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. 2004 Nov 30;101(48):16727-32.
doi: 10.1073/pnas.0407543101. Epub 2004 Nov 19.

Synthesis of galmic: a nonpeptide galanin receptor agonist

Susana Conde Ceide  1 , Laurent Trembleau, Gebhard Haberhauer, Laszlo Somogyi, Xiaoying Lu, Tamas Bartfai, Julius Rebek Jr
Affiliations

Synthesis of galmic: a nonpeptide galanin receptor agonist

Susana Conde Ceide et al. Proc Natl Acad Sci U S A. .

Abstract

Galanin is a neuropeptide with a wide variety of biological functions. Few nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin and the tripeptidomimetic galnon, a combinatorial library was formulated, synthesized, and screened against the galanin receptor. An active compound, galmic, was identified and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. The present work describes the total synthesis of galmic, the synthesis of its oxazole precursors, the coupling of the building blocks into a linear trimer, and the macrolactamization reaction.

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Figures

Fig. 1.
Fig. 1.
Nonpeptide ligands of the galanin receptor.
Fig. 2.
Fig. 2.
Synthesis of the libraries.
Fig. 3.
Fig. 3.
Retrosynthetic disconnection of galmic.
Fig. 4.
Fig. 4.
Hydrolysis and decarboxylation of 9.
Fig. 5.
Fig. 5.
Synthesis of the oxazole monomers. Reagents and conditions: (i) i-PrOH, N,N-dicyclohexylcarbodiimide, DMAP, DCM, RT, overnight (84%); (ii) LiOH, tetrahydrofuran/H2O, RT, 30 min (98%); (iii) cyclohexylmethylamine 2, diphenylphosphine azide, DIEA, DMF, RT, overnight (68%) or 9-fluorenylamine 3, isobutyl chlorocarbonate, N-methylmorpholine, DMAP, DCM, –20°C to RT, 5 h (65%); (iv) NaOH 5%, EtOH, RT, 6 h (98%); (v) H-Thr-OBn, EDCI, HOBt, DIEA, DMF, RT, overnight (17a: 80%; 17b: 78%); (vi) Dess-Martin periodinane, DCM, RT, 1 h; (vii) triethylamine, DMAP, DCM, RT, 1 h then Ph3P, I2, 0°C to RT, 2 h (18a: 81%; 18b: 87%); (viii) TFA, DCM, RT, 3 h (95%).
Fig. 6.
Fig. 6.
Synthesis of the linear trimer and macrocyclization step. Reagents and conditions: (i) EDCI, HOBt, DIEA, DMF (70%); (ii) H2/Pd-C (10%); (iii) 8b, EDCI, HOBt, DIEA, DMF (60%, two steps); (iv) H2/Pd-C (10%); (v) C6F5OH, N,N-dicyclohexylcarbodiimide, DCM; (vi) TFA, DCM, RT, 3 h (82%, three steps); (vii) DMAP, toluene, 95°C (72%).
Fig. 7.
Fig. 7.
Introduction of the lysine side chain. Reagents and conditions: (i) LiOH·H2O, acetone, RT, 30 min (72%); (ii) εt-Boc-l-lysine, EDCI, HOBt, DMF, DIEA (85%); (iii) TFA, DCM, RT, 3 h (quantitative).
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