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Experimental and theoretical studies of cyclic di-amino acid peptides in the solid state

Experimental and theoretical studies of cyclic di-amino acid peptides in the solid state

Mendham, A.P., Chowdhry, B.Z. and Dines, T.J. (2010) Experimental and theoretical studies of cyclic di-amino acid peptides in the solid state. In: 30th European Congress on Molecular Spectroscopy 2010 (EUCMOS 2010), 29 Aug–3 Sep 2010, Florence, Italy.

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Cyclic di-amino acid peptides (CDAPs) i.e. diketopiperazine (DKP) derivatives have been of long-standing interdisciplinary scientific interest, particularly as potential anti-cancer and anti-microbial agents [1, 2]. Single crystal x-ray studies of different derivatives have indicated that the six membered DKP ring adopts either a planar (cyclo(Gly-Gly), cyclo(L-Ser-L-Ser)) or boat conformation (cyclo(L-Ala-L-Ala) cyclo(L-Asp-L-Asp), cyclo(L-Glu-L-Glu)), in the solid state [3]. In addition, due to steric constraints, both amide bonds always adopt a cis conformation. Unfortunately, the inability to grow crystals of suitable diffraction quality makes it necessary to use other methods for determining solid state structures. In this study a selection of different CDAPs, have been investigated by experimental techniques such as Raman, infra-red spectroscopy and solid state NMR spectroscopy in order to relate structural and conformational relationships with theoretically calculated data. Theoretical gas phase structures have been calculated using DFT calculations (Gaussian03 molecular modeling package), utilizing the B3-LYP/cc-pVDZ basis set. Solid state DFT calculations have also been undertaken, using the pseudopotential-plane-wave CASTEP program.

The minimum energy conformation (gas phase) for cyclo(Gly-Gly), cyclo(L-Ala-Gly), cyclo(L-Ala-L-Ala), cyclo(L-Ser-L-Ser), cyclo(L-Asp-L-Asp) and cyclo(L-Glu-L-Glu) indicates that the DKP ring preferentially adopts a boat conformation. When the DKP ring is constrained to adopt a planar conformation a higher energy structure is produced. In the case of cyclo(GlyGly) the planar conformation is higher in energy by only 0.945 kJ mol-1. Simulated theoretical Raman spectra for both planar and boat conformations of cyclo(Gly-Gly) have indicated significant conformational shifts for both the CH2 stretching vibrations and the cis amide II mode. The cis amide II mode is, predominantly, an out of phase C-C-N stretch with a lower degree of contribution from the N-H in plane bend than in the trans amide II mode. The cis amide II mode appears as quite a strong signal in the Raman spectra, but is not observed in the FT-IR spectra [3].

The theoretical calculations are in good agreement with the experimental Raman results, which indicate a potential link with respect to the conformation of the DKP ring, in that a boat conformation has a cis amide II mode at a lower wavenumber than that with a planar/near planar DKP ring conformation. For example, the amide II vibrations for the planar/near planar conformations in cyclo(Gly-Gly), cyclo(D-Ala-L-Ala) and cyclo(L-Ala-Gly) are observed at wavenumbers of 1517, 1523, and 1522 cm-1, respectively, whereas the amide II modes for the boat conformations of cyclo(L-Glu-L-Glu), cyclo(L-Asp-L-Asp) and cyclo(L-Met-L-Met) are located at 1493, 1489, and 1493 cm-1, respectively [3]. The results indicate the significant potential for structural and conformational analysis using a combination of molecular modeling and experimental spectroscopic results.

Item Type: Conference or Conference Paper (Paper)
Additional Information: [1] This paper was given on 30th August 2010 as an oral presentation within the Biological and Medical Applications session during the 30th European Congress on Molecular Spectroscopy (EUCMOS 2010) held from 29th August - 3rd September 2010 in Florence, Italy.
Uncontrolled Keywords: vibrational spectroscopy, diketopiperazine, cyclic diamino acid peptides
Subjects: Q Science > QD Chemistry
Faculty / Department / Research Group: Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences
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Last Modified: 17 Oct 2016 09:12
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None

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