Supramolecular Pharmacy 9. Porous solids, metal-organic frameworks (MOFs) Ondřej Jurček 1 Coordination compounds 2 • 0-D distinct coordination complexes • Coordination polymers refer to any structure based on metal ions linked into an infinite chain (1D), sheet (2D), or three-dimensional architecture by bridging ligands (usually containing organic carbon) Coordination compounds 3 • 0-D distinct coordination complexes • Coordination polymers refer to any structure based on metal ions linked into an infinite chain (1D), sheet (2D), or three-dimensional architecture by bridging ligands (usually containing organic carbon) 1D 2D 3D Coordination polymers, metal organic framework (MOF) 4 • Infinite coordination polymers (ICP) can be amorphous and crystalline • 3D infinite crystalline and porous coordination polymers are called metal-organic frameworks (MOFs), MOF-n – n usually signs chronological order, e.g., MOF-5 • Secondary building unit (SBU) – geometry of metal coordination cluster fragment unit • Reticular synthesis – the synthesis of periodic repeating nets • Isoreticular expansion – increasing of the length of the spacer while retaining the same network topology (isoreticular MOF = IRMOF-n) • Decoration means replacing a vertex within a net with a series of vertices • Interpenetration – mutual intergrowth of two or more networks (no chemical link) • Supramolecular isomerism – the existence of more than one type of network superstructure for the same molecular building blocks Supramolecular isomerism (polymorphism) 5 • Defined by Zaworotko: „existence of more than one type of network superstructure for the same molecular building blocks“ • related to structural isomerism at the molecular level Porosity 6 • Len Barbour defined porosity in following terms: 1) Permeability should be demonstrated (e.g. by gas sorption measurements, spectroscopic evidence of guest exchange or crystallography) 2) The host framework should remain substantially unaffected by guest uptake and removal • Porosity by pore size: 1) Microporous (smaller than 2 nm) 2) Mesoporous (2-50 nm) 3) Macroporous (larger than 50 nm) Barbour, L. J. ‘Crystal porosity and the burden of proof’ Chem. Commun. 2006, 1163–1168. Metal-organic frameworks (MOFs) 7 • 1989 synthesis of the first MOF by the group of Richard Robson • 1999 discovery of MOF-5 by the group of Yaghi: important, produced commercially • Octahedral zinc(II) oxo-centered SBU + terephthalic acid a) Hoskins, B. F.; Robson, R. J. Am. Chem. Soc. 1989, 111, 5962; b) Yaghi O. et al. Nature 1999, 402, 276-279. {Cu[C(C6H4·CN)4]}n n+ MOF-5 8O. Yaghi, ch. 9: Macrocyclic and Supramolecular Chemistry: How Izatt–Christensen Award Winners Shaped the Field MOF-5 9 • 1999 synthesis of MOF-5 quasi-solvothermally in DEF using terephthalic acid and Zn(AcO)2·4H2O at 85-105 °C in a closed vessel yields 90 % of solid crystalline phase • The structure can be further expanded by using larger linear dicarboxylates – isoreticular synthesis (IRMOFs) • Stable true porosity even without adsorbed guests • Guest adsorption ranges based on the size of the organic linker, e.g., IRMOF-6 adsorbs 240 cm3/g of methane IRMOFs of MOF-5 10 Zeolites • Are naturally occurring and artificial porous aluminosilicates • Their anionic framework is balanced by cations • General structure by IUPAC: • Globally produced in mil. tons • Catalysis, separation, petrochemical industry (separations, catalytic cracking), ion exchange (water softeners), etc. • Highly