Synthesis of an analogue of the substance P C-terminal hexapeptide with modification at the glutaminyl and methioninyl residues and increased activity in NK-2 receptor type: Structure-activity relationships

Manolopoulou, Amalia; Poulos, Constantine; Tsegenidis, T.

doi:10.1016/0223-5234(92)90027-x

European Journal of Medicinal Chemistry

1992

DOI: 10.1016/0223-5234(92)90027-x

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Synthesis of an analogue of the substance P C-terminal hexapeptide with modification at the glutaminyl and methioninyl residues and increased activity in NK-2 receptor type: Structure-activity relationships

Amalia Manolopoulou

Constantine Poulos

T. Tsegenidis

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Cited by 8 publications

(1 citation statement)

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“…Z-Phe-OH was preactivated using HOSu/DCC and the resulting activated ester reacted with 9 in a mixture of 1 M KHCO 3 and THF yielding the dipeptide 10. Amidation of 10 was carried out using HOBt/EDC activation followed by treatment with saturated ammonium hydroxide, 25 and the hydroxyl group in 11 was protected with a TBDPS group. The bis(trifluoroacetoxy)iodobenzene (BTI)-mediated Hofmann rearrangement was employed to convert the amide 12 to the corresponding mono-acylated gem-diamine derivative 13.…”

mentioning

confidence: 99%

Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Jiang

2007

Bioorganic & Medicinal Chemistry Letters

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confidence: 99%

Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Jiang

2007

Bioorganic & Medicinal Chemistry Letters

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Modified chemotactic peptides: synthesis, crystal conformation, and activity of For‐Hse(Me)‐Leu‐Phe‐OMe

et al. 1994

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The presence of the sulfur atom of the methionine side chain exerts significant effects at different levels on biochemical behavior of chemotactic N-formylpeptides. In order to acquire more information on this point, the synthesis, the conformation in the crystal, and the activity of For-Hse(Me)-Leu-Phe-OMe (2)--an oxygen analogue of For-Met-Leu-Phe-OMe (fMLP-OMe) containing the O-methyl-L-homoserine in place of the native methionine at position 1--is reported. The new analogue 2 adopts a conformation that is extended at the first two residues and folded at the C-terminal phenylalanine. This conformation is different from that of the parent fMLP-OMe and strikingly similar to that adopted by fMLP-OBu(t). The side-chain spatial orientation of 2 corresponds to that adopted by fMLP-OH when cocrystallized with an immunoglobulin possessing binding properties similar to those of neutrophil receptors. When tested on human neutrophils the formylpeptide 2 is more active than the parent in the stimulation of directed mobility and maintains both the granule enzyme release activity and the superoxide anion production.

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Case histories of peptidomimetics: Progression from peptides to drugs

Adang

Hermkens

Linders

et al. 1994

Recl. Trav. Chim. Pays‐Bas

107

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Abstract. There is a growing number of biologically active peptides which have potential for the development of new therapeutics. However, native peptides are only rarely directly usable as drugs, due to inherent limitations which include rapid proteolysis and metabolism, poor transport properties, rapid excretion by the liver and kidneys, and low oral activity. Furthermore, peptides are often aselective in their actions owing to their flexible structure. In efforts to address these limitations, peptides are modified into mimetics with specific physical, chemical and biological characteristics. These so-called peptidomimetics are derived from peptides by partly or completely removing the amide bonds while retaining essential amino acid side chains in a defined, spatial relationship. They can be developed in a rational design cycle which starts either from a lead compound obtained in a screening programme or from the parent peptide. In the latter approach, which is the focus of this overview, first the smallest, active sequence is found, and the significance of each amino acid for the biological activity is determined. In the following steps the bioactive conformation is defined by the introduction of local and global constraints. In the final step the essential amino acid side chains are positioned onto a scaffold, preferably a small, polyfunctional ring of defined stereochemistry, using structural information obtained in earlier steps. Five examples of the application of the peptidomimetic design cycle in medicinal chemistry are described here, illustrating the progression from native peptides to therapeutically useful drugs.

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Synthesis of an analogue of the substance P C-terminal hexapeptide with modification at the glutaminyl and methioninyl residues and increased activity in NK-2 receptor type: Structure-activity relationships

Cited by 8 publications

References 24 publications

Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Modified chemotactic peptides: synthesis, crystal conformation, and activity of For‐Hse(Me)‐Leu‐Phe‐OMe

Case histories of peptidomimetics: Progression from peptides to drugs

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