Endothelin biological activity

In the case of endothelin (6), the initial gene product consisting of 212 amino acid residues 56 is first converted into the so-called big-ET-1 (8) by cleavage at the Lys-Arg sites, followed by scission of the Trp-Val bond between position 21 and 22 (Scheme 3). Since folding processes in vivo produce exclusively the biologically active compounds, addition of a part of the prosequence of 6 was expected to possibly favor the correct oxidative folding even when performed in vitro. The C-terminal extension of 6 by the 17-residue prosequence to the big-ET-1 form (8) was without any effect, since isomers 1 and 2 are produced in the same ratio as in the case of 6 (Scheme 3). 57 ... 

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

Pairet L, Wrigley SK, Chetland I, Reynolds EE, Hayes MA, Holloway J, Ainsworth AM, Katzer W, Cheng X-M, Hupe DJ, Charlton P, Doherty AM (1995) Azaphilones with Endothelin Receptor Binding Activity Produced by Penicillium sclerotiorum Taxonomy, Fermentation, Isolation, Structure Elucidation and Biological Activity. J Antibiot 48 913... 

The multiple potential pharmacophore method, used in an absolute or relative sense, provides a powerful new tool for 3D similarity studies. As an example, two endothelin receptor antagonists with about 20 nM activity as antagonists of the ETA receptor were compared [21], Figure 9 shows the numbers of potential 4-point pharmacophores and overlapping pharmacophores. The two compounds have very low 2D similarity, but have significant overlap of their 4-point potential pharmacophores, illustrating the power of the method to find similarity between compounds with similar biological activities. 

Subsequently it was found that the human genome encodes for three endothelin isoforms, one of which, endothelin-1 (ET-I), is identical to the peptide which was isolated from porcine aortic endothelial cells [2]. Endothelin-2 (ET-2) is [Trp ,Leu ]ET-l and endothelin-3 (ET-3) is [Thr Phe Thr Tyr Lys Tyr ]ET-l Figure 8.2). Human big ET-1 is a 38 amino acid peptide and differs from porcine big ET-1 in that it lacks Ser and has VaF instead of Ile Figure 8.1). The endothelins also bear remarkable similarity, both in structure Figure 8.2) and biological activity. 

In terms of smaller molecules, there is a claim that n-pentanoyl-tryptophan (5) inhibits the vasoconstrictive effects of endothelin, but no details of biological activity are quoted [82]. 

Of course, the main interest in the Homer-Wadsworth-Emmons reaction is its application in synthesis. New biologically active molecules synthesised include endothelin receptor antagonist S-0139, which requires phosphonate... 

Jackson M, Burres NS, Karwowski JP, Alder LA, Humphrey PE, Kohl WL, McAlpine JB. Aselacins, novel compounds that inhibit binding of endothelin to its receptor I. The producing organism, fermentation and biological activity. J Antibiot 47 523 -527, 1994. 

J., Ainsworth, A. M., Katzer, W, Cheng, X.-M., Hupe, D. J., Charlton, P., and Doherty, A. M. (1995) Azaphilones with endothelin receptor binding activity produced by Peniciibum sclerotiorum taxonomy, fermentation, isolation, structure elucidation and biological activity. J Antibiot. 48,913-918... 

The biological actions of ET-2 are, for the most part, similar to those of ET-1 but have been studied less extensively. The activity profile of ET-3 is different, this being ascribed to receptor subtype affinity (see section on endothelin receptors). The big endothelins are considerably less potent and rely to a large extent on conversion to their mature forms for activity. 

In 1991 inhibition of PKC activity was found to be at the basis of the vascular smooth muscle cell growth arrest induced by a-tocopherol [16,17]. A number of reports have subsequently confirmed the involvement of PKC in the effect of a-tocopherol on different cell types, including monocytes, macrophages, neutrophils, fibroblasts and mesangial cells [8,18-20]. a-Tocopherol, but not P-tocopherol, was found to inhibit thrombin-induced PKC activation and endothelin secretion in endothelial cells [21]. a-Tocopherol, and not P-tocopherol or trolox, inhibits the activity of PKC fi-om monocytes, followed by inhibition of phosphorylation and translocation of the cytosolic factor p47(phox) and by an impaired assembly of the NADPH-oxidase and of superoxide production [22]. a-Tocopherol has the important biological effect of inhibiting the release of the proinflammatory cytokine, IL-lp, via inhibition of the 5-lipoxygenase pathway [23]. 

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