stable, but limited structural variability and possibility for size increase Zeolites AlPO4-5 - AFIFaujasite - FAU Linde type ASodalite ZSM-5 The vertices represent the positions of AlO4 – or SiO4 tetrahedra while straight lines represent Si–O–Si or Si–O–Al linkages. Zeolites Processes in MFI type zeolites Diffusion selectivity Cracking and alkylation Transforming benzene Separation and cracking MOF properties (compared to zeolites) 14 • Surface area is larger, it can range between 1 000 – 10 000 m2/g of material • Possibility to fine-tune their properties having at hand a large amount of various organic linkers (polycarboxylates, phosphonates, sulfonates, imidazolates, amines, pyridyl, phenolates ) and metal nods • Possibility for surface or internal post-synthetic modifications to further control their physicochemical properties • MOFs have larger panel of pore size and shape unlike zeolites MOF synthesis: Control of particle size 15 • Preparation of homogeneous, monodispersed, and stable nanoparticles is an important issue for biomedical applications • Particle size represents limitations for some administration routes • E.g., parenteral route requires stable solutions/suspensions of nanocrystals smaller than 200 nm to freely circulate through capillaries • Conventional hydro/solvothermal synthesis • Reverse phase microemulsion – CTABr micelles in isooctane/1-hexanol/water mixture (large volumes, hard to isolate) • Sonochemical synthesis • Microwave assisted hydro/solvothermal synthesis – local superheated nucleation spots • Avoid toxic solvents, usual are DMF, pyridine, or methanol with LD50 values (oral administration in rats) of 2800, 891, and 5628 mg·kg-1 MOF synthesis: Control of particle size 16 • Preparation of homogeneous, monodispersed, and stable nanoparticles is an important issue for biomedical applications • Particle size represents limitations for some administration routes • E.g., parenteral route requires stable solutions/suspensions of nanocrystals smaller than 200 nm to freely circulate through capillaries • Conventional hydro/solvothermal synthesis • Reverse phase microemulsion – CTABr micelles in isooctane/1-hexanol/water mixture (large volumes, hard to isolate) • Sonochemical synthesis • Microwave assisted hydro/solvothermal synthesis – local superheated nucleation spots • Avoid toxic solvents, usual are DMF, pyridine, or methanol with LD50 values (oral administration in rats) of 2800, 891, and 5628 mg·kg-1 Crystallization synthetic technique 17 • Hydrothermal (solvothermal) method Analysis of MOFs 18 • Single crystal X-ray diffraction • Powder X-ray diffraction • Differential scanning calorimetry • Thermogravimetry • Vibrational spectroscopy (IR, Raman) • Solid state magic angle spinning NMR • Neutron diffraction Host-guest chemistry – how to get a drug inside MOF? 19 • MOF synthesis • Filtration • Structural study • MOF with sufficient pore size and volume matching with a size of a guest • MOF activation using vacuum (heating) – removal of volatile components (solvents) • Re-check of MOF structure (risk of collapsing upon removal of solvents) • Suspension of crystals added to solution of guest, adsorption (penetration) • Filtration (washing of the crystals), analysis, quantification of guest uptake • Stability study, drug release study • Biological study Biomedical applications of MOFs 20 • MOFs for biomedical application require biocompatible composition • So far, the data are mostly evaluated