Supramolecular Pharmacy
2. Host-guest chemistry (cyclodextrins)
Ondřej Jurček
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Host-Guest Chemistry
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• 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
3
k1
k-1
Examples of host-guest complexes
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siderophore enterobactin
Determination of binding constant
• Any analytical method which can detect concentration of H-G complex in
function of changing concentration of host (H) and guest (G)
• Potentiometric titration
• Charged species, acid-base titration (protonated/deprotonated)
• Nuclear magnetic resonance (NMR) spectroscopy
• Slow exchange on the NMR scale – the binding constant can be
evaluated based on integration of bound/unbound host or guest
• Fast – average between free and bound species
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Determination of binding constant
• Nuclear magnetic resonance (NMR) spectroscopy
• Procedure (NMR titration): small aliquots of guest are added to the
solution of host with known concentration (or vice versa) in a
deuterated solvent and the chemical shifts (Δδ) are monitored as a
function of the guest concentration of host:guest ratio
• the most shifting NMR signals are those which are interacting
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• the shape of the titration curve gives
quantitative information about the
binding constant (analyzed by leastsquares
curve fitting program, e.g,
HypNMR)
• useful for determination of binding
constants in range 10-104 M-1
Determination of binding constant
• Nuclear magnetic resonance (NMR) spectroscopy
• Job plot. Solutions with varying host:guest ratios while the total
concentration of host and guest is constant
• a peak at 0.5 corresponds to 1:1 ratio, 0.66 to 2:1 stoichiometry, etc.
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• the concentration of the complex is
related to some observable quantity such
as Δδ
Determination of binding constant
• Fluorescence titration
• based on proportion of fluorescent intensity to concentration of
fluorophore (fluorescent species in solution)
• UV-Vis spectrophotometric titration
• monitoring the intensity of an electronic absorption band at a
particular wavelength that is characteristic of either the complex or
free host or guest (both are more sensitive than NMR)
81 : 1 equilibrium and association constant K = 450 ± 30 M-1
Org. Biomol. Chem. 11, 4585 (2013)
Determination of binding constant
• Calorimetric – Isothermal Titration
Calorimetry (ITC)
• careful measurement of the heat
(enthalpy) evolved from a carefully
insulated sample as a function of added
guest or host concentration
• the gradient of the ITC curve can be fitted
to determine the binding constant and
hence ΔGcomplex, integration of the total
area under the ITC plot gives the
complexation enthalpy (ΔHcomplex), thus
we can get all thermodynamic parameters
ΔGcomplex = ΔHcomplex – TΔScomplex
• binding constants that range from ca. 102
– 107 M-1
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µcal s-1 for each addition of NBu4
+Cl-
NBu4
+Cl- to guest
Isotherm 1:1
Determination of binding constant
• Extraction experiment
• distribution (partition) coefficient Kd and extraction coefficient Ke
between the aqueous and organic phase can be used to explore the
selectivity of the host to range of guests in given conditions
• usually, picrate salts are used as guests and chloroform as an organic
phase, host must be insoluble in water
• concentration ca be determined by UV-vis
• quick but relatively inaccurate technique, binding energies in the range
25–70 kJ mol-1 (i.e., binding constants of ca. 104–1012). Binding
energies in excess of 70 kJ mol-1 are assessed by competition with
hosts of known binding energy
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Selectivity =
𝐾 𝑔𝑢𝑒𝑠𝑡1
𝐾 𝑔𝑢𝑒𝑠𝑡2
Very popular host in pharmacy: cyclodextrin (CD)
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• Macrocyclic hosts built of glucose molecules
• Cyclodextrins are prepared from starch or cellulose (via
dextrins): degradation of starch by glucosyltransferase
enzyme results in hydrolysis of glycosidic linkages and
formation of cyclodextrins, which are isolated by
complexation with non-polar guests (e.g., toluene)
• 3 main types of cyclodextrins containing 6, 7, or 8 glucose units: α-, β-, γ-CD
• The most common, the most studied and the cheapest hosts
Properties of cyclodextrins (CDs)
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Cyclodextrins (CDs) α β γ
No. of Glc units 6 7 8
Solubility in water (g/L,
25 °C)
145 18.5 232
Cavity volume (Å3) 174 262 427
Hydrolysis by α-amylase Negligible Slow Rapid
Common guests Benzene,
phenol
Naphtalen Anthracene,
crown ether,
cholesterol
Crystalline water (wt-%) 10.2 13.2-14.5 8.13-17.7
Decreasing ring rigidity
alfadex betadex gammadex
Cyclodextrin rims, cyclodextrin derivatives
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• Primary and secondary hydroxyl groups
• Various chemical modifications available
• Synthetic modifications changes properties of CDs (e.g., solubility,
bioavailability)
• Hydroxypropyl (HP), sulfobutylether (SBE), randomly methylated (RM)
• Disturbs the intra- and intermolecular HB, increases solubility, extension of
hydrophobic cavity
, H or -CH2CH2CH2CH2SO3Na, H or -CH3
Complexation of CDs
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• Larger cyclodextrins have poorer complexation due to flexibility
• Usually the complexes with non-polar compounds in water are formed as 1:1
but also 2:1 inclusion complexes
• The complexation is driven by:
• Steric fit
• Release of high energy water
• Hydrophobic effect
• VdW interactions and dispersive
forces
• Dipole-dipole interactions
• Charge transfer interactions
• Electrostatic interactions
• H-bonding
Nature Reviews, VOLUME 3 | DECEMBER 2004 | 1023
Effect of complexation (guest size) on crystal packing
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• The complexation in liquid state can be detected by various methods, e.g.,
nuclear magnetic resonance spectroscopy (NMR), etc.
