NS
N
H
N S
N
H
N S
N
H
H
H
H
CF3
F3C
CF3
NS
N
H
N S
N
H
N S
N
H
H
H
H
F3C
CF3
CF3
CF3
CF3
CF3
Cyclohexane tris-thioureasDecalin bis-squaramides
12 13 14
17
18
15
16
13 + Me4N+Cl(X-ray
crystal
structure)
Supramolecular Pharmacy
1. Introduction to supramolecular chemistry
(non-covalent interactions)
Ing. Ondřej Jurček, Ph.D. et Ph.D.
Assistant Professor
Department of Natural Drugs
1
Course Information
2
• 2 h/week on Tuesdays, 8:00-9:40 Učebna botaniky, 221
• 3 credits
• Attendance (- 2 classes), completion by a written exam complemented by a
discussion
• In case of missing more than 2 classes there will also be a mid-term test on
lecture week 6 (29.10., 8:00-8:30)
Literature: Selected chapters of Supramolecular Chemistry, Jonathan W. Steed,
Jerry L. Atwood, ISBN: 978-1-119-58251-9, complemented by selected research
articles with suprapharmaceutical relevance to selected topics.
Sylabus
3
1. Introduction to supramolecular, material chemistry, and nanoscience. Drug
delivery strategies. Natural products and renewable raw materials
2. Macrocyclic compounds in drug delivery
3. Metallo-supramolecular cages: ligand design, preparation,
characterization, and application
4. Artificial anion transporters and covalent cages for pharmaceutical
applications
5. Polymers and their applications
Sylabus
4
6. Mid-term test (8:00-8:30), followed by Gels and metallogels: components,
preparation, characterization, and applications
7. Co-crystallization and polymorphism, their description, synthesis,
characterization, and applications
8. Porous solid materials, silicates, Metal-Organic Frameworks (MOFs),
preparation, characterization, and applications
9. MOFs in medicinal applications: drug loading and delivery strategies
10. Nanoparticles in drug delivery (nanocrystals, micelles, liposomes, and
other)
Sylabus
5
11. Photomedicine
12. Molecular machines
Would you be interested in any other field of supramolecular chemistry?
What is the Supramolecular Chemistry?
6
• it is chemistry beyond molecule, chemistry of molecular assemblies and the
intermolecular bond (J.-M. Lehn – Nobel Prize winner in 1987)
• some also say that it is chemistry of non-covalent bond
molecular precursors
+
+ +
Molecular chemistry
Covalent molecule:
Chemical nature,
shape, redox
properties, HOMOLUMO
gap, polarity,
vibration and rotation,
magnetism, chirality
guest host
Supramolecular chemistry Supramolecule
(complex):
Degree of order,
interactions between
subunits, symmetry of
packing, intermolecular
interactions
Specific characteristic, function, or properties:
Recognition, Catalysis, Transport
Importance of Supramolecular Chemistry
7
• supramolecular chemistry is everywhere among us, e.g., ranging from human
body (DNA double helix, various cellular transports, ion channels) to toilet
fresheners…
The field of Supramolecular Chemistry has been twice recognized by
the Nobel Prize in Chemistry:
1987: Jean-Marie Lehn, Donald J. Cram, Charles J. Pedersen "for their
development and use of molecules with structure-specific interactions of high
selectivity„
2016: Jean-Pierre Sauvage, Sir J. Fraser Stoddart, Bernard L. Feringa "for the
design and synthesis of molecular machines"
30 years of Supramolecular Chemistry
8
host-guest
sphere Pd48L96 molecular machines
cryptands Mg4L6
blue box
air-stable P4
History
9
• 1891 – Villiers and Hebd: cyclodextrin inclusion compounds
• 1893 – Alfred Werner: coordination chemistry
• 1894 – Emil Fischer: lock and key concept
• 1939 – Linus Pauling: hydrogen bonds are included in the groundbreaking
book The Nature of the Chemical Bond
• 1953 – Watson and Crick: structure of DNA
• 1967 – Charles Pedersen: crown ethers
• 1969 – Jean-Marie Lehn: synthesis of the first cryptands
• 1973 – Donald Cram: spherand hosts produced to test the importance of
preorganisation
• 1978 – Jean-Marie Lehn: introduction of the term ‘supramolecular chemistry’,
defined as the ‘chemistry of molecular assemblies and of the intermolecular
bond’
• 1983 – Jean-Pierre Sauvage introduces catenanes (mechanical bond)
History
10
• 1987 – Award of the Nobel prize for Chemistry to Donald J. Cram, Jean-Marie
Lehn and Charles J. Pedersen "for their development and use of molecules
with structure-specific interactions of high selectivity„
• 1991 – J. Fraser Stoddart introduces rotaxanes
• 1999 – Bernard L. Feringa developed molecular motor
• 2004 – J. Fraser Stoddart: the first discrete Borromean-linked molecule, a
landmark in topological synthesis
• 2016 – Jean-Pierre Sauvage, Sir J. Fraser Stoddart, Bernard L. Feringa "for
the design and synthesis of molecular machines"
What do we study?
