1 Highlights from 50 Years Biosynthetic Supramolecular Chemistry Hans-Jörg Schneider FR Organische Chemie der Universität des Saarlandes , D 66041 Saarbrücken/ Germany This is a presentation for/from only one hour- so many important contributions had to be neglected this version has short questions marked Q1 etc on most pages- possible answers are at the end Outline Some History Artificial Enzymes Affinity and Selectivity of supramolecular complexes Complexation of Peptides Nucleotides /Nucleosides Interference with Biopolymers DNA/RNA –e.g.a artificial helicase protein –drug interactions protein-protein interactions Nanoparticles binding biomolecules Molecular Recognition with Microarrays / Chips Artificial photosynthetic systems / Light energy conversion Supramolecular chemistry with polymers -Artificial Muscles
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50 Years Bio Mimetic Supra Molecular Chemistry HJ Schneider
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Highlights from 50 Years Biosynthetic Supramolecular Chemistry
Hans-Jörg Schneider
FR Organische Chemie der Universität des Saarlandes , D 66041 Saarbrücken/ Germany
This is a presentation for/from only one hour- so many important contributions had to be neglected
this version has short questions marked Q1 etc on most pages- possible answers are at the end Outline
Some History
Artificial Enzymes
Affinity and Selectivity of supramolecular complexes
Complexation of
Peptides
Nucleotides /Nucleosides
Interference with Biopolymers
DNA/RNA –e.g.a artificial helicase
protein –drug interactions
protein-protein interactions
Nanoparticles binding biomolecules
Molecular Recognition with Microarrays / Chips
Artificial photosynthetic systems / Light energy conversion
Supramolecular chemistry with polymers -Artificial Muscles
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Some History
Emil Fischer. Lock and Key as Enzyme Model 1894
Inclusion Compounds
Paul Pfeiffer Organische Molekülverbindungen 1927
1950- 1975 mostly : principles of enzyme mechanisms / models
Koshland: induced fit : Proc Natl Acad Sci U S A. 1958
Covalent enzyme models e.g. Bruice BBA 1958, 208 Proc. Nat. Acad. Sci. USA 1960
W.P. Jencks, Catalysis in Chemistry and Enzymology, 1989
Catalysis of Decarboxylation by Cyclodextrins - a Model Reaction for Mechanism of Enzymes. J. Am. Chem. Soc. 1965, 1115
Catalysis of Fission of Pyrophosphates by Cyclodextrin J. Am. Chem. Soc. 1965, 1121 Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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R Breslow, P Campbell - J. Am. Chem. Soc. 1969 ,3805
Regioselectivity change :
o-anisol inside a -CD : Q2b other possible hosts ?
+ HOCl : substitution ratio changes from p:o = 1.5
to 22 with a -CD
Artificial Enzymes :
ML Bender, M Komiyama: Cyclodextrin Chemistry, Reactivity and Structure 1978
(e.g. FM Menger, ML Bender J. Am. Chem. Soc.1966, 131 )
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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CH2Br
NaNO2 R-NO2 R-ONO+
Neat 2 : 1
+CP66 6.3 : 1
+ Me4NCl 0.15 : 1
+ Me4NCl has opposite effect : 40-fold change of regioselectivity
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
Change of Regioselectivity Q3a why? and of Speed Q3b why?
Schneider, Busch Ang Chem 1984
N (CH2)n N
NN (CH2)n
CH2H2C CP66
For most chemical reactions there are no enzymes – Q3a alternatives ?
but supramolecular catalysts
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C
CCOOEtH
H COOEtCOOEt
COOEt
COOEt
COOEt
e.g. Catalysis of Diels-Alder Reactions by Cyclodextrins (CD)
Breslow et al 1980 f
Schneider et al 1986
without CD: 48 : 1
with CD: 112 : 1
C
CCOOEtH
EtOOC HCOOEt
COOEt
b) Chiral induction 21% Q4c how to improve ?
Rate increase: max. 70
Q4b limitation why ?
with ethylfumarate EF : inhibition
a) Diastereoselectivity increase Q4a why ?
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Non-covalent interactions as basis: ADH /NADH mimics
Vekemans, Buck (1989) => 95% ee Q5 why ? Kellog ( 1985) =>90 % ee
supramolecular complexes perform not always better
Other NADH analogs ( see e.g. Murakami Chem. Rev: 1996, 721:
Behr and Lehn / Skog and Wennerström / Toda / Engbersen / Murakami / Inoue /Bourguignon / Davies / Gelbard / Iwata / Meyers ….
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Synthetic HydrolasesBreslow, R.; Zhang, B. J. Am. Chem. Soc. 1994, 116, 7893,
(Related hydrolases with cyclophanes : Tabushi, Murakami, Lehn, Diederich….)
220 000-times faster than uncatalyzed / at least 50 turnovers: Q6a what is the drawback ?
