Synthesis, spectral and structural elucidation of squaric acid derivatives and Au(III) complexes of peptides

Aim

Cisplatin is one of the most widely utilized anticancer agents. However, some of the clinical inconveniences still remain, such as acquired drug resistance and serious side effects. These facts have promoted extensive studies on the application of other metals in medicine. Au(III) has a configuration isoelectronic with Pt(II) and therefore corresponding complexes were explored for this anticancer potential which has been experimentally proved on some Au(III) complexes. The complexes of this metal ion with peptides could be potential anticancer drugs due to the ligands possessing bioactivity. On the other hand, the peptides in the living cell occur in protonated forms giving a number of conformers in dependence of the anionic moiety which could result in different biological activity. The choice of squaric acid as anionic counter ion in Au (III) complexes is based on its own biological activity. Therefore, the goal of these investigations is design, synthesis, spectroscopic and structural elucidation of Au(III) complexes with hydrogensquarates and their ester-amides with peptides as potential anticancer drugs.

Approach

We have synthesized the hydrogensquarates and Au(III) complexes with peptides as presented in the figure 29. Modern methods as single crystal X-ray diffraction, ¹H- and ¹³C-NMR, conventional and linear-polarized IR- and Raman spectroscopy in solution and solid-state, UV-VIS, HPLC and tandem MS-MS, ESI-MS, FAB-MS, TGV and DSC were applied. To elucidate the structure theoretical ab initio and DFT calculations were used for supporting the structural and spectroscopic data.

Figure 29: Scheme of the investigated peptides and hydrogensquarates

Results

'''Au(III)-complexes'''

Au(III) complexes with dipeptides ''H-Trp-Trp-OH'', ''H-Tyr-Trp-OH'', ''H-Trp-Phe-OH'', ''H-Gly-Ala-OH'', ''H-Phe-Tyr-OH'' and ''H-Ala-Phe-OH'' as well as with tripeptide ''H-Gly-Ala-Ala-OH'' were characterized by spectroscopic methods. Dipeptides coordinated in a tridentate manner via -NH₂, -COO^- and H^---groups. One Cl^- ion is attached to the metal centre as a terminal ligand, yielding a planar AuN₂OCl chromophor. Only ''H-Ala-Phe-OH'' coordinates in a bidentate manner via an O-atom of the COO^---group and N-amide nitrogen, after a previous deprotonation of the NH-group has taken place. Two Cl^- ions are attached to the metal centre as terminal ligands, yielding a completely planar geometry.

'''Hydrogensquarates'''

Hydrogensquarates of dipeptides ''H-Gly-Ala-OH'', ''H-Ala-Ala-OH'', ''H-Phe-Tyr-OH'', ''H-Thr-Ser-OH'' and tripeptides ''H-Gly-Gly-Gly-OH'', ''H-Gly-Gly-Met-OH'' and ''H-Met-Gly-Gly-OH'' are conforming the positive charged peptide moiety and negative hydrogensquarate anion, stabilized by strong intermolecular hydrogen bonds.

Funding

German Academic Exchange Service (DAAD) within the Stability Pact for South-East-European Countries

Contact

Prof. Dr. Tsonko Kolev
Bulgarian Academy of Sciences
kolev@orgchm.bas.bg
Phone: +35 (92) 9606106

Univ.-Prof. Dr. Dr. h.c. Michael Spiteller
M.Spiteller@infu.uni-dortmund.de
Phone: +49-(0)231-755-4080

Paper

1. Kolev, T.; Cherneva, E.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2006):
   "L-Methioninamide ester amide of squaric acid diethyl ester" Acta Cryst., E 62, o1390-o1392.
   more informations...

2. Kolev, T.; Koleva, B. B. ; Spiteller, M. (2006):
   "Spectroscopic and theoretical characterization of hydrogensquarates of L-threonyl-L-serine and L-serine. Prediction of structures of the neutral and protonated forms of the dipeptide" Amino Acids, 33, 719-725.

3. Kolev, T.; Koleva, B. B.; Spiteller, M. (2007):
   "Solid-state linear-polarized spectroscopy of alanyl-containing peptides and their hydrogensquarates" Journal of Molecular Structure, 877, 79-88.