based on toxicity of components • Dose, frequency, application route • Exogeneous and endogenous linkers • Polycarboxylic or imidazolate linkers are not very toxic (rat oral doses of 1.1, 5.5 and 8.4 g/kg for terephthalic, trimesic, 2,6-napthalenedicarboxylic acid • Muconate, gallate – low MOF porosity, cyclodextrins – low stability • MIL-100(Fe) trimesic acid, CPO-27(Mg) 2,5dihydroxyterephthalate, or BioMOF-1 zinc adeninate-4,4´-biphenyldicarboxylate P. Horcajada, G. Férey, R. E. Morris, C. Serre et al. Chem. Rev. 2012, 112, 1232–1268. MIL-100 BioMOF-1 CD-MOF-1 21J. F. Stoddart: J. Am. Chem. Soc. 2012, 134, 406–417. Asymmetric unit Unit cell Crystal packing CD-MOF-1 • 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 Porous drug carriers: Examples from our lab 23 • Anticancer ruthenium(III) complex in CD-MOF-1 Marzabad M. A. et al. under revision in Cryst. Growth Des. 1) TBDMSCl, pyridine; 2a) NaH, MeI, DCM; 3) TBAF, THF; 2b) NaH, BnBr, DCM; 4) NaH, MeI, DCM; 5) Pd/C, H2, EA/MeOH 2,3-O-PG-α-CD 2,3-O-PG-β-CD 2,3-O-PG-γ-CD 6-O-PG-α-CD 6-O-PG-β-CD 6-O-PG-γ-CD 18 CD-ligands Development of novel CD-MOFs using modifed CDs 24 Methylated cyclodextrin (10 mg) α β γ M salt/BS RbF/MeOH evapor. (7,3) X evapor. (6,3) CRS evapor. (5,5) X RbF/MeOH - - EA (5,5) CRS, C RbF/MeOH - ACN (6,3) ACN (5,5) CRS RbF/MeOH H (7,3) H (6,3) H (5,5) RbF/MeOH E (7,3) CS E (6,3) C E (5,5) F H2O evapor. X evapor. X evapor. X RbF/H2O evapor. (7,3) X evapor. (6,3) X evapor. (5,5) CRS ZnBr2/MeOH E (11,8) N, C E (11,8) E (10,4) ZnBr2/MeOH DIP (11,8) P - ZnBr2/MeOH DIP (11,8) P, N, C - - 2 MeOH E E E, C , N, F 2 RbF/MeOH E (1 mg, 1 eq.) C , CRS - - 2 RbF/MeOH E (2,7, 3), N, C - - 2 RbF/MeOH E (5,5, 6) C - - 2 RbF/EtOH E (5,5, 6) C , CRS - - 3 RbF/EtOH - - E (5,5) 1 H, CRS, G, C 4 RbF/EtOH - E (6,3) E (5,5) 4 RbF/EtOH - H (6,3) H (5,5) 4 RbF/EtOH - ACN (6,3) ACN (5,5) 4 RbF/EtOH - - EA (5,5) 5 KAcO/MeOH E (5,2) - - 5 KOH/MeOH E (3,5) N, C - - 5 Zn(AcO)2/MeOH E (11,5) CRS - - 5 Zn(NO3)2.6H2O/MeOH E (15,7) E (15,6) E (13,7) Methylated cyclodextrin (10 mg) α M salt/BS EuCl3.6H2O/ MeOH E (19,3) + TMAOH (22 μL) EuCl3.6H2O/ MeOH E (19,3) ZrCl4/MeOH E (12,3) + TMAOH (22 μL) ZrCl4/MeOH E (12,3) ZrOCl2.8H2O/MeOH E (17) C MoO2(doaa)/MeOH/H2O (20) freezer -20, (34) TiCl4/MeOH E (5,8 μL) Y(NO3)3.5H2O/MeOH E (19,2) UO2(AcO)2.2H2O/MeOH E (22,3, 6 eq.) + TMAOH (22 μL) UO2(AcO)2.2H2O/MeOH DIP (22,3, 6 eq.) LiOH/MeOH/H2O evapor. (1,3 mg) Methylated amino-cyclodextrin γ M salt/BS No/MeOH E, C No/water EtOH ZrOCl2.8H2O/MeOH E (17) C RbF/MeOH E (5,5) P, G RbF/water EtOH (5,5) ZnBr2/MeOH E (11,9) Zn(NO3)2.6H2O/MeOH DIP (15,7) Game of cyclodextrins, metal complexation, crystallization 25 MeO-α-CD + ZnBr2 Development of novel CD-MOFs 26 Sandwich-like dimeric structures using Rb(I) and Ag(I) 27 Jurček O. et al. Cryst. Growth Des. 2020, 20, 6, 4193–4199. 28 Porous sandwich-type complexes (STCs) 29Jurček O. et al. Cryst. Growth Des. 2020, 20, 6, 4193–4199. Porous sandwich-type complexes (STCs) Drug delivery 30 • Drugs faces problems with low stability in biological conditions, poor solubility and/or inadequate ability to bypass natural barriers • 1970s started development of drug carriers to protect both the organism from toxic side effects and the API from biological degradation increasing drug’s efficiency and intracellular penetration • Moreover, nanotechnologies allow specific targeting of tissues, cells and even subcellular structures • General issues are low drug loading capacity (<5 