Untitled

On-resin peptide macrocyclization using thiol–ene click chemistry

“…Peptide macrocyclization, including peptide stapling, 2 has been shown to address these limitations and result in a molecule with increased potency. Cyclic peptides show increased stability to proteolytic degradation 3 relative to their linear precursors and are able to bind to their intended target at decreased effective concentrations, mainly attributed to the constrained conformation lowering the entropic cost of binding. 4 …”

“…(ii) DMPA (1 equiv. ), hn (365 nm, 20 mW cm À2 ), 20-60 min; (iii) TFA/ TIPS/H 2 O. Alkenes were incorporated using Fmoc-Lys(Alloc)-OH monomer(1,3) or on-resin modification using 5-norbornene-2-carboxylic acid (2, 4).…”

Development of Conformationally Restricted Analogues of Bradykinin and Somatostatin Using Constrained Amino Acids and Different Types of Cyclization

“…Some years later, Bass et al introduced disulfide-linked cyclic octapeptide antagonists which contained a DCys in position 6 and LCys in position 27 -Ac-(4-NO 2 -Phe)-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 [189] 28 DC-38-48 Nal-c(DCys-Pal-DTrp-Lys-Val-Cys)-Nal-NH 2 [188] 29 PRL-2970 Cpa-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-Nal-NH 2 [190] 30 PRL-2915 Nal-c(DCys-Pal-DTrp-Lys-Tle-Cys)-Nal-NH 2 [190] 31 AC-178,335 Ac-DHis-DPhe-DIle-DArg-DTrp-DPhe-NH 2 [191] Abbrevation: Ahp, 7-aminoheptanoyl; Nal, 3-(2-naphthyl)alanine; Cpa, 4-chlorophenylalanine; Pal, 3-pyridylalanine; Tle, tert.-leucine; 11 relative to SRIF. One peptide (27) displayed high affinity binding to sst2 comparable to native somatostatin but reversed the somatostatin-mediated cAMP accumulation in rat somatomammotroph GH 4 C 1 cells as well as SRIFstimulated growth of sst2 expressing yeast cells. The antagonistic effect was assigned to the inverted chirality in position 6, since replacement by LCys led to the conversion into an agonist (Table 5) [189].…”

“…Since we found incomplete condensation of hydrophobic amino acids onto N α -functionalised building units we prefer the utilisation of preformed dipeptide building units. Both, the solution syntheses of suitable building units as well as the assembly of backbone cyclic peptide hormones on the solid phase were described by different authors and published in corresponding chemical journals [for a selection see [26][27][28].…”

“…The potent and highly sst5 selective heptapeptide PTR 3046 (Table 4, (24)) contained Naminoethyl-Phe and N-carboxypropyl-Phe in positions 6 and 11, respectively [26]. In a similar approach we have introduced N-functionalised dipeptide building units of different types into octapeptide analogues of somatostatin [27]. The two types of dipeptide building units used for backbone cyclization differed in the peptide bond modification which can be an alkylated (Ψ[CON(R)]) or an acylated reduced peptide bond (Ψ[CH 2 N(COR)]).…”