• In solid state, e.g., by X-ray crystallography: solid state complexes can be
divided into channels, cages, layers depending on the guest and the
organization of the CD molecules, i.e., cages are observed with small guests
(benzen, methanol), channels are observed with larger guests (ferrocene)
which do not fit inside the cavity thus lead to extension
Cyclodextrins as excipients in pharmacy
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• To increase bioavailability and stability of poorly water-soluble drugs
• Can lower the free concentration of drugs and thus the pharmacokinetics and
pharmacodynamics can be changed significantly
• CDs can reduce or prevent gastrointestinal and ocular irritation, reduce or
eliminate unpleasant smells or tastes, prevent pre-systemic drug-drug or
drug-additive interactions within a formulation, or to convert oil and liquid
drugs into microcrystalline or amorphous powders
• There is a number of pills, aqueous parenteral solutions, nasal sprays, eye
drop solutions, or even vaccines
CD applications
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• Non-toxic, high-temperature stable, cheap, slow-release, delivery media and
enzyme mimics
• Food industry: odor, color, pigment, and flavor carriers and binders –
cholesterol binders, prevents oxidation, photochemical degradation, thermal
decomposition, loss by sublimation
• Pharmaceutical industry: prevents premature drug metabolism, modify
solubility and biological transportation properties, relieves local irritation and
drug-induced damages, masks unpleasant taste
• Separations: as additive to mobile phase or stationary phase
Safety concerns in use of cyclodextrins (2017, EMA)
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• European Medicines Agency (EMA) - is an agency of the European Union
which is in charge of the evaluation and supervision of pharmaceutical
products (9 October 2017 EMA/CHMP/495747/2013 Committee for Human Medicinal Products)
CD-containing drugs
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• The first drug was prostaglandin E1 with α-CD (Japan, 1976, vasodilator)
• Development: 24 (2004), 35 (2007), 48 (2013), 129 (2022) approved
pharmaceutical ingredients formulated with either parent CDs or their
hydroxypropyl, sulfobutyl, randomly methylated or sulfolipo derivatives
a) Puskás, I., Szente, L., Szőcs, L., Fenyvesi, É. "Recent List of Cyclodextrin-Containing Drug Products", Periodica Polytechnica Chemical
Engineering, 67(1), pp. 11–17, 2023. b) Journal of Inclusion Phenomena and Macrocyclic Chemistry (2020) 98:171–186.
CD-containing drugs
20Puskás, I., Szente, L., Szőcs, L., Fenyvesi, É. "Recent List of Cyclodextrin-Containing Drug Products", Periodica Polytechnica Chemical Engineering,
67(1), pp. 11–17, 2023. https://doi.org/10.3311/PPch.21222
Examples of CD-containing drugs
Puskás, I., Szente, L., Szőcs, L., Fenyvesi, É. "Recent List of Cyclodextrin-Containing Drug Products", Periodica Polytechnica Chemical Engineering, 67(1), pp. 11–17, 2023.
Bromhexin β-CD Bisolvon tablet Sanofi
Cetirizineβ-CD Zyrtec, chewing tablet Losan Pharma, UCB Pharma
WalZyr OD tablet Sandoz, Walgreen, Sawai Pharm.
Revicet dry syrup Nichi-Iko, Takeda
Cholecalciferol β-CD Vitamin D3 tablet Natures Aid (U.K.)