wt%), the presence of a burst release, poor biological barrier bypass and/or toxicity • MOFs offer interesting alternative P. Horcajada, G. Férey, R. E. Morris, C. Serre et al. Chem. Rev. 2012, 112, 1232–1268. MOF formulations 31 • Oral administration • Requirements for chemically and mechanically stable formulations under the corresponding biological conditions, i.e., acidic stomach or basic intestinal conditions, intestinal motility, enzymes, etc.) • Powders, pellets, tablets, or gels are suitable • Cream/ointment or patch/membrane • E.g., wound healing antibacterial dressing based on NO-loaded nickel carboxylate CPO-27(Ni) particles and hydrocolloids (cellulose, polyisobutanol (PIB)) was studied. This composite patch is able to release NO over 10 days. P. Horcajada, G. Férey, R. E. Morris, C. Serre et al. Chem. Rev. 2012, 112, 1232–1268. Drug delivery 32 • Anti-inflammatory and analgesic ibuprofen was studied in model mesoporous rigid chromium carboxylates MOFs, MIL-100(Cr), MIL-101(Cr), MIL-53(Fe, Cr) – continuous delivery of drug for 3 weeks • Cationic antiarrhythmic drug, procainamide (short in vivo half-life, administration every 3-4 h), introduced BioMOF-1 (22 %wt loading in 15 days) – release has been achieved in 3 days in phosphate buffer (PBS at pH 7.4) a) J. An et al. J. Am. Chem. Soc. 2009, 131, 8376. b) P. Horcajada, G. Férey, R. E. Morris, C. Serre et al. Chem. Rev. 2012, 112, 1232–1268. Bioactive MOFs 33 • MOFs are likely to be degraded in bodily fluids releasing exogenous organic linker and potentially toxic metal salts • Ideally using endogenic ligands or the actual bioactive compounds as a building block • Vitamin B3, nicotinic acid, can be used with Fe(II)/Fe(III) for synthesis of BioMOF BioMIL-1 (pellagra-curative, vasodilating and antilipemic effect) P. Horcajada, G. Férey, R. E. Morris, C. Serre et al. Chem. Rev. 2012, 112, 1232–1268. Limitations in MOFs‘ use 34 • Large scale production is limited • Avoiding the use of expensive and dangerous reactants • Introducing low pressure conditions and ideally room temperature synthesis • There are already some MOFs produced at ton scale by BASF, e.g., HKUST-1 (copper trimesate), MIL-53 (aluminium terephthalate), etc., but mostly for separation or catalytic purposes • Additional toxicity data for biomedical MOFs are needed Amorphous infinite coordination particles (ICPs) 35 • Unlike MOFs, these ICPs exhibit a higher level of structural tailorability, including sizeand morphology-dependent properties, and therefore, the promise of a wider scope of utility • Various methods of their preparation are available offering a control over their morphology • ICP structures can be depolymerized (sometimes reversibly) much faster and under milder conditions than MOFs, which makes them attractive for a variety of biomedical applications C. Mirkin et al. Chem. Soc. Rev. 2009, 38, 1218–1227. • 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 membrane component Bile acids as scaffolds of unsymmetric chiral ligands Jurček O. et al. Molecules 2022, 27(9), 2961. Jurček O. et al. under revision in Angew. Chem. Int. Ed. 37 Distinct metallosupramolecular complexes UDCA CDCA 38 Self-organization of large coordination complexes Jurček O. et al. Cell Rep. Phys. Sci. 2021, 2, 100303. UDCA-based In the next class… Nanoparticles for drug delivery Thank you for your attention! With many thanks to Jonathan W. Steed, Jerry L. Atwood for Supramolecular Chemistry, ISBN: 978-1-119-58251-9.