4th EucheMs chemistry congress

thursday, 30-Aug 2012
s776
chem. Listy 106, s587–s1425 (2012)
organic Chemistry, Polymers – i
Natural products, Drugs – ii
o - 4 8 1
BioinSPired CheMiStry with PePtideS
h. wenneMerS 1
1 ETH Zürich, Laboratorium für Organische Chemie, Zürich,
Germany
In nature, proteins fulfill manifold different functions and
are crucial as, for example, enzymes or templates for the
controlled formation of structural components such as bones or
seashells. My research group is intrigued by the question whether
also peptides with significantly lower molecular weights
compared to proteins, can fulfill functions for which nature
evolved large macromolecules. For example, we are engaged in
the development of peptides as asymmetric catalysts and
templates for the controlled formation of inorganic nanoparticles.
1. Tripeptides of the general type H-Pro-Pro-Xaa
(Xaa = amino acid with a carboxylic acid) are effective catalysts
for aldol reactions [1, 2] and conjugate addition reactions between
aldehydes and nitroolefins. [3, 4] The peptides allow for enamine
catalysis with catalyst loadings of as little as 0.1-1 mol % and
provide the synthetically versatile products in high to excellent
stereoselectivities. The scope of these peptide catalyzed reactions
will be presented.
2. The development of peptides as templates for the
controlled formation of silver nanoparticles (AgNPs) in defined
sizes will be presented. Utilizing combinatorial chemistry
different tripeptides were identified that allow for the formation
of AgNPs in significantly different sizes. [5] More recently, a
correlation between the length of oligoproline-based templates
and the size of the resulting AgNPs was observed. [6]
references:
1. P. Krattiger, R. Kovasy, J. D. Revell, S. Ivan,
H. Wennemers, Org. Lett. 2005, 7, 1101.
2. J. D. Revell, H. Wennemers, Adv. Synth. Catal. 2008, 350,
1046..
3. M. Wiesner, J. D. Revell, H. Wennemers, Angew. Chem.
Int. Ed. 2008, 47, 1871.
4. J. Duschmalé, H. Wennemers, Chem. Eur. J. 2012, 18, 1111.
5. K. Belser, T. V. Slenters, C. Pfumbidzai, G. Upert,
L. Mirolo, K. M. Fromm, H. Wennemers, Angew. Chem.
Int. Ed. 2009, 48, 3661-3664.
6. G. Upert, F. Bouillere, H. Wennemers, Angew. Chem. Int.
Ed. 2012, 124, 4307-4310.
Keywords: Peptide; Nanoparticles;
Natural products, Drugs – ii
4 th EucheMs chemistry congress
o - 4 8 2
PePtido SuLfonyL fLuorideS AS new
ProteASe inhiBitorS
r. LiSKAMP 1
1 Utrecht University, Pharmaceutical Sciences, Utrecht, Netherlands
We have employed the sulfonamide moiety as a transitionstate
isostere of the hydrolysis of the amide bond. Incorporation
of the sulfonamide moiety led to peptidosulfonamide-peptide
hybrids capable of protease inhibition or resistant to proteolytic
degradation. The versatile preparation of b-peptidosulfonamides,
in which all peptide-amide bonds have been replaced by
sulfonamide moieties, enticed investigation of the foldamer
properties of this class of peptidomimetics.
We have found that the required amino acid derived sulfinyl
chlorides or amino acid derived sulfonyl chlorides intermediates
can also be employed for the preparation of new “electrophilic
traps” useful for the synthesis of protease inhibitors. Thus, amino
acid based sulfinyl chlorides were converted into the
corresponding a-chloromethylsulfoxides capable of inhibition of
for example papain. Moreover, amino acid derived sulfonyl
chlorides could be converted into the corresponding sulfonyl
fluorides, which are crucial building blocks in the preparation of
peptido sulfonyl fluorides comprising a new class of protease
inhibitors. Apart from inhibition of chymotrypsin, protease
activity of the proteasome can be efficiently inhibited. This offers
opportunities for using peptido sulfonyl fluorides as powerful
selective protease inhibitors in cancer treatment but also as
potential anti-malaria compounds. Both the presence of a peptide
fragment and the amino acid derived sulfonyl fluoride offer great
possibilities for profiling but also for tuning the reactivity and
specificity of the protease of interest.
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc