Chiral Synthesis of a New Protected γ-Lactam Bridged Dipeptide

Nj, Ede; Rae, ID; Hearn, Mtw

doi:10.1071/ch9910891

Cited by 16 publications

(8 citation statements)

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“…The introduction of Bgl into peptides was first reported during studies of the insulin potentiating and hypoglycemic activities of the fragment [6][7][8][9][10][11][12][13] of human growth hormone (hGH) in which replacement of Asp 11 by (S)-Bgl conserved biological activity and extended the duration of action. [22][23][24][25] In addition, Bgl peptide analogues have exhibited CCK-A receptor agonism with high affinity and selectivity, 26 as well as enhancement of the binding of [ 3 H]N-propylnorapomorphine to dopamine receptors. 27 Systematic scans of a peptide with Agl and Bgl residues may provide information concerning the structural requirements for biological activity by placing a constraint about the ψ-dihedral angle.…”

Section: Introductionmentioning

confidence: 99%

Positional Scanning for Peptide Secondary Structure by Systematic Solid-Phase Synthesis of Amino Lactam Peptides

et al. 2009

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Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined alpha- and beta-amino gamma-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates 9 and 8 minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 lactam derivatives and validated the effectiveness of this approach on peptides bearing aliphatic, aromatic, branched, charged, and heteroatomic side chains. The binding affinity IC(50) values of the GHRP-6 lactam analogues on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogues. In these cases, lactam analogues were prepared exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biological activity.

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Section: Introductionmentioning

confidence: 99%

Positional Scanning for Peptide Secondary Structure by Systematic Solid-Phase Synthesis of Amino Lactam Peptides

et al. 2009

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“…His-(R)-Agl-Ala-Trp-D-Phe-Lys-NH 2 (26) Structure-Activity Analysis of the Growth Hormone Secretagogue GHRP-6 (33) …”

Section: His-(r)-agl-ala-trp-d-phe-lys-nh 2 (26)mentioning

confidence: 99%

“…We now report the synthesis of eleven new GHRP-6 lactam analogs employing (R )-Agl (25)(26)(27)(28)(29) and (R )-Bgl residues (30)(31)(32)(33)(34)(35) in an efficient split-and-mix approach using IRORI Kan TM techniques and cyclic sulfamidate reagents (R )-3 and (R )-4. The respective (R )-amino lactam peptides have been tested for binding affinity with receptors CD36 and GHS-R1a and compared with their (S)-lactam counterparts in a summary of the biological data.…”

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confidence: 99%

“…b-Amino-c-lactam (Bgl, 2, Figure 2) has been less frequently used to study peptide structure. Replacement of Asp 11 by (S)-Bgl in the fragment [6][7][8][9][10][11][12][13] of human growth hormone conserved insulin-potentiating activity and provided extended duration of action (24)(25)(26)(27). In addition, Bgl peptide analogs have exhibited CCK-A receptor agonism with high affinity and selectivity (28), as well as significant enhancement of the binding of [ 3 H]N-propylnorapomorphine to dopamine receptors (29).…”

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confidence: 99%

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Structure–Activity Analysis of the Growth Hormone Secretagogue GHRP‐6 by α‐ and β‐Amino γ‐Lactam Positional Scanning

et al. 2009

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Incorporation of amino lactams into biologically active peptides restricts conformational mobility and may enhance selectivity and increase potency. a-and b-amino c-lactams (Agl and Bgl), in both S and R configurations, were introduced into the growth hormone secretagogue GHRP-6 using a Fmoc-compatible solid-phase protocol relying on N-alkylation with five-and six-membered cyclic sulfamidates, followed by lactam annulation under microwave heating. Using this protocol in conjunction with IRORI Kan TM techniques furnished eleven new GHRP-6 analogs, and their binding affinity IC 50 values on both the growth hormone secretagogue receptor 1a (GHS-R1a) and CD36 receptors are herein reported. The results indicate that selectivity towards one receptor or the other can be modulated by lactam substitution, typically at the Ala 3 and the D-Phe 5 positions.

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“…The 2-pyrrolidinone (γ-lactam) ring system is present in a large number of molecules possessing medicinal values such as psychotropic agents [1,2], muscarinic acid agonists [3], antihypertensive agents [4], peptide mimics [5,6]. γ-Lactams are also versatile synthetic intermediates, particularly of pyrrolidine alkaloids and γ-aminobutyric acid analogues [7][8][9].…”

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confidence: 99%

Synthesis of 1-acyl-2-oxo-3-pyrrolidinecarbonitriles by the reaction of 2-acylamino-4,5-dihydro-3-furancarbonitriles with sodium iodide

Yamagata

Okabe

Maruoka

et al. 2005

Journal of Heterocyclic Chemistry

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The reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles 1 with sodium iodide in N,N‐dimethyl‐formamide gave the corresponding 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles 2 in good yields. Successive treatment of 1 with titanium(IV) chloride and potassium carbonate resulted in the formation of N‐acyl‐1‐cyanocyclopropanecarboxamides 4. The same compounds 2 were also obtained by treatment of 4 with sodium iodide. The starting compounds 1 were synthesized by the reaction of 2‐amino‐4,5‐dihydro‐3‐furan‐carbonitrile with acyl chlorides in pyridine.

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Chiral Synthesis of a New Protected γ-Lactam Bridged Dipeptide

Cited by 16 publications

References 0 publications

Positional Scanning for Peptide Secondary Structure by Systematic Solid-Phase Synthesis of Amino Lactam Peptides

Positional Scanning for Peptide Secondary Structure by Systematic Solid-Phase Synthesis of Amino Lactam Peptides

Structure–Activity Analysis of the Growth Hormone Secretagogue GHRP‐6 by α‐ and β‐Amino γ‐Lactam Positional Scanning

Synthesis of 1-acyl-2-oxo-3-pyrrolidinecarbonitriles by the reaction of 2-acylamino-4,5-dihydro-3-furancarbonitriles with sodium iodide

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