- 1,4-disubstituted-[1,2,3]triazolyl-containing analogues of MT-II: Design, synthesis, conformational analysis, and biological activity
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Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The CuI-catalyzed azide-alkyne 1,3-dipolar Huisgen's cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.
- Testa, Chiara,Scrima, Mario,Grimaldi, Manuela,D'Ursi, Anna M.,Dirain, Marvin L.,Lubin-Germain, Nadège,Singh, Anamika,Haskell-Luevano, Carrie,Chorev, Michael,Rovero, Paolo,Papini, Anna M.
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- β-methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligand-receptor interactions and prolonged biological activity
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Topographically modified melanotropin side chain pharmacophore residues Phe7 and Trp9 in a cyclic peptide template (Ac-Nle4-c[Asp-His-Xaa7-Arg- Yaa9-Lys]-NH2) and Phe7 in a linear peptide template (Ac-Ser-Tyr-Ser- Nle4-Glu-His-Xaa7-Arg-Trp-Giy-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of β- methylphenylalanine (β-MePhe)7 and β-methyltryptophan (β-MeTrp)9 and the two isomers of 1,2,3,4-tetrahydro-β-carboline (Tca)9. Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the β-MePhe7 stereoisomeric peptides; up to a 476-fold difference in potency resulted for the β-MeTrp9 peptides, and about a 50-fold difference between the Tca9-containing peptides. Up to a 40-fold difference in potency resulted for the β-MePhe7 stereoisomeric peptides using the linear template in these assays. The relative potency ranking for modifications 'in the cyclic template of β-MePhe7 were 2R,3S > 2S,3S = 2S,3R > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of β-MeTrp9 were 2R,3S > 2R,3R > 2S,3S >> 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca9 were DTca > LTca in both assays. Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the β-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of β- MeTrp9 stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.
- Haskell-Luevano, Carrie,Toth, Kate,Boteju, Lakmal,Job, Constatin,Castrucci, Ana Maria De L.,Hadley, Mac E.,Hruby, Victor J.
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- Microwave-assisted solid-phase synthesis of side-chain to side-chain lactam-bridge cyclic peptides
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Side-chain to side-chain lactam-bridged cyclic peptides have been utilized as therapeutic agents and biochemical tools. Previous synthetic methods of these peptides need special reaction conditions, form side products and take longer reaction times. Herein, an efficient microwave-assisted synthesis of side-chain to side-chain lactam-bridge cyclic peptides SHU9119 and MTII is reported. The synthesis time and efforts are significantly reduced in the present method, without side product formation. The analytical and pharmacological data of the synthesized cyclic peptides are in accordance with the commercially obtained compounds. This new method could be used to synthesize other side-chain to side-chain lactam-bridge peptides and amenable to automation and extensive SAR compound derivatization.
- Tala, Srinivasa R.,Schnell, Sathya M.,Haskell-Luevano, Carrie
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- Potent and Prolonged Acting Cyclic Lactam Analogues of α-Melanotropin: Design Based on Molecular Dynamics
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Utilizing results from previous structure-activity relationships and theoretical studies of α-melanotropin (α-MSH, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its related superpotent analogues, Ac-4,D-Phe7>-α-MSH and , we have designed a new class of α-MSH4-13 and α-MSH4-10 cyclic lactam fragment analogues of α-melanotropin.The cyclic peptides have the following general structures: and , where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr.Formation of the lactam bridge between the side-chain groups Xxx and Yyy was performed either in solution or on a solid-phase support.Seven cyclic peptides were prepared and bioassayed for their melanotropic potency by using standard frog (Rana pipiens) and lizard (Anolis carolinensis) skin bioassays.Relative to α-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: α-MSH (1); (6); (100); (9); (90), (20); (5); (5).Similar results were obtained in the frog skin bioassay, but the analogues were much less potent.Cyclic melanotropins with 23-membered rings exhibited 100-fold higher melanotropic potency than α-MSH with selectivity for the lizard melanocyte receptors over the frog melanocyte receptors.Increasing or decreasing the ring size of these cyclic melanotropins from 23 diminishes the biological potency of the resulting cyclic peptide.The 23- and 24-membered ring analogues showed prologed (residual) biological activities in both biological assays, but the smaller ring systems (20, 21, 22) did not.These results provide new insights into the structural and conformational requirements of α-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.
- Al-Obeidi, Fahad,Castrucci, Ana M. de L.,Hadley, Mac E.,Hruby, Victor J.
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p. 2555 - 2561
(2007/10/02)
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