A tetradecapeptide somatostatin dicarba-analog: Synthesis, structural impact and biological activity

Martín‐Gago, Pablo; Ramón, Rosario; Aragón, Eric; Fernández‐Carneado, Jimena; Martín-Malpartida, Pau; López‐Ruiz, Pilar; Colás, Begoña; Cortés, María Alicia; Ponsati, Berta; Macias, María J.; Riéra, Antoni

doi:10.1016/j.bmcl.2013.11.065

Cited by 23 publications

(21 citation statements)

References 35 publications

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“…The affinity for SSTR3 dropped one order of magnitude compared to peptide 1 , whereas that towards SSTR2 increased. Overall, the geometry of peptide 4 was similar to that of Somatostatin analogs with Msa in position 7, previously described by our group222324. The main difference was that the π−π interaction was now offset-stacked instead of edge-to-face .…”

Section: Resultssupporting

confidence: 55%

“…Moreover, some of these new 14-residue peptides showed high conformational stability (particularly those that also had a D-Trp in position 8), thereby allowing the determination of their 3D structures by NMR for the first time, in a similar way as previous studies devoted to short-ring analogs, including Octreotide. These structures confirmed the relevance of non-covalent interactions between aromatic residues in positions 6, 7 and 11 in the modulation of the conformation and binding behavior of the correspondent Somatostatin analogs222324.…”

supporting

confidence: 70%

“…Peptides 1–6 (Fig. 1) were prepared by standard Fmoc/ t Bu solid-phase peptide synthesis (SPPS)35 using 2-chlorotrityl chloride resin222324. The schematic representation of the synthetic strategy used for the six peptides is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3′,5′difluorophenyl)-alanine

Martín‐Gago

Rol

Todorovski

et al. 2016

Sci Rep

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Somatostatin is a 14-residue peptide hormone that regulates the endocrine system by binding to five G-protein-coupled receptors (SSTR1–5). We have designed six new Somatostatin analogs with L-3-(3′,5′-difluorophenyl)-alanine (Dfp) as a substitute of Phe and studied the effect of an electron-poor aromatic ring in the network of aromatic interactions present in Somatostatin. Replacement of each of the Phe residues (positions 6, 7 and 11) by Dfp and use of a D-Trp8 yielded peptides whose main conformations could be characterized in aqueous solution by NMR. Receptor binding studies revealed that the analog with Dfp at position 7 displayed a remarkable affinity to SSTR2 and SSTR3. Analogs with Dfp at positions 6 or 11 displayed a π-π interaction with the Phe present at 11 or 6, respectively. Interestingly, these analogs, particularly [D-Trp8,L-Dfp11]-SRIF, showed high selectivity towards SSTR2, with a higher value than that of Octreotide and a similar one to that of native Somatostatin.

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Section: Resultssupporting

confidence: 55%

supporting

confidence: 70%

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Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3′,5′difluorophenyl)-alanine

Martín‐Gago

Rol

Todorovski

et al. 2016

Sci Rep

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“…Other examples of hydrocarbon bridges as isosteric replacements of disulfides in bioactive peptides have been reviewed [4,6] and reported in the literature, among others, to arrive at redox-stable analogs of sunflower trypsin inhibitors [88], cyclic dermorphin tetrapeptides [89], cyclic enkephalin peptides [90,91], octreotide- [92][93][94] and somatostatin-derived peptides [95], and an antimicrobial human β-defensin-1 derivative [96] and leucocin A analogs [97].…”

Section: Dicarba Analogs By Rcm To Mimic Disulfide and Thioether Bridgesmentioning

confidence: 98%

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

Rijkers

2015

Topics in Heterocyclic Chemistry

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This review surveys developments in the field of ring-closing metathesis and cross-metathesis reactions applied to the synthesis of constrained amino acids, peptides, and peptidomimetics. Examples, in which metathesis is used as one of the synthetic tools to arrive at the desired peptide molecules as well as examples that describe in-depth optimized metathesis protocols, will be discussed. Currently, metathesis reactions are well-accepted synthetic tools within the field of peptide chemistry and provide peptides unprecedented properties like conformational, metabolic, and chemical stability and improved bioactivity.

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“…After optimizations, the intramolecular Suzuki-Miyaura coupling afforded the desired macrocycle 225 in 50% yield. A similar RCM cyclization on an on-resin peptide has been recently used by Gago and co-workers, for the synthesis of a series of somatostatin analogues (Scheme 45) [85]. To compare the effects of the resin on the cyclization step, the peptides have been elongated on two types of resin (chlorotrityl resin and HMBA rink amide resin), according to a conventional Fmoc/tBu strategy: the authors used a low substitution level on the resins, in order to avoid cross-metathesis.…”

Section: Scheme 44mentioning

confidence: 99%

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

et al. 2016

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This review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. Green syntheses and solvent-free procedures have been introduced whenever possible. The syntheses discussed herein have been selected to illustrate the huge potential of microwave in the synthesis of highly functionalized molecules with potential therapeutic applications, in high yields, enhanced reaction rates and increased chemoselectivity, compared to conventional methods. More than 100 references from the recent literature are listed in this review.

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A tetradecapeptide somatostatin dicarba-analog: Synthesis, structural impact and biological activity

Cited by 23 publications

References 35 publications

Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3′,5′difluorophenyl)-alanine

Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3′,5′difluorophenyl)-alanine

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

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