4th EucheMs chemistry congress

Poster Session 1
s896
chem. Listy 106, s587–s1425 (2012)
Poster session 1 - life sciences
P - 0 0 7 2
AntiCAnCer ACtivity of PhthALAzinyL
hydrAzoneS
J. rAK 1 , B. deJLová 1 , r. KAPLáneK 1 , J. KráLová 2 ,
v. KráL 1
1 Institute of Chemical Technology in Prague, Dept. of
Analytical Chemistry, Prague 6, Czech Republic
2 Academy of Sciences of the Czech Republic, Institute of
Molecular Genetics, Prague 4, Czech Republic
Heteroaryl hydrazones are compounds with significant
biological activity including anticancer activity. Therefore we
designed set of phthalazinyl hydrazones for testing their activity
against cancer cells. Anticancer activity evaluation on the human
promyelocytic leukemia cells (HL60) and mouse mammary
carcinoma cells (4T1) showed that some phthalazinyl hydrazones
have significant inhibitory effect against both cancer cell lines.
Complexation studies toward biologically important metal ions
(Cu2+ , Co2+ , Cr3+ , Fe2+ , Fe3+ , Mn2+ , Ni2+ , Zn2+ ) at biologically
relevant conditions show general ability to bind Cu2+ , Co2+ , Ni2+ and Fe3+ (with some exceptions) and rarely Zn2+ and Fe2+ . There
is not any clear correlation of binding ability with anticancer
activity; however many derivatives able to bind Zn2+ display very
high activity (IC < 1 µM for HL60) and opposite way all
50
derivatives without binding ability towards Co2+ do not display
any significant activity (IC > 10 µM for both lines). Phthalazinyl
50
hydrazones are known to display tautomerism; QD/MD
calculations in aqueous media show significant preference of
hydralazine form in contrast to preference of phthalazone form
described in literature (obtained from in vacuo calculations).
Calculations also show that metallo-complexes of derivatives are
relatively planar and thus potentially allow intercalation into DNA
in contrast to derivatives themselves. This is in good agreement
with experimental observation that metallo-complexes of many
derivatives display ability to interact with DNA but derivatives
themselves do not.
Acknowledgement: Financial support was provided from
Specific university research (MSMT No. 21/2012, Grants
A1_FCHI_2012_003 and A2_FCHI_2012_021 provided by IGS
VSCHT) and the Grant Agency of the Czech Republic (Grants
No. GA203/09/1311 and GAP303/11/1291).
Keywords: Hydrazones; Schiff bases; Antitumor agents;
4 th EucheMs chemistry congress
P - 0 0 7 3
SoLuBLe SynthetiC MiniAMyLoidS
A. roeder 1 , y. rÖttGer 2 , L. Andrei-SeLMer 3 ,
A. StündeL 2 , M. BACher 2 , r. dodeL 2 , A. Geyer 1
1 Philipps-University Marburg, Department of Chemistry,
Marburg, Germany
2 Philipps-University Marburg, Department of Neurology,
Marburg, Germany
3 Rheinische Friedrich-Wilhelms University Bonn, Department
of Neuroanatomy, Bonn, Germany
Based on the proposed contact surfaces between individual
β-amyloid peptides (Aβ) within fibrillar aggregates [1] we
synthesized soluble Miniamyloids as chemically consistent
dimers, trimers and other oligomers, respectively. Selected Aβ
fragments were linked in different relative orientations by a
combination of protecting group strategy and click chemistry.
Several unnatural amino acids were synthesized and incorporated
into the Miniamyloids to assemble the antiparallel and parallel
oligomers of the peptide strands.
Aβ derivatives are characterized by their notoriously high
aggregation tendency. To prevent fiber formation and to improve
solubility, anionic and cationic amino acids were incorporated
aside the native sequence. By varying the charge pattern and in
combination with the different arrangements of the peptides
strands a broad set of Miniamyloids was obtained. These peptides
are a valuable and unique tool to understand how naturally
occurring antibodies against Aβ (nAbs-Aβ) [2] recognize
oligomeric Aβ and Aβ aggregation itself. [3] For instance they can
be used for affinity chromatography experiments to specify the
pool of polyclonal nAbs-Aβ.
references:
1. T. Lührs, C. Ritter, M. Adrian, D. Riek-Loher,
B. Bohrmann, H. Dobeli, D. Schubert, R. Riek,
Proc. Natl. Acad. Sci. USA 2005, 102, 17342-17347.
2. R. C. Dodel, Y. Du, C. Depboylu, H. Hampel, L. Frölich,
A. Haag, U. Hemmeter, S. Paulsen, S. J. Teipel,
S. Brettschneider, A. Spottke, C. Nölker, H. J. Müller,
X. Wei, M. Farlow, N. Sommer, W. H. Oertel, J. Neurol.
Neurosurg. Psychiatry 2004,75, 1472-1474.
3. R. Dodel, M. Bacher, K. Balakrishnan, A. Geyer,
A. M. Roeder, Patent 2011, PCT/EP2011 071239.
Keywords: amyloid-ß peptide; protein aggregation;
Alzheimer’s disease;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc