4th EucheMs chemistry congress

Poster Session 2
s1313
chem. Listy 106, s257–s1425 (2012)
Poster session 2 - organic chemistry
P - 0 9 0 1
SynthetiC StudieS towArd SeLeCtive And
StABLe inhiBitorS of dnA PoLyMerASe ALPhA:
CArBoCyCLiC AnALoGS of dehydroALtenuSin
S. KovACovA 1 , K. PAruCh 1
1 Masaryk University, Department of Chemistry, Brno, Czech
Republic
DNA polymerases play a key role in replication and
maintaining of genome stability and some of them can help cancer
cells tolerate DNA damage. Their selective inhibition is therefore
considered viable strategy for therapeutic intervention in
oncology. [1] Accordingly, depletion of DNA polymerase alpha (pol
alpha) combined with inhibition of CHK1 kinase afforded
synthetic lethal phenotype in cancer cells. [2]
Dehydroaltenusin is virtually the only known
sub-micromolar selective inhibitor of pol alpha [3] that exhibited
in vivo biological activity (include mice HeLa xenograft model). [4]
However, the mechanism of action and potential usefulness of
dehydroaltenusin are rather questionable as the compound is
unstable and in polar solvents it exists as equilibrium mixture of
two species: tricyclic lactone and its spirocyclic isomer. [5]
We have prepared racemic carbocyclic analogs of both
forms of dehydroaltenusin. The target structures as well as some
of the key intermediates contain novel, potentially useful
pharmacophores. As the compounds are chemically stable, they
could serve as appropriately robust chemical biology probes and
good starting points for further medicinal chemistry optimization.
references:
1. Lange, S. S.; Takata, K.; Wood R. D. Nat. Rev. Cancer
2011, 11, 96.
2. Parry, D. A.; Taricani, L. PCT Int. Appl.WO2008/063558.
3. Ljungman M. Chem. Rev. 2009, 109, 2929.
4. Naoki Maeda et al. Biochem. Biophys. Res. Commun.
2007, 352, 390.
5. Kamisuki S. et al. Bioorg.Med. Chem. 2004, 12, 5355.
Keywords: Medicinal chemistry; Inhibitors; Spiro compounds;
4 th EucheMs chemistry congress
P - 0 9 0 2
SuPerBASe ProMoted StereoSeLeCtive
Azetidine SyntheSiS
e. KovACS 1 , G. turCzeL 1 , f. ferenC 1
1 Budapest University of Technology and Economics,
Department of Organic Chemistry and Technology, Budapest,
Hungary
Email: erkovacs@mail.bme.hu
In the framework of an ongoing research project optically
active 2-3-disubstituted oxetanes were prepared in our laboratory
via superbase induced enantioselective rearrangements of chiral
benzyloxymethyl oxiranes [1, 2] . From these oxetanes pyrrolidine
derivative can be formed from in three steps [3] .
Starting from that findings, our new aim was the further
investigation of the stereoselective intramolecular rearrangement
reaction with the intetntion to get azetidine derivatives. First we
prepared oxirane derivatives which are substituted with
benzylaminomethyl group instead of benzyloxymethyl function.
These compounds were treated with LIDAKOR superbase.
The reaction provided the desired new azetidine derivatives
containing the ring substituents in trans position, exclusively. The
1-methyl-2-phenyl-3-(1-(trimethylsilyloxy)-2-(trityloxy)ethyl)azetidine
was prepared by TMSCl from the 1-(1-methyl-2-phenylazetidin-
-3-yl)-2-(trityloxy)ethanol. Now we try to prepare pyrrolidine
derivatives from this compound.
The derivatives of the synthesized compounds can be
valuable intermediates of drugs in pharmaceutical research [4] , and
can be used as chiral ligands in enantioselective catalytic
reactions.
This work is connected to the scientific program of the
“Development of quality-oriented and harmonized R+D+I
strategy and functional model at BME” project. This project is
supported by the New Hungary Development Plan (Project ID:
TÁMOP-4.2.1/B-09/1/KMR-2010-0002) and was carried out in
the framework of a bilateral scientific cooperation between the
Hungarian Academy of Sciences and CNR Italy.
references:
1. A. Mordini, S. Bindi, S. Pecchi, A. Degl’Innocenti,
G. Reginato, A. Serci: J.Org.Chem.,61, 4374 (1996)
2. A. Thurner, F. Faigl, L. Toke, A. Mordini, M. Vallachi,
G. Reginato, G. Czira: Tetrahedron, 57, 8173 (2001)
3. E. Kovács, A. Thurner, F. Farkas, F. Faigl, L. Hegedus,
Journal of Molecular Catalysis A, 339, 32 (2011)
4. US4622327 patent
Keywords: superbase; rearrangement; enantioselective
synthesis; heterocycles; azetidines;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc