Novel sst₅-Selective Somatostatin Dicarba-Analogues: Synthesis and Conformation−Affinity Relationships

Abstract

We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst 1-5) of a few analogues of the cyclic octapeptide octreotide (1), where the disulfide bridge was replaced by a dicarba group. These analogues were prepared by on-resin RCM of linear hepta-peptides containing two allylglycine residues; first- and second-generation Grubbs catalyst efficiencies were compared. The C=C bridge was hydrogenated via two different methods. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by (1)H NMR spectroscopy. Conformation-affinity relationships confirmed the importance of D-Phe(2) orientation for sst2 affinity. Moreover, helical propensities well correlates with the peptide sst5 affinity. The presence of the bulky aromatic side chain of Tyr(Bzl)(10) favored the formation of a 3(10)-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

“…It is well-known from NMR studies in water and in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 36 substantially alter the secondary structure in the active region. 24 These NMR studies also suggest that there exists a conformational equilibrium between the antiparallel β-sheet structural cluster and a second conformational ensemble involving folded structures for the C-terminal residues. This hypothesis is in good agreement with previously reported findings for 1 that indicate that C-terminal amino acids fold into a 3 10 -helix-like array or in a similar helical ensemble.…”

“…The assembly of the dicarba analogue of octreotide was performed as previously described. 23,24 Briefly, Fmoc-L-threoninol p-carboxyacetal (1.8 mol equiv) was first coupled using DIPC (1.8 mol equiv) and HOBt (1.8 mol equiv) in anhydrous DMF for 1 h. The following Fmoc-protected amino acids (2.4 mol equiv) were incorporated with HATU (2.3 mol equiv) and DIPEA (4.8 mol equiv)…”

“…66 Furthermore, it is important to consider that the structure of 2 in the region of the N-terminal D-Phe 2 and C-terminal Thr(ol) 15 is significantly different from that previously reported for 1, 66 which might explain the differences in affinity for somatostatin receptors. 24 Given the implication of these amino acids both in the affinity and in the specificity for somatostatin receptors, we investigated whether the covalent attachment of metal complexes to the N-terminal end of 2 through a polyethylenglycol linker might alter the active conformation of the peptide and, in particular, the structure around D-Phe 2 and Thr-ol 15 .…”

Solid-phase synthesis and DNA binding studies of dichloroplatinum(ii) conjugates of dicarba analogues of octreotide as new anticancer drugs

“…Given the high affinity of platinum(II) for the thioether group, we chose CH=CH and 15 CH 2 -CH 2 linkages since both dicarba analogues of octreotide (4 and 5, respectively; Scheme 1) retain relatively high binding affinity toward the sst 2 receptor. 11 Furthermore, onresin ring closing metathesis (RCM) and hydrogenation reactions can be used to generate such analogues. 11,12 Thus, 20 we envisaged a stepwise solid-phase strategy to regioselectively introduce the platinum(II) moiety at the Nterminal end of both octreotide analogues through a spacer to keep it away from the pharmacophore sequence (Scheme 2).…”

“…11 Furthermore, onresin ring closing metathesis (RCM) and hydrogenation reactions can be used to generate such analogues. 11,12 Thus, 20 we envisaged a stepwise solid-phase strategy to regioselectively introduce the platinum(II) moiety at the Nterminal end of both octreotide analogues through a spacer to keep it away from the pharmacophore sequence (Scheme 2).…”