Artificial RNAses Breslow etc Q6b why is RNA hydrol faster than of DNA ?
binding group reaction sitesubstrate
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Artificial Nucleases :
E. Kimura ; J. Chin; J. N. Burstyn; R. Krämer; J. Engbersen/ D. N. Reinhoudt, R. Franklin; M. Komiyama, J. R. Morrow, H. Lönnberg; JM Lehn ; HJ Schneider, A.Yatsimirski , T. Bruice, W. Göbel, A. Hamilton …
BNPP as model for DNA , Parathion , Soman, VX etc hydrolysis
M= Eu(III);
BNPP: ko = 2.5 x 10-8 [s-1] at 75°C; t ½ 100.000 hrs
kcat/kuncat = 107 (Schneider et al TL 2002 )
Q7a any practical applications ?
Q7b role of metalion ? of naphthyl units ?
Q7c adanvantage of Ln instead of e.g. Zn ions?
kcat/kuncat = 107 Hegetschweiler et al, Inorg. Chem., 2001,4918
Q7d role of metalion ?
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Alkaline Phosphatase Q8d identify role of the diffent amínoacids E.E.Kim; H.W.Wyckhoff J.Mol.Biol. (1991) 449
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Chitosan hydrogel + 10 mM AcOH
950 % volume increase
(a), (b) : Hydrogel expansion
(c), (d) : Hydrogel contraction / e.g. for drug release
uni-directional
Artificial Muscles - Supramolecular chemistry with polymers:
recognition sites in chemomechanical polymers => stimulation by external effector (guest ) compounds
Q29a required properties of the polymer ? how to improve response speed (Q29b) and sensitivity (Q29c) ?
Schneider et al in „Intelligent Materials“ (2008); J. Mat. Chem. (2008);
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Answers to the questions – ( possible answers ! )
Q1a why so few practical applications ? Science in these years was more oriented towards fundamentals and theory
Q1b why are Cramers papers often forgotten ? Cramer changed this field too early ( he became big shot in nucleic acid chemistry )
Q3 – not enough (native )enzymes : alternatives ? a) enzyme mutants; b) catalytic antibodies (drawbacks ?)
always a problem (also for synth enzymes): product binding /saturation- what to do ? remove products , eg in flow reactors
Q3a Change of Regioselectivity why ? The hard oxygen side of the NO2 anions accumulate at N+ centers,
leading to more soft soft-combination /alkylation ( pure speculation !)
Q3b Change of Speed why ? concentration and vicinity effect - the NO2 anions accumulate at N+ centers,
close to guest better (Km) value
Q4a Diastereoselectivity increase why ? Diene and dienophile in restricted orientation inside cavity – which: unpredictable
Q4b Rate increase: max. only 70: why ? Only concentration and vicinity effect (Km value) , no special TS stabilization
Q4c Chiral induction only 21% - how to improve ? Make CD cavity less symmetrical, e.g. by monosubstitution at the rim
Q5a: origin of the stereoselectivity ? Orientation of edcucts by coordination at the Mg, and by stacking and/or C-H hydrogen
bonds
Q6a what is the drawback ? Very special binding groups (Adamantanes) must be there Q6b why is RNA hydrol faster than of DNA ? The 2’-OH group in ribose allows formation of the cyclic intermediate
Q7a any practical applications ? removal of warefare ( biocide agents etc
Q7b role of metalion ? Coordination improves Km, Lewis catalysis + stabilization of phosphate leaving group
of naphthyl units ? stacking improves Km
Q7c adanvantage of Ln instead of e.g. Zn ions? Higher charge density : improves Lewis catalysis + stabilization of phosphate leaving group
Q7d role of metalion ? Coordination improves Km, Lewis catalysis + stabilization of phosphate leaving group
Q8a role of metalion ? Coordination improves Km, Lewis catalysis + stabilization of phosphate leaving group
Q8b why 2 ions? One can act for Lewis catalysis, the other for stabilization of phosphate leaving group
Q8c how does it work ? Both Imidazole and –COOH can help hydrolysis mechanisms
Q8d identify role of the diffent amínoacids The His and Ser can help hydrolysis mechanisms , these +the others can bind metal ions
Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry
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Q9a the basis of the selectivity ? Watson-Crick base pairing
Q9b analytical method ? Sequence analysis by electrophoretic separation, after 32-P labeling autoradiography
Q9c adanvantage of Ce4+ instead of e.g. Zn2+ ions? Higher charge density : improves Lewis catalysis + stabilization of phosphate leaving group
Q10a drawback of the substrate ? Very special binding groups (Adamantanes) must be there
Q10b which metal ions work ? Fe, Mn
Q10c why so many F ? Protect against (self-)oxidation
Q13a practical use of Biotin-Avidin interaction ? Countless- for immobilization of almost everything (e.g. on surfaces- bionanotechnology etc)
Q13b why so high affinity ? Multivalent binding (chelate effect ) mostly hydrogen bonds
Q13c why is small TS so unusual ? Usually strong binding leads to more loss of mobility
Q14a theor. reason for Selectivity-Affinity Correlation ? If G increases also the differences G between two complexes should increase, but see
next
Q14b why more scatter ? Theory 14a only holds if no addtl groups (e.g. substituents at the host) contribute much to the selectivity
Q14c why less selective than calix-crown ? In calix crown the binding space /cavity if more confined
Q15a Role of Cu? Why Cu ? Large coordination sphere of Cu, Cu(II) binds well with Imidazole N
Q15b which interaction mechanisms ? Besides hydrogen bonding to crown stacking of Phe and porphyrin