Journal of Medicinal Chemistry
Brief Article
δ: 1.05 (6H, d, D-Ala CH3), 2.53 (4H, t, hβ3Phe hβCH2), 2.71−2.85
(4H, m, Tyr βCH2), 2.73−2.80 (4H, m, hβ3Phe βCH2), 3.53−3.61
(4H, m, Gly αCH2), 3.85 (2H, t, Tyr αCH), 4.15 (2H, m, hβ3Phe
αCH), 4.34 (2H, t, D-Ala αCH), 6.65−7.01 (8H, m, Tyr Ar), 7.12−
7.27 (10H, m, hβ3Phe Ar), 7.88 (2H, d, hβ3Phe NH), 8.05 (6H, d, Tyr
REFERENCES
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+
NH3 ), 8.17 (2H, t, Gly NH), 8.52 (2H, d, D-Ala NH), 9.44 (2H, s,
OH), 10.03 (2H, s, NH−NH). ESI-HRMS calcd for C52H62F6N10O14
m/z: 1165.4429 [M + H]+; found 1165.4431.
2 TFA·(Tyr-D-Ala-βAla-Phe-NH)2 (2). Rf = 0.41 (n-Bu-OH/AcOH/
1
H2O 4:1:1). Rt (HPLC) = 19.26 min. HNMR (DMSO-d6) δ: 1.21
(6H, d, D-Ala CH3), 2.16−2.27 (4H, m, βAla CH2−CO), 2.70−2.80
(4H, m, Tyr βCH2), 2.77−2.86 (4H, m, Phe βCH2), 3.54−3.71 (4H,
m, βAla CH2−N), 3.85 (2H, t, Tyr αCH), 4.38−4.49 (2H, m, D-Ala
αCH), 4.52 (2H, t, Phe αCH), 6.69−6.96 (8H, m, Tyr Ar), 7.09−7.25
+
(10H, m, Phe Ar), 7.76 (2H, d, βAla NH), 8.04 (6H, d, Tyr NH3 ),
8.20 (2H, d, Phe NH), 8.36 (2H, d, D-Ala NH), 9.36 (2H, s, OH),
10.21 (2H, s, NH−NH). ESI-HRMS calcd for C52H62F6N10O14 m/z:
1165.4429 [M + H]+; found 1165.4431.
2 TFA·(Tyr-βAla-Gly-Phe-NH)2 (3). Rf = 0.39 (n-Bu-OH/AcOH/
1
H2O 4:1:1). Rt (HPLC) = 19.55 min. HNMR (DMSO-d6) δ: 2.27−
2.32 (4H, m, βAla CH2−CO), 2.67−2.81 (4H, m, Tyr βCH2), 2.87−
2.92 (4H, m, βAla CH2−N), 2.91−2.99 (4H, m, Phe βCH2), 3.28−
3.39 (4H, m, Gly αCH2), 3.77 (2H, t, Tyr αCH), 4.24 (2H, t, Phe
αCH), 6.65−6.95 (8H, m, Tyr Ar), 7.11−7.28 (10H, m, Phe Ar), 7.71
+
(2H, d, βAla NH), 8.07 (6H, d, Tyr NH3 ), 8.16 (2H, t, Gly NH),
8.22 (2H, d, Phe NH), 9.25 (2H, s, OH), 10.19 (2H, s, NH−NH).
ESI-HRMS calcd for C50H58F6N10O14 m/z: 1137.4116 [M + H]+;
found 1137.4120.
̈
̈
2 TFA·(hβ3Tyr-D-Ala-Gly-Phe-NH)2 (4). Rf = 0.53 (n-Bu-OH/
1
AcOH/H2O 4:1:1). Rt (HPLC) = 29.48 min. HNMR (DMSO-d6)
δ: 1.12 (6H, d, D-Ala CH3), 2.61 (4H, t, hβ3Tyr βCH2), 2.78 (4H, t,
hβ3Tyr hβCH2), 2.96−3.01 (4H, m, Phe βCH2), 3.37−3.49 (4H, m,
Gly αCH2), 3.66−3.74 (2H, m, hβ3Tyr αCH), 4.19−4.23 (2H, m, D-
Ala αCH), 4.60 (2H, m, Phe αCH), 6.60−6.93 (8H, m, hβ3Tyr Ar),
+
7.07−7.20 (10H, m, Phe Ar), 7.81 (6H, d, hβ3Tyr NH3 ), 8.07 (2H, t,
Gly NH), 8.21 (2H, d, Phe NH), 8.33 (2H, d, D-Ala NH), 9.38 (2H, s,
OH), 10.15 (2H, s, NH−NH). ESI-HRMS calcd for C52H62F6N10O14
m/z: 1165.4429 [M + H]+; found 1165.4426.
ASSOCIATED CONTENT
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S
* Supporting Information
Synthetic procedures, characterization of intermediates, bio-
logical assays, and stability assay. This material is available free
(6) Seebach, D.; Beck, A. K.; Bierbaum, D. J. The world of β- and γ-
peptides comprised of homologated proteinogenic amino acids and
other components. Chem. Biodiversity 2004, 1, 1111−1239.
AUTHOR INFORMATION
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Corresponding Author
Notes
(7) (a) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar,
M. I. Design and Synthesis of Inhibitors Incorporating β-Amino Acids
of Metalloendopeptidase EC 3.4.24.15. J. Pept. Sci. 2000, 6, 470−477.
(b) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hintermann,
T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V.; Oberer, L.; Hommel, U.;
Widmer, H. β2- and β3-Peptides with Proteinaceous Side Chains:
Synthesis and Solution Structures of Constitutional Isomers, a Novel
Helical Secondary Structure and the Influence of Solvation and
Hydrophobic Interactions on Folding. Helv. Chim. Acta 2003, 86,
2098−2103.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported in part by grants from the U.S. Public
Health Service, Natural Institutes of Health, DA00624 and
DA13449.
(8) (a) Seebach, D.; Matthews, J. L. β-Peptides: a surprise at every
turn. Chem. Commun. 1997, 21, 2015−2126. (b) Seebach, D.; Abele,
S.; Gademann, K.; Guichard, G.; Hintermann, T.; Jaun, B.; Matthews,
J. L.; Schreiber, J. V.; Oberer, L.; Hommel, U.; Widmer, H. β2- And β3-
Peptides with Proteinaceous Side Chains: Synthesis and Solution
Structures of Constitutional Isomers, a Novel Helical Secondary
Structure and the Influence of Solvation and Hydrophobic Interactions
on Folding. Helv. Chim. Acta 1998, 81, 932−982.
ABBREVIATIONS USED
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DOR, δ-opioid receptor; EDC, 1-ethyl-(3-dimethylaminoprop-
yl)-carbodiimide; ESI-HRMS, electrospray ionization−high
resolution mass spectrometry; GPI, guinea pig ileum; [3H]-
DAMGO, [3H]-[D-Ala(2), N-Me-Phe-(4), Gly-ol(5)] enkepha-
lin; HOBt, 1-hydroxybenzotriazole; icv, intracerebroventricular;
iv, intravenous; MOR, μ-opioid receptor; MVD, mouse vas
deferens; NMM, N-methylmorpholine; RP-HPLC, reversed
phase high performance liquid chromatography
(9) (a) Stachowiak, K.; Khosla, M. C.; Plucinska, K.; Khairallah, P. A.;
Bumpus, F. M. Synthesis of angiotensin II analogues by incorporating
β-homotyrosine or β-homoisoleucine residues. J. Med. Chem. 1979, 9,
3422
dx.doi.org/10.1021/jm301456c | J. Med. Chem. 2013, 56, 3419−3423