11
• Molecular recognition,
attraction, activity
• Lock and key concept
• Binding constant
Paul Ehrlich, father of chemotherapy
12
• The recognition by Paul Ehrlich in 1906 that molecules do not act if they do
not bind, ‘Corpora non agunt nisi fixata’; in this way Ehrlich introduced the
concept of a biological receptor.
• Ehrlich, for example, was working on the treatment of a range of infectious
diseases. As part of his work he noticed that the dye methylene blue has a
surprising affinity for some living cells, staining them an intense blue. ‘If only
certain cells are coloured,’ reasoned Ehrlich, ‘then may there not be dyestuffs
which colour only the carriers of illnesses and at the same time destroy them
without attacking the body’s own cells?’ Ehrlich eventually went on to develop
the arsenic-based anti-syphilis drug Salvarsan in 1910, one of the most
effective drugs known for that disease (replaced in 1940s by penicillin). In the
process he became the founder of modern chemotherapy.
What is the size here?
1313
Nanomachines are 1000 x thiner than hair
Inspiration in nature from bacteria
Richard Feynman – nanotechnology
180cm
18cm
100nm
1 nm = 0.0000001 cm
1.5–3mm
1 mm = 0.01 cm
4 nm
1000 nm
How do we study these?
14
• nuclear magnetic resonance (NMR) spectroscopy,
scanning electron microscopy (SEM), transmission electron microscopy (TEM),
X-ray diffraction, mass spectrometry (MS), etc., will be introduced in each chapter
What non-covalent forces are studied in supramolecular
chemistry?
15
1. Ion-ion interactions = ionic bond, 100-350 kJ mol-1 (close in strength to
covalent)
2. Ion-dipole interactions, 50-200 kJ mol-1
3. Dipole-dipole interactions, 5-50 kJ mol-1
4. Hydrogen bonding, 4-60 kJ mol-1
5. Halogen bonding
6. Interactions of π-systems (cation-π, anion-π, π-π)
7. Van der Waals forces and close packing
Hydrophobic effects
Solvation
Cooperativity (chelating effect)
Ion-ion interactions
16
• 100-350 kJ mol-1
Ion-dipole interactions
17
• 50-200 kJ mol-1, observable in liquid and solid state
• Na+ has similar environment + chelate effect + preorganization
• Ion-dipole also includes coordinative bonds, electrostatic, some have covalent
component = strong. They have also well-defined geometries which is very useful
in design and crystal engineering of supramolecular complexes. They are also
kinetically labile allowing reorganization.
Angew. Chem. Int. Ed. 2015, 54, 14890 –14893
Dipole-dipole interactions
18
• 5-50 kJ mol-1, relatively strong in solid state, weak in liquid state (aceton b.p.)
