Jose Carlos Jimenez

Structure−Activity Relationship of Kahalalide F Synthetic Analogues

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.

Kahalalide B. Synthesis of a natural cyclodepsipeptide

Abstract 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.

Synthesis of peptides containing α, β-didehydroamino acids. Scope and limitations

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.

Solid‐Phase Synthesis of Peptides Containing α,β‐Didehydroamino Acids

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.

Solid-Phase Total Syntheses of Trunkamide A and Kahalalide F, Cyclic Peptides from Marine Origin

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.