Supramolecular Pharmacy
3. Metallo-supramolecular cages
Ondřej Jurček
1
Supramolecular chemistry
2
Can be divided into three main branches based on interactions used in
assembly process:
• (i) those that utilize H-bonding motifs in the supramolecular architectures;
• (ii) processes that primarily use other noncovalent interactions such as ionion,
ion-dipole, π-π stacking, cation-π, van der Waals, and hydrophobic
interactions;
• (iii) those that employ strong and directional metal-ligand bonds for the
assembly process.
Coordination chemistry
3
• Organometallic compound x (metal-organic) coordination compound
= chemical compound containing at least one chemical bond between a carbon
atom of an organic molecule and a metal x organic ligands bind the metal
through a heteroatom such as oxygen or nitrogen
• Studies of supramolecular complexes of metal cations is the coordination
chemistry of relatively labile (i.e. ligand substitution is relatively rapid under
ambient conditions) metal ions and relatively elaborate, usually chelating or
multidentate ligands
Coordination complex
4
• Ligand (from the Latin ligare, to bind) – ion or a molecule which is bonded to
the central atom(s) in a complex compound. Ligands are generally Lewis
bases (electron donors; often lone pair donors) capable of independent
existence. Ligands can have one or more donor atoms and the number is
then referred to as denticity (chloride, 1,2-diaminoethane).
• Metal (oxidation state, coordination number, geometry)
• Bonding ranges from ionic ion-dipole type interactions, where ligand‘s lone
pair of electrons forms a dative bond to a positively charged metal cation to
entirely covalent in which there is significant orbital overlap between metal
and ligand valence orbitals.
Metallosupramolecular chemistry
5
• Metal-organic frameworks (MOFs)
• metal−organic porous coordination polymers consisting of metal ions or
clusters and organic linkers that are connected by metal−ligand
coordination bonds
• Supramolecular coordination cages (SCCs)
• Well-defined, discrete 2D or 3D molecular entities with suitable metal
centers undergoing coordination-driven self-assembly with ligands
containing multiple binding sites
Metal geometry
6
• the coordination number and geometry of the complex is dependent on the
number of ligands that can pack around the small metal center (majority 4-6)
• 6 coordinate geometry is octahedron or trigonal prism
• 4 coordinate geometry is tetrahedral or square planar
• metals in lower oxidation states or those with unfilled sub-shells such as the
transition metals tend to form more covalent complexes with well-defined
coordination geometries and a preference for more polarisable ligands
Hard and soft acids and bases (HSAB)
• Using concept of Lewis acids and bases, so that acids are electron
acceptors and bases are electron donors
• Hard acids: the acceptor atom is of high positive charge, small size, and
does not have easily excited outer electrons, i.e. non-polarisable. E.g.: H+,
Na+, Ca2+, high oxidation states of the transition metals.
• Soft acids: the acceptor atom is of low positive charge, large size, and has
several easily excited outer electrons, i.e. it is polarisable. E.g.: Pt2+, Pd2+,
Rh+, Hg2+, low oxidation states of the transition metals.
• Hard bases: the donor atom is of low polarisability, high electronegativity,
hard to reduce, and associated with empty orbitals of high energy and hence
inaccessible. E.g.: F-, ligands with oxygen or to some extent nitrogen donor
atoms.
• Soft bases: the donor atom is of high polarisability, low electronegativity,
easily oxidised and associated with empty, low-lying orbitals. E.g. : I-, R2S, H-
Hard and soft acids and bases (HSAB)
• Hard to hard and soft to soft
Chirality of coordination complexes
Right-handed twist Left-handed twist
Coordination driven self-assembly
10
• Preparation: certain amount of ligand and metal in suitable solvent (heating)
• The kinetic reversibility between complementary building blocks, reaction
intermediates, and self-assembled architectures provides a way for the
system to self-correct (an “incorrectly” formed bond can dissociate and
reassociate “correctly”) leading to a product that is thermodynamically more
stable than the starting components and any kinetically formed intermediates
• Transition metals, with their preferred coordination geometries, have served
as acceptor units that can logically self-assemble with various rigid or flexible
donors into predictable architectures
Coordination driven self-assembly
11
• Rational synthesis of molecular squares in early 90s (Fujita, Stang)
• The era of cage-like structures begun in 2002
a) Stang et al. J. Am. Chem. Soc. 1997,119, 2524-2533. b) Saalfrank et al. Chem. Eur. J. 2002, 8, No. 12, 2679.
