Jack A. J. den Hartog

Solid phase ring-closing metathesis: Cyclization/cleavage approach towards a seven membered cycloolefin

Abstract The application of solid phase ring-closing metathesis (RCM) in a cyclization/cleavage strategy was demonstrated for the first time by the successful synthesis of the seven membered cycloolefin 4 . Probably due to intermolecular metathetical dimerizations at the resin, 4 could not be obtained in higher yields than 54%.

Solid-phase synthesis of peptidosulfonamide containing peptides derived from Leu-enkephalin

Using Boc or Fmoc-protected β-substituted aminoethanesulfonyl chlorides (2-substituted taurylchlorides) the solid-phase synthesis of dipeptidosulfonamides as well as peptidosulfonamide containing peptides derived from Leu-enkephalin is described. The binding activity of the peptidosulfonamide YGGFL derivatives is reported.

Structure ± Activity Studies on the Corticotropin Releasing Factor Antagonist Astressin, leading to a Minimal Sequence necessary for Antagonistic Activity

Corticotropin Releasing Factor (CRF) antagonists are considered promising for treatment of stress‐related illnesses such as major depression and anxiety‐related disorders. We report here the design, synthesis and biological evaluation of 91 truncated astressin analogues in order to deduce the pharmacophoric amino acid residues. Such truncated peptides may serve as valuable lead structures for the development of new small, non‐peptide‐based CRF antagonists. N‐Terminal truncation of astressin led to active CRF antagonists that are substantially reduced in size and are selectively active at the human CRF receptor type 1 in vitro and in vivo. Subsequently, an alanine scan in combination with further truncated derivatives led to the proposal of a new pharmacophoric model of peptide‐based CRF antagonists. It was found that the astressin(27–41)C sequence is the shortest active CRF antagonist. The first eight N‐terminal amino acid residues were found to be an important structural determinant and were replaceable by alanine residues, thus enhancing the α‐helical propensity. A covalent structural constraint is of utmost importance for the preorganization of the C‐terminal amino acid residues. The C‐terminal heptapeptide sequence, however, was found to be crucial for the antagonistic activity, since substitution or deletion of any residue led to inactive compounds.

Two novel syntheses of the histamine H3 antagonist thioperamide

Abstract The previously described route for the synthesis of the histamine H 3 antagonist thioperamide 3 has been improved considerably. Furthermore, two straightforward novel synthetic routes towards 3 are described herein. The last synthetic route (Scheme 3) is preferable as it is very suitable for the production of multigram quantities of thioperamide 3.

Structure-Activity Studies on the Corticotropin Releasing Factor Antagonist Astressin, Minimal Sequence Necessary for Antagonistic Activity: Implications for a New Pharmacophoric Model

Corticotropin Releasing Factor (CRF) is an important physiological regulator of the body response to stressful stimuli [1]. Over-expression of CRF is involved in endocrine, neurologic and psychiatric diseases such as feeding disorders, major depression and anxiety-related disorders. To obtain more insight into the physiological role of CRF, potent peptide antagonists have recently been developed mainly based on the amino acid sequence of CRF, which ultimately led to the discovery of astressin, one of the most potent peptide-based CRF antagonists reported until now [2].