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US5990273A - Synthesis of cyclic peptides - Google …

04/06/2015 · Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

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Cyclic Peptide Synthesis with Thioacids - ResearchGate

Cyclic peptides are generally considered to be more stable against proteolytic enzymes than their linear counterparts and can facilitate elucidation of bioactive conformations that are important for biological activity. To date, a cyclic peptide that acts as an inhibitor of LSD1 has not been described. Peptides having less than 16 amino acid residues bind poorly to LSD1, and optimal binding appears to require 21 amino acid residues. Thus, we used ligand-based techniques to design and synthesize a series of linear and cyclic peptides based on the 21 amino acid H3K4 binding region. Because it is a potent peptide-based inhibitor of LSD1, the X-ray crystallographic structure of LSD1-CoREST bound to 6 was used as the basis for the design of these cyclic peptide inhibitors. The X-ray crystallographic conformation of the bound [Met]4 H3 (1–21)–OH peptide 6 revealed that the side chains of certain amino acid residues are in proximity to each other in three dimensions. For example, Arg2 and Gln5, Arg2 and Ser10, Arg2 and Gly12, Arg2 and Lys14, and Gln5 and Ser10 were identified as pairs of amino acid residues situated in close proximity (Figure ) during LSD1 binding to 6.

Cyclic peptides where the amino acids are connected by nonmatrix synthesis

We next evaluated the efficacy of a photolabile -substituent and the scope of a macrolactonization protocol. As shown in , -alkylated peptide 6 was produced by an Ugi reaction in good yield and subsequently subjected to saponification and standard macrolactonization with EDC. Final DMB cleavage led to isolated cyclic depsipeptide 7b in 68% yield over three steps. Alternatively, 2-nitrobenzylamine (NB) and phenylalanine-derived Nenajdenko isocyanide were employed in the multicomponent synthesis of the -alkylated peptide 8, which was subsequently deprotected and macrocyclized with T3P for 12 h. In this case, the cyclization/oNB cleavage protocol produced the cyclic peptide 9b in 48% yield after HPLC purification. HPLC/ESI-MS analysis after DMB cleavage showed 75% of purity for the cyclic monomer, with only 4% of the -terminal epimer. On the other hand, HPLC traces of a parallel macrocyclization with the non--alkylated analogue showed 51% of purity of cyclopeptide 9b, with 7% of the dimer and 9% of the -terminal epimer. Again, the Ugi-derived fragment improved the cyclization efficiency as compared with the canonical peptide and reduces cyclodimerization. It should be mentioned that these examples encompass the ligation of tripeptide carboxylic acids and amino acid-derived isocyanides, which move the -alkylation position away from the favorable middle and place it one amino acid toward the -terminus. However, even if this is not the ideal positioning, the turn inducer produced better results than without it.

Cyclic peptide synthesis with thioacids.

To produce peptides that were constrained in the bound conformation of 6, we constructed peptides substituted in select positions with one Lys residue and one Glu residue, and cyclized these residues to form a lactam bridge (Table ). Standard N-Fmoc/Bu chemistry was used to construct all linear and cyclic peptide analogues in this study (See the for a complete description of the chemical synthesis). Polystyrene resin with low substitution (0.36 mmol/g) was used as a polymer support to yield all peptides as C-terminal carboxyamides.

Herein, we extend this multicomponent strategy to the synthesis of backbone amide-linked peptides and their subsequent derivatization by peptide growth and final cyclization. As illustrated in , our approach does not require the initial incorporation of a cleavable aldehyde linker and subsequent reductive amination and acylation, but instead it comprises the direct incorporation of an Fmoc-amino acid and an isocyanide peptide or amino acid to the polymer support having the Rink amide linker. To carry out the on-resin Ugi-4CR, an aminocatalytic transimination step using paraformaldehyde and piperidine is required prior addition of the acid and the isocyanide. Other aldehydes can be employed without such transimination step but may result in a final mixture of two diastereomers. As at least a tripeptide is attached to the resin in the first step, this enables bypassing the difficult acylation step of the secondary amine and, even more important, avoids diketopiperazine (DKP) formation, which is common in BAL approaches if Fmoc deprotection is used at the dipeptide stage. In addition, our multicomponent strategy preserves high flexibility for protecting groups, as either ethyl or allyl esters can be used at the -terminus and Boc/Bu groups at the side chains, being orthogonal to the Fmoc methodology employed for peptide elongation.