Mg4L6
Synthetic and design strategies
12
• Many design and synthetic strategies have been developed using
metal-ligand coordination, e.g., directional bonding, symmetry
interaction, molecular paneling
Stang et al. Chem. Rev. 2011, 111, 6810–6918.
Makoto Fujita Peter J. Stang Kenneth N. Raymond
Directional bonding strategy
13
• Directional bonding strategy: complementary precursor units must be
structurally rigid with predefined bite angles; and second, the
appropriate stoichiometric ratio of the precursors must be used
Stang et al. Chem. Rev. 2011, 111, 6810–6918.
Symmetry interaction strategy
14
• rational synthetic approach for the synthesis of
high-symmetry coordination assemblies using
metal-ligand bonds (Raymond)
• multibranched chelating ligands with rigid
backbones are used in conjunction with
transition metals or main group metals
Stang et al. Chem. Rev. 2011, 111, 6810–6918.
Molecular paneling strategy
15
• pioneered by Fujita and co-workers, formation of various functional
and aesthetically elegant 3D architectures that resemble platonic
solids (polyhedras are reduced to molecular components)
• e.g., tetrahedron can be designed by stitching together four triangular
panels, while an octahedron can be prepared by bringing together
eight such triangular panels
Stang et al. Chem. Rev. 2011, 111, 6810–6918.snub cube (snub cuboctahedron)
Molecular paneling strategy
16Stang et al. Chem. Rev. 2011, 111, 6810–6918.
Supramolecular coordination self-assemblies
17Stang et al. Chem. Rev. 2011, 111, 6810–6918.
metallacycles
18Stang et al. Chem. Rev. 2011, 111, 6810–6918.
Supramolecular coordination self-assemblies
30 nm
And the greatest supramolecular chemist is: Nature
8.2 nmθ = 150°
30 nm
Fujita D., Ueda Y., Sato S., Yokoyama H., Mizuno N., Kumasaka T., Fujita M.: Chem 2016, 1, 91-101.
M30L60
And the greatest supramolecular chemist is: Nature…
and Prof. Fujita
Pd48L96
21
Ligands of increasing bend angle leading to complexes from Pd6L12 up to Pd48L96 spheres
S. Saha, I. Regeni, G. H. Clever, Coord. Chem. Rev. 2018, 374, 1-14.
D. Fujita, Y. Ueda, S. Sato, N. Mizuno, T. Kumasaka, M. Fujita, Nature 2016, 540, 563-566.
Ditopic pyridyl ligands and their PdnL2n self-assemblies
Functionalized systems
22Nitschke et al. Science 2009, 324, 1697.
• By functionalization of 3D supramolecular assemblies we can
emulate biological systems leading to their applications in various
fields such as host-guest chemistry, cavity directed synthesis,
catalysis, photonics, redox activity, magnetic behaviour, selforganization,
sensing, and medicine
air-stable P4
Host-Guest Chemistry
23
• A molecule binding another molecule producing host-guest complex
• Ignoring the electronic effects, it can be imagined as hand catching a ball
• One of the first cage-like host-guest definition by H.M. Powell 1948 (Oxford)
• Cavitands = hosts having permanent intramolecular cavities
• Forces = mostly electrostatic – complex; less specific, weaker non-directional
interaction, van der Waals, crystal close packing = cavitate, clathrate
Cram et al.: J. Am. Chem. Soc., 1977, 99, 2564–2571
Determination of strength of host-guest interaction
• Binding constant K = thermodynamic stability of a host-guest complex in a
given solvent at a given temperature (dm3 mol-1, M-1) (also formation,
dissociation, association, or stability constant)
• K =
[𝐻𝐺]
𝐻 [𝐺]
or K =
𝑘1
𝑘
−
1
(rate constants)
• Gibbs energy (accociation process)
–ΔG 0 = 𝑅𝑇 ln 𝐾
24
k1
k-1
Supramolecular coordination cages (SCCs) and their
biomedical applications
25Casini et al. Inorg. Chem. 2017, 56, 14715−14729.
Biomedical applications
26a) Casini et al. Inorg. Chem. 2017, 56, 14715−14729. b) Ahmedova (ed. Crowley) Front. Chem. 2018, 6, 620.
