesis of the natural cyclodepsipeptide of marine origin Kahalalide B to be carried out.

The sea is a great source of biodiversity, because life conditions there create unique mechanisms of chemical defense. Herein, the solid-phase total synthesis of Trunk-amide A [1] and Kahalalide F [2] (Figure 1), two cyclic peptides from marine origin which are currently in preclinical and clinical phase I trials respectively, are discussed. Trunkamide A contains a thiazoline heterocycle and Ser and Thr with the hydroxy function modified as reverse prenyl (rPr). Kahalalide F contains: (i) an ester bond between two sterically hindered amino acids (Val and D-allo-Thr); (ii) the didehydro-amino butyric acid (Dhb); and (iii) a rather hydrophobic sequences with two fragments containing several β-branched amino acids in a row, one of them terminated with an aliphatic acid. Common features of both syntheses are: (i) solid-phase peptide chain elongation using a quasi orthogonal protecting scheme with allyl, t-butyl, fluorenyl based groups, on a chlorotrityl resin; (ii) concourse of HOAt based coupling reagents; and (iii) cyclizations in solution.