Patent US5596078 - Synthesis of cyclic peptides - …

Lysine specific demethylase 1 (LSD1) selectively removes methyl groups from mono- and dimethylated histone 3 lysine 4 (H3K4), resulting in gene silencing. LSD1 is overexpressed in many human cancers, resulting in aberrant silencing of tumor suppressor genes. Thus, LSD1 is a validated target for the discovery of antitumor agents. Using a ligand-based approach, we designed and synthesized a series of cyclic and linear peptides that are effective inhibitors of LSD1. Linear peptide 7 and cyclic peptide 9 inhibited LSD1 in vitro by 91 and 94%, respectively, at a concentration of 10 μM. Compound 9 was a potent LSD1 inhibitor (IC50 2.1 μM; i 385 nM) and had moderate antitumor activity in the MCF-7 and Calu-6 cell lines in vitro. Importantly, 9 is significantly more stable to hydrolysis in rat plasma than the linear analogue 7. The cyclic peptides described herein represent important lead structures in the search for inhibitors of flavin-dependent histone demethylases.

The on-resin macrocyclization of hexapeptides proceeded smoothly to furnish cyclic peptides 18 and 19 in good overall yield and without cyclodimerization. Peptide 18 derives from the initial incorporation of Fmoc-Ile-OH and isocyanide CN-Phe-Gly-OMe, while the synthesis of 19 begins with Fmoc-Phe-OH and ethyl isocyanoacetate. To further prove the scope of this method, we undertook the total synthesis of the natural product crassipin B. This cyclic heptapeptide was produced in overall 53% yield through the initial multicomponent attachment of Fmoc-Phe-OH and ethyl isocyanoacetate to the resin, followed by peptide growing using the Fmoc strategy and consecutive macrocyclization and acidic cleavage from resin. In summary, this new multicomponent BAL strategy can be considered as a valuable and efficient improvement in peptide synthesis. Several factors such as the low synthetic cost for incorporating the first three or four amino acids into the resin, the great tolerance of protecting groups, and the complete absence of DKP formation, among others, make it a plausible alternative to classic BAL approaches. It is especially valuable for cyclic peptides having at least one Gly or Aib residue or for the construction of D/L peptide library including natural and non-natural amino acids, as higher aldehydes can be used leading to the two diastereomers.

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  • Patent US5990273 - Synthesis of cyclic peptides - …

    Abzena focus on synthesising high purity (>98%) and difficult to produce, cyclic and conjugated peptides

  • SYNTHESIS OF CYCLIC PEPTIDE - Patent - Europe PMC

    Solid-Phase Synthesis of Cyclic Peptide−DNA Hybrids

  • Solid-Phase Synthesis of Cyclic Peptide−DNA Hybrids Colleen F

    Cyclic Peptide Synthesis - Small Molecule, Big Dream

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Cyclic citrullinated MBP87–99 peptide …

The head-to-tail cyclization of short peptides stands as one of the most challenging procedures in synthetic chemistry. Typical problems encountered in this process are the -terminal epimerization and cyclooligomerization. Whereas new coupling reagents and synthetic tools have been developed to partially solve these issues, they are intrinsically dependent on both the sequence and the ring size and, therefore, difficult to generalize in short peptides. Besides the classic solutions of either conducting the peptide macrocyclization at extreme dilution (even 0.01 mM) or employing pseudo-dilution conditions, the most successful strategy has been the incorporation of turn-inducing elements capable of facilitating the macrocyclic ring closure by bringing both termini closer.

Custom Peptide Synthesis Services($1.9/AA) - …

In conclusion, we have developed an efficient strategy to assist peptide macrocyclization both in solution and on the solid phase. The approach uses the versatile Ugi-4CR for the ligation of peptides and the simultaneous incorporation of a removable -alkyl substituent that serves as a turn-inducing moiety and facilitates the macrocyclic ring closure. Its assistance to the macrocyclization was proven with a variety of tetra- to heptapeptides. An extension of this concept to the solid phase led to the development of a new BAL strategy, relying for the first time on the multicomponent incorporation of at least three amino acids in one step instead of the three on-resin steps required in traditional BAL protocols for attaching a dipeptide fragment. Owing to its synthetic prospects, this concept can be very useful for the peptide, combinatorial, and medicinal chemistry communities.

Custom Peptide Synthesis - New England Peptide

2. Peptidomimetic development - With the information obtained from the peptide optimization, Mimotopes will explore a number of modifications, including bioisosteres, modified terminal endings, and amino acid modifications to increase the stability, bioavailability and pharmacokinetics of the leading compound(s). This process also includes the use of cyclic peptides, an approach which has been successful in the development of drugs which are now on market. Mimotopes has developed proprietary technology for the efficient synthesis of collections of C-N cyclic peptides, ideal for this phase of the project.

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