• Inspired by the clinically used or tested metallodrugs derived from
Pt(II), Ru(II), or Ru(III)
• Pioneered by Therrien, organometallic Ru(II) metallacycles and cages
• Three main areas: metallacycles, metallacages, metallohelicates (and
nanoparticles derived)
Enhanced permeability and retention (EPR) effect
27Xie et al. Curr. Cancer Drug Target 2019, 19(4), 257.
• high–molecular weight nontargeted drugs and prodrugs accumulate
in tissues that offer increased vascular permeability, such as in sites
of inflammation or cancer
Biomedical applications
28a) Casini et al. Inorg. Chem. 2017, 56, 14715−14729. b) Ahmedova (ed. Crowley) Front. Chem. 2018, 6, 620.
• The Pt(II) metallacycles bind to DNA
• Metallacages can be excellent hosts for bioactive guests or have
bifunctional molecular moieties
• Metallahelicates can have specific helicity that is capable of selective
interactions with biomolecules with certain conformation, such as
DNA fragments
• Allow combination of therapeutic and diagnostic properties –
theranostic applications
Biomedical applications
29Crowley et al. Chem. Sci. 2012, 3, 778–784. b) Casini et al. Inorg. Chem. 2017, 56, 14715−14729.
• Classic work by Crowley
Biomedical applications
30Casini et al. Inorg. Chem. 2017, 56, 14715−14729.
Biomedical applications
31Casini et al. Inorg. Chem. 2017, 56, 14715−14729.
Biotin-targeted metallocage-loaded emissive nanoparticles
32Stang et al. PNAS 2016, 113(48), 13720.
Biotin-targeted metallocage-loaded emissive nanoparticles
33Stang et al. PNAS 2016, 113(48), 13720.
Biomedical applications challenges
34
• Attaining a selective and spatially controlled release of guest
molecules remains a difficult task – stimuli responsive building blocks
mechanisms exploiting pH, temperature, redox reactions, polarity,
light, or electric field (e.g., in tumor tissues)
• Possibility of encapsulating different drug molecules in the same
supramolecular metallacage
• Possibility of controlling destiny of SCCs in a physiological
environment in order to avoid possible side effects (related also to
toxicity of naked and encapsulated drug, stability in vitro, in vivo,
solubility, etc.)
35
Different types of unsymmetric bidentate ligands
D. Tripathy, N. B. Debata, K. C. Naik, H. S. Sahoo, Coord. Chem. Rev. 2022, 456, 214396-214423.
R. Li, A. Marcus, F. Fadaei-Tirani, K. Severin, Chem. Commun. 2021, 57, 10023-10026.
Our contribution to the field
• Enterohepatic circulation, transmembrane transport activity
lanosterol
cholesterol
19 steps
7α-hydroxycholesterol
deoxycholic acid
(DCA)
cholic acid (CA)
lithocholic acid
(LCA)
ursodeoxycholic acid
(UDCA)
chenodeoxycholic acid
(CDCA)
PrimarybileacidsSecondary
• prodrug design, carriers
Bile acid as scaffold of unsymmetric chiral ligands
• pyridyl moiety is often used in supramolecular chemistry in design of ligands for
metallo-coordination self-assemblies, SYMMETRIC, ACHIRAL
• bile acid ligands are ASYMMETRIC, CHIRAL, AMPHIPHILIC, e.g., UDCA with
bend angle 110 °
110 °
Ursodeoxycholic acid
UDCA
4-AP
Conjugates of 4-AP and bile acids = ligands
37
Flower-like structure
Barrel-like structure
38
In C3 symmetry two possible constitutional Pd3L6 isomers
Jurček O., Bonakdarzadeh P., Kalenius E., Linnanto J. M., Ihalainen J. A., Rissanen K.: Angew. Chem. Int. Ed. 2015, 54, 15462-15467.
2 nm
Crown-like Pd3L6 isomer is the one
40
Logical structure-transformation analysis
• water soluble ligand with amphiphilic character
• expectation of easier crystallization
• transmetalation synthetic approach
• stable in aqueous solution
• forms gelly substance with water
41
Tritopic bile acid-based ligand
• water soluble ligand with amphiphilic character
• expectation of easier crystallization
• transmetalation synthetic approach
• stable in aqueous solution
• forms gelly substance with water
42
Tritopic bile acid-based ligand
• water soluble ligand with amphiphilic character
• expectation of easier crystallization
• transmetalation synthetic approach
• stable in aqueous solution
• forms gelly substance with water
43
Tritopic bile acid-based ligand
Jurček O., Nonappa, Kalenius E., Jurček P., Linnanto J. M., Puttreddy R., Valkenier H., Houbenov N., Babiak M., Peterek M., Davis A. P., Marek R., Rissanen
K.: Cell Rep. Phys. Sci. 2021, 2, 100303.