Garlic Extract β-CD various dragees Various
Menthol/camphor β-CD Pain relief gel ointment MMA Elite,Doctor Hoy‘s
Nicotine β-CD Nicorex, Nicorette tablet Pierre Fabre
Nicogum,chewing gum Pfizer
Nitroglycerin β-CD Nitropen sublingual tablet Nippon Kayaku
Acetaminophen HP-β-CD Paracetamol infusion, chewable tablet Uni-Pharma, 7T Pharma
Examples of CD-containing drugs
Puskás, I., Szente, L., Szőcs, L., Fenyvesi, É. "Recent List of Cyclodextrin-Containing Drug Products", Periodica Polytechnica Chemical Engineering, 67(1), pp. 11–17, 2023.
Ad26.COV2.S HP-β-CD Jcovden (previously COVID-19 Vaccine Janssen)vaccine J&J
Diclofenac HP-γ-CD Voltaren Ophta CD, Voltarol eye drop Novartis
Docetaxel HP-β-CD Docetaxel Teva Generics infusion Teva
Larotrectinib HP-β-CD Vitrakvi capsules, oral solutions Bayer
Carbamazepine SBECD Carnexiv i.v. Lundbeck
Remdesivir SBECD Veklury i.v. Gilead Sciences
Chloramphenicol RAMEB Clorocil eye drop Oftalder
Estradiol RAMEB Aerodiol nasal spray Servier
Inactivated Sulfolipo-CD Suvaxin-PCV vaccine Pfizer
porcine circovirus
Use of cyclodextrins as drugs
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• Sugammadex – used as reversal of neuromuscular blockade induced by
rocuronium and vecuronium in general anaesthesia (by competing for the
cholinoceptors at the motor end plate, thereby exerting its muscle-relaxing
properties, which are used adjunctively to general anesthesia)
• EMA ()
Drugs 2009, 69, 919–942
acetylcholin
sugammadex
rocuronium
HG-complex
acetylcholin receptor
Na+
• Using the strong afinity between adamantane and β-CD
Self-healing soft materials
Collect. Czech. Chem. Commun. 1933, 5, 1-5
Ikura et al. NPG Asia Materials (2022) 14:10
• γ-CDs for Organic Nano-Cubes (ONCs) developed by
(metal-organic frameworks – CD-MOFs
• in cosmetics (NOBLE antiaging skin care), but also chemical and petrochemical industry, home and personal
care, food and beverages and pharmaceuticals
a) Stoddart J. F. et al.: J. Am. Chem. Soc. 2012, 134, 406-417. b) Yaghi, O. M.; Stoddart J. F. et al.: Angew. Chem. Int. Ed. 2010, 49, 8630-8634.
Interesting supramolecular applications of CDs – CD-MOF
• α-CDs for isolation of gold from crude ores, patented 2014 (avoiding use of mercury)
Liu, Z.; Frasconi, M.; Lei, J.; Fahrenbach, A. C.; Botros, Y. Y.; Farha, O. K.; Hupp, J. T.; Mirkin, C. A.; Stoddart, J. F. Nat. Commun. 2013, 4, Article 1855.
Gold extraction
• Using the strong afinity between steroidal compounds and β- (or γ-CD)
Waste water treatment
a) Environmental Science and Pollution Research (2022) 29:1585–1604, b) Carbohydrate Polymers (2017) 173: 37-49
Cyclodextrins as carriers of Ru(III)-metallodrugs
Cell Reports Physical Science 4, 101461, July 19, 2023
• Enantiomers or optical isomers are stereoisomers which are not superposable – analogous to left
and right hand
• Thalidoimide case (Contergan) (1957-1961) – R- and S-isomers
• Originally for trouble sleeping, anxiety, morning sickness
• (S)-thalidoimide is terratogenic, (R) is not
• The (R) is interconverted into the (S) in vivo
• 10000 children affected by serious birth defects
(40 % children died in the first year of life)
Separation of enantiomers
(S)-(+)-lactic acid (R)-(-)-lactic acid
(R) (S)
• Diastereomers like enantiomers share the same molecular formula and are not superposable,
however, they are not mirror images
• Enantiomers in achiral environment are not distinguishable, in chiral environment they can behave
like diasteromers and can be distinguished and separated
• CDs form chiral environment for chiral resolution or racemic mixtures (enantiomers in 1:1 ratio)
Separation of enantiomers
D-ErythroseD-Threose
Diastereomers
Other macrocycles used in supramolecular chemistry
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In the next class…
Metallo-supramolecular cages
Thank you for your attention!
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