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. 2007 Jun 28;50(13):3138-42.
doi: 10.1021/jm061048b. Epub 2007 Jun 1.

Synthesis of stable and potent delta/mu opioid peptides: analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis

Adriano Mollica  1 , Giovanni Guardiani, Peg Davis, Shou-Wu Ma, Frank Porreca, Josephine Lai, Luisa Mannina, Anatoli P Sobolev, Victor J Hruby
Affiliations

Synthesis of stable and potent delta/mu opioid peptides: analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis

Adriano Mollica et al. J Med Chem. .

Abstract

Ring-closing metathesis has emerged as a powerful tool in organic synthesis for generating cyclic structures via C-C double bond formation. Recently, it has been successfully used in peptide chemistry for obtaining cyclic molecules bridged through an olefin unit in place of the usual disulfide bond. Here, we describe this approach for obtaining cyclic olefin bridged analogues of H-Tyr-c[D-Cys-Gly-Phe-Cys]-OH. The synthesis of the new ligands was performed using the second generation Grubbs' catalyst. The resulting cis-8 (cDADAE) and trans-9 (tDADAE) were fully characterized and tested at delta, mu, and kappa opioid receptors. Also the linear precursor 13 (lDADAE) and the hydrogenated derivative 11 (rDADAE) also were tested. All the cyclic products containing a olefinic bond are slightly selective but highly active and potent for the delta and mu opioid receptors. Activity toward the kappa opioid receptors was absent or very low.

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Figures

Figure 1
Figure 1
First (A) and second (B) generation Grubbs’ catalysts.
Figure 2
Figure 2
Structures of cDADAE (8), tDADAE (9), rDADAE (11), and lDADAE (13).
Figure 3
Figure 3
Double bond geometry in 8 (cis conformer) and 9 (trans conformer).
Scheme 1
Scheme 1
Synthesis of Fully Protected H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH Analogues 5, 6, and 7 and Linear Deprotected Product 13 Reagents and conditions: (a) SOCl2/MeOH 10 min at 0 °C, then 6 h at rt; (b) Boc-Phe-OH/EDC/HOBT•H2O/DMF/NMM, 16 h at rt; (c) TFA/CH2Cl2 (1:2) 1 h, rt; (d) Boc-Gly-OH/EDC/HOBT•H2O/NMM/DMF, 16 h at rt; (e) Boc-D-Allyl-Gly-OH/EDC/HOBT•H2O/NMM/DMF, 16 h at rt; (f) Boc-Tyr-OH/EDC/HOBT•H2O/NMM/DMF, 16 h at rt; (g) Grubbs’ catalyst second generation (20%)/CH2Cl2 at rt; (h) TFA/CH2Cl2 (1:2) 1 h at rt; (i) NaOH 1 N 6 equiv/MeOH, 4 h at rt.
Scheme 2
Scheme 2
Synthesis of the Bismethylene Analogue 11: Route A, Catalytic Hydrogenation of (6 + 7) Mixture; Route B, Catalytic Hydrogenation of cis-8 (cDADAE) Reagents and conditions: (a) H2/Pt/C 10%/MeOH, 48 h, rt; (b) NaOH (1 N, 3 equiv), 6 h, rt; (c) TFA/CH2Cl2 1:2, 1 h, rt.
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