NMR-Solution Structures and Affinities for the Human Somatostatin G-Protein-Coupled Receptors hsst1–5 of CF3 Derivatives of Sandostatin® (Octreotide)
✍ Scribed by Dieter Seebach; Hans Widmer; Stefania Capone; Richard Ernst; Tobias Bremi; Iris Kieltsch; Antonio Togni; Dominique Monna; Daniel Langenegger; Daniel Hoyer
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- German
- Weight
- 394 KB
- Volume
- 92
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
The previously reported (Helv. Chim. Acta 2008, 91, 2035) derivatives of octreotide (1) with a (CF 3 )-Trp substitution, i.e., 3, and with open-chain structures, i.e., 2, 4, and 5, have been tested for their affinities to hsst 1-5 receptors and subjected to a detailed NMR analysis. Their affinities vary from 15 nm to 5 mm, as compared to 0.6 nm to 0.8 mm for octreotide itself (Table ). This decreased bioactivity may have had to be expected for the open-chain compounds 4 and 5; possible reasons for this decrease in the case of CF 3 derivative of octreotide, 3, are discussed. NMR Analysis (Tables and) provides evidence for increased dynamics of all new derivatives 2 -5. The dynamics of the octreotide molecule 1 was analyzed by (natural-abundance) longitudinal 13 C-T 1 -relaxation time measurements (Table ), from which the conclusion is drawn that the backbone of the macrocycle is rather rigid on the time scale of this method.
We have recently reported the selective S-trifluoromethylations of cystein side chains in peptides [1], using the new electrophilic hypervalent iodine(III)-CF 3 reagents developed in one of our laboratories . One of the substrates used in these investigations was the open-chain, reduced form 2 of octreotide (1; Sandostatin ). Besides the seven amide bonds in the backbone, this octapeptide derivative 2 contains two NH 2 , three OH, and two SH groups on the side chains, and, in addition, it carries a highly nucleophilic 1H-indol-3-yl group in its Trp residue. Still, the trifluoromethylation can be carried out (in a protic medium MeOH/H 2 O!) with preferred attack (> 80%) on the two S-atoms to give product 4. Two other compounds 3 and 5 have also been isolated, in which the 1H-indole ring is trifluoromethylated at C(2). The isolation,