• Often observed for organic compounds with carbonyls
Hydrogen bonding
19
• 4-60 kJ mol-1, very important in solid and liquid state
• D-H---A (donor-H---acceptor) „masterkey interaction in supramolecular chemistry“
• Hydrogen atom is attached to electronegative atom (N, O, S, even C) and
attracted to a neighbouring dipole of adjacent molecule or functional group
• Responsible for shape of proteins, enzyme recognition, DNA
• Strength is relative to distance between atoms measured in X-ray
Hydrogen bond categories
20
Hydrogen bonding in DNA
21https://en.wikipedia.org/wiki/Base_pair#/media/File:DNA_base-pair_diagram.jpg
Interactions of π-systems
22
• Interactions of double, triple bonds, and aromatic rings: cation-π, anion-π, π-π
• cation-π – usually with alkaline/alkaline earth metals
• anion-π – rare, the interaction between anion and π-electron system seems
repulsive, but there is a charge difference between an overall neutral aromatic
ring and anion gives possibility for a weak electrostatic attraction
• π-π – direct overlap is repulsive, face-to-face or
edge-to face mode
stabilizes the double
helix of DNA
Van der Waals forces
23
• Polarization of an electron cloud by the proximity of and adjacent nucleus
resulting in weak nondirectional electrostatic attraction
• Typically inclusion complexes
• Interaction energy is proportional to the surface area of contact
• Usually refers to C···C, C···H, or H···H interactions
Cell Reports Physical Science 4, 101461, July 19, 2023
Close packing
24
• Nature abhors a vacuum.
• Close packing in crystal structure caused by maximizing the favorable van der
Waals interactions
Cell Reports Physical Science 2, 100303, January 20, 2021
Hydrophobic effects
25
• Exclusion from polar solvents, especially water (water has strong intermolecular
attraction via hydrogen bonding so it is difficult for nonpolar compounds to stay
in)
• Important for protein and polynucleotide structures, phospholipid bilayer (cell
wall), organic inclusion complexes in water (cyclodextrin)
• Energy gain: high energy water inside cavity released (enthalpy), two organic
molecules in solution creates two „holes“ in the continuous structure of water
(entropy)
Solvation
26
• Very important in liquid but also in solid state
• Solvent competes for noncovalent interactions and is in large excess
• Polar versus nonpolar solvents and binding constants of host-guest complexes
Cooperativity, chelating effect
• Cooperativity is when two or more binding sites of host cooperate on guest
binding; positive and negative cooperativity
• Chelate effect: metal complexes of multidentate ligands are significantly more
stable than closely related complexes with monodentate ligands
• The stabilization depends on size of chelate ring and the size of metal cation
vancomycin
Cooperativity, chelating effect
28
• Polydentate ligands: proteins, polysaccharides, polynucleic acids, metalloenzyme
• In 1960s developed method of enhancing mineral absorption by chelating with
amino acids
• EDTA was developed, but this is too stable, coordinating also other metals
• Antidote for poisoning by mercury, arsenic, (iron) and lead (approved by FDA)
• Calcium edetate against disodium edetate (treatment of hypercalcemia – cornea)
EDTA
Allosteric effect in supramolecular chemistry
Allosteric regulation (enzymes)
• Allosteric effect: Cooperativity in cases where the binding of a first guest influences (particularly
enhances) the affinity of a host for a second guest at a remote site
Preorganization
30
• Binding sites are organized in space prior to guest binding
10 000x more stable than
complex with podand
more stable than corand
Complementarity
31
• A host must have binding sites that are of the correct electronic character to
complement those of the guest (hydrogen bond donors must match acceptors,
Lewis acids must match Lewis bases, etc.) and they must be in correct
conformation (spatial organization)
• Donald Cram said: To complex, host must have binding sites which cooperatively
contact and attract binding sites of guests without generating strong nonbonded
repulsions
Complementarity
32https://en.wikipedia.org/wiki/Base_pair#/media/File:DNA_base-pair_diagram.jpg
Host design
• Considering the chelate, macrocyclic
effect, complementarity, and
preorganization
• Considering the target, e.g., metal
cation – size, charge density, hardness
• Spacing the binding side, the more
interactions the better, complementarity
• Character of the host - solubility
Chem. Sci., 2017, 8, 4056-4061
Anthony P. Davis, 20 years of research, Ziylo sold to Novo Nordisk, worth of 800 mil. USD
Summary
34
• What does supramolecular chemistry study?
• What forces are important in supramolecular chemistry?
• What are the basic principles of design in supramolecular chemistry?
In the next class…
Host-guest chemistry (cyclodextrins)
Thank you for your attention!
35