4. Kolev, T.; Koleva, B. B.; Spiteller, M. (2006):
   "Synthesis, spectroscopic and structural elucidation of tetrapeptide glycyl-prolyl-glycyl-glycine and its hydrochloride and hydrogensquarate" Biopolymers in preparation.

5. Kolev, T.; Koleva, B. B.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2008):
   "Benzamidinium D-glucuronate: spectroscopic and structural elucidation" Journal of Molecular Structure, 879, 30-39.

6. Kolev, T.; Koleva, B. B.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2006):
   "Synthesis, Spectroscopic elucidation, Structure, and Vibrational Analysis of Tyrosinamide hydrogensquarate monohydrate" JACS in preparation.

7. Kolev, T.; Koleva, B.B.; Cherneva, E.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2006):
   "Crystal structure, IR-LD spectroscopic, theoretical and vibrational analysis of valinamide ester amide of squaric acid" Struct. Chem., 17, 491-499.

8. Kolev, T.; Spiteller, M. (2005):
   "L-Tyrosinamide hydrochloride monohydrate" Acta Cryst., E 61, o3819-o3821.
   more informations...

9. Kolev, T.; Spiteller, M. (2007):
   "Synthesis, spectroscopic and theoretical characterization of hydrogensquarate and mononuclear Au(III)-complex of dipeptide phenylalanyltyrosine" Journal of Molecular Structure, 855, 104-110.

10. Kolev, T.; Spiteller, M. (2006):
    "Au(III) complexes of di- and tripeptide glycylglycine and glycylglycylglycine" Inorg. Chim. Acta., 359, 4367-4376.

11. Kolev, T.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2005):
    "1-(Aminocarbonyl)ethylammonium hydrogensquarate monohydrate" Acta Cryst., E 61, o4292-o4294.
    more informations...

12. Kolev, T.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2006):
    "4-Acetyl-N-methylaniline" Acta Cryst., E 62, o774-o776.
    more informations...

13. Kolev, T.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2006):
    "L-Argininamidium bis(hydrogensquarate" Acta Cryst., C62, o299-o300.
    more informations...

14. Kolev, T.; Spiteller, M.; van Almsick, T. ; Mayer-Figge, H.; Sheldrick, W.S. (2007):
    "2-(Indol-3-yl)ethylammonium dihydrogenphosphate" Acta Cryst., E63, o179-oo181.

15. Kolev, T.; Yancheva, D.; Spiteller, M.; Sheldrick, W. S.; Mayer-Figge, H. (2006):
    "L-Prolinamidium hydrogensquarate" Acta Cryst., E 62, o463-o465.
    more informations...

16. Koleva, B B.; Kolev, T.; Spiteller, M. (2006):
    "The effect of protonation on conformations and IR-spectroscopic properties in solid state of histidine containing peptides H-His-Leu-OH and Hipp-His-Leu-OH" Peptides in preparation.

17. Koleva, B. B.; Kolev, T.; Spiteller, M. (2006):
    "Structural and spectroscopic analysis of hydrogensquarates of glycine-containing tripeptides" Biopolymers, 83, 498-507.

18. Koleva, B. B.; Kolev, T.; Spiteller, M. (2006):
    "Mononuclear Au(III)-complexes with tryptophan-containing dipeptides: synthesis, spectroscopic and structural elucidation" Inorganica Chimica Acta, 360, 2224-2230.

19. Koleva, B. B.; Kolev, T.; Spiteller, M. (2007):
    "Spectroscopic and structural elucidation of tyrosine containing dipeptides H-Val-Tyr-OH and H-Tyr-Ala-OH" Spectrochimica Acta Part A, 68, 1187-1196.

20. Koleva, B. B.; Kolev, T.; Spiteller, M. (2006):
    "Mononuclear Au(III) complexes with histidine containing peptides" J. Coord. Chem. in press.

21. Koleva, B.B.; Kolev, Ts.; Zareva, S.Y.; Spiteller, M. (2007):
    "The dipeptide alanylphenylalanine (H-Ala-Phe-OH) - protonation and coordination ability with Au(III" J. Mol. Struct., 831, 165-173.