Syntheses and Properties of Silicon- and Germanium-Containingα-Amino Acids and Peptides: A Study on C/Si/Ge Bioisosterism

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Abstract

The unnatural silicon-containing α-amino acids (R)- and (S)-H2NCH(CH2SiMe3)COOH [(R)-2 and (S)-2], (R)-H2NCH(CH2SiMe2Ph)COOH [(R)-4], and (R)-H2NCH(CH2SiMe2CHCH2)COOH [(R)-6] as well as the unnatural germanium-containing α-amino acids (R)- and (S)-H2NCH(CH2GeMe3)COOH [(R)-3 and (S)-3] and (R)-H2NCH(CH2GeMe2Ph)COOH [(R)-5] were prepared in three-step syntheses, starting from (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine [(R)-10]. All amino acids were isolated as enantiomerically pure (≥99% ee) compounds. The (R)- and (S)-enantiomers of β-(trimethylsilyl)alanine [(R)-2 and (S)-2] and β-(trimethylgermyl)alanine [(R)-3 and (S)-3] are sila-analogues and germa-analogues, respectively, of the (S)- and (R)-enantiomers of the nonproteinogenic amino acid β-tert-butylalanine [(S)- and (R)-H2NCH(CH2CMe3)COOH; (S)-1 and (R)-1]. The C/Si/Ge-analogous (l-configurated) amino acids (S)-1, (R)-2, and (R)-3 were treated with (fluoren-9-yl)methyl chloroformate to give the corresponding N-Fmoc derivatives (S)-26, (R)-27, and (R)-28. These N-Fmoc-protected amino acids were used as building blocks for the solid-phase syntheses of the C/Si/Ge-analogous decapeptides 7−9 [Ac-d-Nal1-4-Cl-d-Phe2-d-Pal3-Ser4-Me3El-Ala5-d-Cit6-Leu7-Arg8-Pro9-d-Ala10-NH2 (7, El = C; 8, El = Si; 9, El = Ge)]. The C/Si/Ge analogues 7−9 are derivatives of the GnRH antagonist CetrorelixINN, which bears an (S)-tyrosine residue [instead of the (S)-Me3C-Ala, (R)-Me3Si-Ala, or (R)-Me3Ge-Ala residue] in position 5 of its decapeptide backbone. The decapeptides 7−9 were studied in vitro in receptor binding and functional assays using recombinant cell lines expressing the human GnRH receptor. All compounds behaved as potent GnRH antagonists, the binding affinities and antagonistic potencies of the three C/Si/Ge analogues being quite similar. Compounds 7−9 were also studied for their in vivo activities in the male rat after s.c. administration. They produced both a strong testosterone suppression (single-dose treatment, 1.5 mg/kg) and a strong LH suppression (castrated male rat; single-dose treatment, 0.05 mg/kg). For the silicon- and germanium-containing decapeptides 8 and 9 the testosterone and LH suppression lasted for a significantly longer period of time compared with the effects of the carbon analogue 7.

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