˘ ˇ ˆ˙ ˝ ˛ˇ ˚ ˙ ˆ ˜ organisms - IASOC | Ischia Advanced ... · Ischia Advanced School of...
9
Ischia Advanced School of Organic Chemistry Ischia (Naples), September 22-26 2012 FOLDAMERS: EXPANDING THE CHEMICAL SPACE Complexity cells biopolymers organisms Diversity & Breadth Jean-Marie Lehn, Supramolecular Chemistry: Concepts and Perspectives, VCH, Weinheim, 1995 A view of the chemical space FOLDAMERS Foldamers: Artificial folded molecular architectures Includes: - Synthetic oligomers - Helical polymers - Modified biopolymers - How large ? - How complex ? - What functions ? Mimicking is not copying ! Folding synthetic oligomers: N O H R
Transcript of ˘ ˇ ˆ˙ ˝ ˛ˇ ˚ ˙ ˆ ˜ organisms - IASOC | Ischia Advanced ... · Ischia Advanced School of...
���������� �������� ��������������������� ���������� � ��������
Ischia Advanced School of Organic ChemistryIschia (Naples), September 22-26 2012
FOLDAMERS:EXPANDING THE CHEMICAL SPACE
Complexity
�cells
biopolymers
organisms
Diversity& Breadth
Jean-Marie Lehn, Supramolecular Chemistry: Concepts and Perspectives, VCH, Weinheim, 1995
A view of the chemical space
FOLDAMERS
Foldamers:Artificial folded moleculararchitectures
Includes:- Synthetic oligomers- Helical polymers- Modified biopolymers
- How large ?- How complex ?- What functions ?
Mimicking is not copying !
Folding syntheticoligomers:
NOH
R
Folded structuresDynamics & Assembly
Functions
NNN
O
H
1 – Designing helical structures
NNN
O
H
local conformationalpreferences
NHN N
HN
HNN
HN
O OON N
O
HNN
HN
HN N
HN
OO O O
Molecular helical programming
Volker Berl… Chem. Eur. J. 2001, 7, 2798
X-ray
120° 120°120°
Parameters:pitch 3.5 Å4.5 units/turn
Hua Jiang… J. Am. Chem. Soc 2003, 125, 3448Hua Jiang… Tetrahedron 2003, 59, 8365
Decreasing the number of units per turn
Stability !ΔΔΔΔG� = 102kJ/mol
X-ray
Parameters:pitch 3.5 Å2.5 units/turn
��� ������
��
�
���
��
���
�
��
����
� ��
���
6-mer 8-mer5-mer 16-mer
Kinetics of racemization (Collab. H. Ihara, M. Takafuji, Kumamoto Univ.)
N. Delsuc, T. Kawanami… ChemPhysChem 2008, 9, 1882T. Qi, H. Noguchi… Chem. Commun 2012, in press
nNH
N
iBuO
O
M (left handed) P (right handed)
Stability depends on the solventCHCl3 < CHCl3/hexane < MeOH < H2O
N
NO2
iBuO
ON
HN
iBuO
NO
7
H
Intramolecular Induction of Handedness
X-RAY: Christel Dolain… J. Am. Chem. Soc. 2005, 127, 12943VCD: Thierry Buffeteau… Chem. Commun. 2006, 2714A. Kendhale… J. Org. Chem. 2011, 76, 195
R enantiomer
-200
-150
-100
-50
0
50
100
150
220 270 320 370 420 470 520 570
wavelength (nm)
Eps
ilon
(L.m
ol-1
.cm
-1)
S chirality => P helixR chirality => M helix
Folded structuresDynamics & Assembly
Functions
NNN
O
H
2 – Protein sized foldamers
vs
helix-helixInteractions ?