44
Tritopic bile acid-based ligand
Jurček O., Nonappa, Kalenius E., Jurček P., Linnanto J. M., Puttreddy R., Valkenier H., Houbenov N., Babiak M., Peterek M., Davis A. P., Marek R., Rissanen
K.: Cell Rep. Phys. Sci. 2021, 2, 100303.
• opposite chirality at C7
• coordination with Pd2+ leads to a mixture
Pd3L6
45
Chenodeoxycholic acid (CDCA) bispyridyl ligand
• opposite chirality at C7
• Ion mobility mass spectrometry is powerful method
46
Chenodeoxycholic acid (CDCA) bispyridyl ligand
Jurček O., Chattopadhyay S., Kalenius E., Linnanto J. M., Kiesilä A., Jurček P., Radiměřský P., Marek R..: Angew. Chem. Int. Ed. 2024, 63, e202409134.
Chenodeoxycholic acid (CDCA) bispyridyl ligand
UDCA CDCA
48
Chenodeoxycholic acid (CDCA) bispyridyl ligand
Jurček O., Chattopadhyay S., Kalenius E., Linnanto J. M., Kiesilä A., Jurček P., Radiměřský P., Marek R..: Angew. Chem. Int. Ed. 2024, 63, e202409134.
Angew. Chem. Int. Ed. 2015, 54, 15462 –15467
Cell Reports Physical Science, 2021, 2, 100303-100323 49
Synthesis of UDCA trispyridyl ligand (tridentate)
1H NMR spectrum measured in DMSO-d6 at 700 MHz and 298.2 K
Ligand complexation
50
+ Pd12L16
Entry Salt M:L Time Pd6L8 (%)a Pd12L16 (%)a
1 Pd(CH3CN)4(BF4)2 1:2 2 days 36.7 54.9
2 Pd(CH3CN)4(BF4)2 1:2 1 hour 27.8 66.3
3 Pd(CH3CN)4(BF4)2 3:4 1 day 22.8 71.1
4 Pd(CH3CN)4(BF4)2 6:4 1 hour 73.8 22.0
5 Pd(NO3)2.2H2O 3:4 1 hour In process In process
a. estimated based on the height of the drift peak in IM-MS
Mass spectrometry
51
SCCs Salt Diffusion coefficient CCS (IM-MS) Hydrodynamic
diameter
Diameter (IM-MS)
Pd12L16 Pd(CH3CN)4(BF4)2 4.21×10-11 m2 s-1 2676 Å ([Pd12L16(BF4)6]18+) 6.1 nm 5.8 nm
Pd6L8 Pd(CH3CN)4(BF4)2 5.04×10-11 m2 s-1 1463.8 Å ([Pd6L8(BF4)]11+) 5.1 nm 4.3 nm
Pd12L16 Pd(NO3)2.2H2O 4.87×10-11 m2 s-1 - 5.2 nm L
- 1.57×10-10 m2 s-1 - 1.6 nm -
1H-DOSY NMR
52
Pd12L16
Octahedron CuboctahedronIcosahedron
Progressions between an octahedron,
pseudoicosahedron, and cuboctahedron.
Structural analysis of complexes
53
- Studied on HepG2 hepatospheroids showing anticancer activity
Anion Co(II) Ni(II) Ca (II) Cr(III) Mg(II) Mn(II) Cu(II) Zr(IV) Fe(III) Zn(II)
NO3
- ✓ ✓ ✓ ✓ ✓ ✓ ✓ - ✓ ✓
AcO- ✓ ✓ ✓ ✓ ✓ ✓ ✓ - ✓ ✓
Cl- ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
L +
• Variable ratios, temperature, time, concentration, solvent system, synthetic method, modulants
54
Porous bile acid-based nanoparticles
Cr(III)
Mn(II)
Zn(II)
Mn(II)
Fe(III)
Ca(II)
• Size: d = 20-200 nm
• Studies of their drug adsorption
• SAXS, PXRD, gas adsorption, IR, ssNMR, TEM, TG, and DSC, EDX
55
Porous bile acid-based nanoparticles
In the next class…
Artificial anion transporters and covalent cages
Thank you for your attention!
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