1378
A. Caporale et al.
The presence of a Ca-tetrasubstituted amino acid in posi-
tion 8 seems to exacerbate the difference in biological
activity while the effect on the CD intensity is less pro-
nounced (see Figure S2 in the Supporting Information).
After CD studies, we carried out the structural analysis
using analogue I as a reference.
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The results presented in this work indicate that the presence
of an (aMe)Nle in position 8 can enhance the a-helical
structure, as can be seen from the superimposition of the
lowest energy structures of analogues I and V (Fig. 5, left).
This result can probably be ascribed to the reduced spatial
freedom of Ca-tetrasubstituted amino acids. Notably, this
result is independent of the absolute configuration of
(aMe)Nle, as can be seen from the superimposition of the
lowest energy structures of analogues V and VI (Fig. 5,
right). The reduced bioactivity of analogue VI relative to
analogue V can be ascribed to the incorrect orientation of
the butyl side chain brought about by the configuration of
(aMe)Nle. The introduction of D-Nle8 (analogue II) caused
not only a strong reduction in bioactivity, but also a
decrease in the a-helical content.
Acknowledgments The authors thank MIUR, Ministry of Educa-
tion and University of Italy, for financial support, Dr. Barbara Biondi
for her kind help in mass analysis and in the synthetic approach, Dr.
Nereo Fiori for his initial NMR analysis and Prof. Stefano Moro and
the Molecular Modeling section of the Dept. of Pharmaceutical Sci-
ences (Padova, Italy) for computational support. In particular, the
authors thank Dr. Iwona Woznica for her kind help in biological tests
carried out at Dept. of Physiology (Tufts University School of
Medicine, Boston, USA).
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