Towards tertiary structures - helix zippers Towards tertiary structures - helix zippers
X-rayTriclinic P-11.2 Angs, R1 = 19%
�
��
�
��
�
�
�
������
��
��
�������� �
��
�
��
�
�
�
������
��
��
�
�
�
�
����� �����������
Scorpion Toxin Protein (65aa)C311H423N86O95S8MW 7.1 kD
MP (X-ray)
PP (X-ray)
Nicolas Delsuc… Angew. Chem. Int. Ed. 2007, 46, 214; J. Am. Chem. Soc. 2011, 133, 3165
Towards tertiary structures - helix zippers
Scorpion Toxin Protein (65aa)C311H423N86O95S8MW 7.1 kD
Synthetic zipperC464H464N70O74MW 8.2 kD
Nicolas Delsuc… Angew. Chem. Int. Ed. 2007, 46, 214; J. Am. Chem. Soc. 2011, 133, 3165
Towards tertiary structures - helix zippers
Scorpion Toxin Protein (65aa)C311H423N86O95S8MW 7.1 kD
Synthetic zipperC464H464N70O74MW 8.2 kD
Nicolas Delsuc… Angew. Chem. Int. Ed. 2007, 46, 214; J. Am. Chem. Soc. 2011, 133, 3165
Folded StructuresDynamics & Assembly
Functions
3 – Spring-like extensions
NHN N
HN
HNN
HN
O OON
OC10H21 OC10H21
NO
OC10H21
HNN
HNC9H19
HN N
HN
OO O
C9H19
O
400 MHz 1H NMRspectra in CDCl3
Kdim = 30 L/molIvan Huc, Volker Berl…Nature 2000, 407, 720Chem. Eur. J. 2001, 7, 2810Hua Jiang…Tetrahedron 2004, 60, 10029
10.5 9.0 8.5ppm 10.0 9.5 8.0 7.5 7.0
24.5 mM
8.2 mM
2.7 mM
0.9 mM
° ° ° °• •••• °
• •••
• ••
•
•
NHN N
HN
HNN
HN
O OON N
O
HNN
HNtBuO
HN N
HN
OO OOtBu
O
Crystals from dmso/CH3CN Crystals from ΦNO2/heptane
Volker Berl, Ivan Huc…Nature 2000, 407, 720Chem. Eur. J. 2001, 2810
HNN
H
HNN
H
HNN
H
HNN
H
HNN
H
HNN
H
HNN
H
HNH2N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
HN N
H
HN N
H
HN N
H
HN N
H
HN N
H
HN N
H
HN N
HOH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
OOOOOOOOH2
OOOOOOO
B-DNA Gramicidin-D Oligoamides
Collagen
SmallestPitchpossible
n = 5 n = 9 n = 11 n = 13Mol. Wt.: 5.4 kDa
Hybridization at different oligomer lengths
n = 7Debasish Haldar, Jiang Zhu, Benoit Baptiste…Chem. Asian J. 2010, 6, 1364
X-rays Quan Gan… Angew. Chem. Int. Ed. 2008, 47, 1715Coll: Prof. Jiang, CAS BeijingYann Ferrand…Angew. Chem. Int. Ed. 2010, 49, 1778
X-rayX-ray
Triplexes... ...and Quadruplexes
How large is the Chemical Space ?myosin, tubulin, actin, collagen
virus
membraneDNA
Controlled molecular motions
Molecular Recognition
Biologicalproperties
4 - Foldamer functions
PETEnhancedreactions
Helical Capsules
� �
�� ��
�
� ��
� �
� �
��
��
��
��
�
�� �
� �
��
Q
P
QF
AF
Q2P3Q2
Q2P7Q2
Q3P3QF2AFQF
2P3Q3
(Q3P3QF8)2
J. Garric… Angew. Chem. Int. Ed. 2005, 44, 1954; Chem. Eur. J. 2007, 13, 8454C. Bao… Angew. Chem. Int. Ed. 2008, 47, 4153; Chem. Eur. J. 2009, 15, 11530
Helical Capsules Second Generation
N N
OiBu OiBu
F ON N
HNNHH
OON
NO2
NO
NH
OiBu
HN
FN
ON
OiBu3 2O H
N NH
ON N
O
NH
NO2
NO
NH
OiBu
HN
FN
ON
OiBu 32
End-cap Polar hollow “F” hollow
Chunyan Bao… Angew. Chem. Int. Ed. 2008, 47, 4153
H2N
OH
X-ray
< 1L-Lactic acid
22Malonic acid
< 1Succinic acid
70(de = 100 %)D/L-Malic acid
750(de = 71 %)D/L-Threitol
350meso-Tartaric acid
5500(de = 100 %)D/L-Tartaric acid
Ka (M-1) in CDCl3/DMSO (90:10 vol/vol)
Guests
HO
HO
OH
O
O
OHOH
OH
HO
O
O
HO
HO
HO
OH
O
O
OH
HO
HO
OH
OHOH
OH
HO
HO
HOOH
O
O
OH
OH
HO
O
O
HO
OH
O
O
OH
O
OH
O
HO
O
HO
OH
Y. Ferrand… J. Am. Chem. Soc. 2010, 132, 7858
-85
-65
-45
-25
-5
15
35
55
75
250 300 350 400 450 500nm
q ( m
deg)
0 eq
0.5 eq
1 eq
2 eq
L (+)
D (-)
HO2CCO2H
HO
OH
HO2CCO2H
HO
OH
Capsules for Chiral Guests (Collab. D. Dubreuil, Univ. Nantes)
ON
H
NO2
NO
NH
OiBu
HNNN
ON
OiBu3 3O H
N
NO2
NO
NH
OiBu
HN N N
ON
OiBu 33
N
NN
N
complete diastereoselectivity !
Y. Ferrand… J. Am. Chem. Soc. 2010, 132, 7858, J. Am. Chem. Soc. 2012, 134, 11282,
Helical Capsules Second Generation (Collab. D. Dubreuil, Univ. Nantes)
ON
H
NO2
NO
NH
OiBu
HNNN
ON
OiBu3 3O H
N
NO2
NO
NH
OiBu
HN N N
ON
OiBu 33
N
NN
N
HO
OH
O
HO
O
OHN
NHL-tartaric acid in M helix
linear spacerpolar hollow
X-ray
complete diastereoselectivity !
Y. Ferrand… J. Am. Chem. Soc. 2010, 132, 7858, J. Am. Chem. Soc. 2012, 134, 11282,
Folded StructuresDynamics & Assembly
Functions
5 – Molecular Motions
HN
HN
OO
OO
FOLDAXANES, Collab. H. Jang, Institute of Chemistry, CAS
End-cap Polar hollow “F” hollow
N N
OiBu OiBu
F ON N
HNNHH
OON
ONH
HN
FN
ON
OiBu 2O H
N NH
ON N
O
NH
ONH
HN
FN
ON
OiBu 2
X-ray
Q. Gan, Y. Ferrand… Science 2011, 331, 1172
��
���
���
�
Too fast to monitor by NMR
Q. Gan, Y. Ferrand… Science 2011, 331, 1172
FOLDAXANES, Collab. H. Jang, Institute of Chemistry, CAS
X-ray
A Helical Molecular Shuttle
k1
k-1
+
Q. Gan, Y. Ferrand… Science 2011, 331, 1172
A AB A AB
Folded StructuresDynamics & Assembly
Functions
6 – Biopolymer recognition
4°) Binding to G-Quadruplex DNA:- high selectivity vs. duplex DNA- record high affinity (ΔΔΔΔT)
O NH3+TFA-
O NH
ONH3
+TFA-
NH 3+TFA-
R1 =
R2 =
NH
O
N
NO2
R
8
O
OH
O
HO2C
NH
NH
S
Biological studies – nucleic acid recognitionCollab. C. Staedel (Univ. Bordeaux), S. Balasubramanian (Univ. Cambridge)
1°) No degradation by proteases2°) Low toxicity to HeLa cells3°) Spontaneous cell internalization
E. Gillies… Angew. Chem. Int. Ed. 2007, 46, 4081P. Shirude… J. Am. Chem. Soc. 2007, 129, 11890P. Jena… J. Am. Chem. Soc. 2009, 131, 12522J. Iriondo… ChemBioChem 2010, 11, 1679
� ���� �!�� �
�
�
�
�
�
�
� �
�
� ��
�
�
�
Deciphering foldamer-DNA interactions by SELEXCollab. J.-J. Toulmé, Univ. Bordeaux
Selex:- 30 nucleotide random window- 10 selection rounds- 60 sequences cloned- 15 G-rich sequences found- parallel G-quadruplex conformations- sub μM binding to foldamer in 1 M KAc- diastereoselectivity- DNA vs RNA selectivity- G-quadruplex sequence selectivity
L. Delaurière, Z. Dong… Angew. Chem. Int. Ed. 2012, 51, 473
Take-home lessons
Aromatic oligoamides fold into very stable yet dynamic structures
Large sizes are well within reach of stepwise synthesis(up to ca 20 kDa so far)
Artificial backbones give access to patterns beyond the reach ofnatural polymers
Rational codes link primary sequence, 3D structure, and function
Selective recognition may occur between artificial backbonesand biopolymers
Some chemical reactions are enhanced by folding
Current Lab. MembersLecturerFrédéric GoddeResearch AssociatesYann FerrandVictor MaurizotPost-DocsKrzysztof ZiachMichael SingletonChi BoChandramouli NagulaSimon DawsonTiny DeschrijverPhDsChristos TsiamantasLaure SebaounGuillaume LautretteQuan GanMisae Kanai (visiting)
FundingEU FP7 (People Program)ANRARCLa LigueCNRSUniv. of BordeauxMinistry of ResearchAquitaine Regional CouncilIndustry (Servier, UCB, Sanofi)
CollaboratorsX-rayDr. B. KauffmannProf. J.-M. LégerDr. S. MassipChiralityProf. M. TakafujiProf. H. IharaDCCDr. J. NitschkeMol. CapsulesProf. H. JiangProf. D. DubreuilBiologyDr. C. StaedelDr. J.-J. ToulméProf. Balasubramanian
