Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization
Donohoe, C.; Schaberle, F.A.; Rodrigues, F.M.S.; Gonçalves, N.P.F.; Kingsbury, C.J.; Pereira, M.M.; Senge, M.O.; Gomes-da-Silva, L.C.; Arnaut, L.G. Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization. J. Am. Chem. Soc. 2022, Article ASAP
The intrinsic challenge of large molecules to cross the cell membrane and reach intracellular targets is a major obstacle for the development of new medicines. We report how rotation along a single C—C bond, between atropisomers of a drug in clinical trials, improves cell uptake and therapeutic efficacy. The atropisomers of redaporfin (a fluorinated sulfonamide bacteriochlorin photosensitizer of 1135 Da) are separable and display orders of magnitude differences in photodynamic efficacy that are directly related to their differential cellular uptake. We show that redaporfin atropisomer uptake is passive and only marginally affected by ATP depletion, plasma proteins, or formulation in micelles. The α4 atropisomer, where meso-phenyl sulfonamide substituents are on the same side of the tetrapyrrole macrocycle, exhibits the highest cellular uptake and phototoxicity.
Nonplanar porphyrins: synthesis, properties, and unique functionalities
Ishizuka, T.; Grover, N.; Kingsbury, C.J.; Kotani, H.; Senge, M.O.; Kojima, T. Nonplanar Porphyrins: Synthesis, Properties, and Unique Functionalities. Chem. Soc. Rev. 2022,Advance Article doi:10.1039/D2CS00391K.
Porphyrins are variously substituted tetrapyrrolic macrocycles, with wide-ranging biological and chemical applications derived from metal chelation in the core and the 18π aromatic surface. Under suitable conditions, the porphyrin framework can deform significantly from regular planar shape, owing to steric overload on the porphyrin periphery or steric repulsion in the core, among other structure modulation strategies. Adopting this nonplanar porphyrin architecture allows guest molecules to interact directly with an exposed core, with guest-responsive and photoactive electronic states of the porphyrin allowing energy, information, atom and electron transfer within and between these species. This functionality can be incorporated and tuned by decoration of functional groups and electronic modifications, with individual deformation profiles adapted to specific key sensing and catalysis applications. Nonplanar porphyrins are assisting breakthroughs in molecular recognition, organo- and photoredox catalysis; simultaneously bio-inspired and distinctly synthetic, these molecules offer a new dimension in shape-responsive host—guest chemistry. In this review, we have summarized the synthetic methods and design aspects of nonplanar porphyrin formation, key properties, structure and functionality of the nonplanar aromatic framework, and the scope and utility of this emerging class towards outstanding scientific, industrial and environmental issues.
Quantitative structure—property relationship modelling for the prediction of singlet oxygen generation by heavy-atom-free BODIPY photosensitizers
Buglak, A..A., Charisiadis, A., Sheehan, A., Kingsbury, C..J., Senge, M..O. and Filatov, M..A., Quantitative Structure—Property Relationship Modelling for the Prediction of Singlet Oxygen Generation by Heavy-atom-free BODIPY Photosensitizers. Chem. Eur. J. 2021, 27, (38), 9934-9947
Heavy-atom-free sensitizers forming long-living triplet excited states via the spin-orbit charge transfer intersystem crossing (SOCT-ISC) process have recently attracted attention due to their potential to replace costly transition metal complexes in photonic applications. The efficiency of SOCT-ISC in BODIPY donor-acceptor dyads, so far the most thoroughly investigated class of such sensitizers, can be finely tuned by structural modification. However, predicting the triplet state yields and reactive oxygen species (ROS) generation quantum yields for such compounds in a particular solvent is still very challenging due to a lack of established quantitative structure-property relationship (QSPR) models. Herein, we analyzed the available data on singlet oxygen generation quantum yields (F?) for a dataset containing > 70 heavy-atom-free BODIPY in three different solvents (toluene, acetonitrile, and tetrahydrofuran)
Crystal structures of 4-bromo-2-formyl-1-tosyl-1H-pyrrole,(E)-4-bromo-2-(2-nitrovinyl)-1-tosyl-1H-pyrrole and 6-(4-bromo-1-tosylpyrrol-2-yl)-4, 4-dimethyl-5-nitrohexan-2-one
Kingsbury, C. J., Sample, H. C., Senge, M. O., Crystal structures of 4-bromo-2-formyl-1-tosyl-1H-pyrrole,(E)-4-bromo-2-(2-nitrovinyl)-1-tosyl-1H-pyrrole and 6-(4-bromo-1-tosylpyrrol-2-yl)-4, 4-dimethyl-5-nitrohexan-2-one. Acta Cryst. 2021, E77, 341-345
he crystal structures of three intermediate compounds in the synthesis of 8-bromo-2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin are reported; 4-bromo-2-formyl-1-tosyl-1H-pyrrole, C12H10BrNO3S, (E)-4-bromo-2-(2-nitrovinyl)-1-tosyl-1H-pyrrole, C13H11BrN2O4S, and 6-(4-bromo-1-tosylpyrrol-2-yl)-4,4-dimethyl-5-nitrohexan-2-one, C19H23BrN2O5S. The compounds show multitudinous intermolecular C—Hef;O interactions, with bond distances and angle consistent in the series and within expectations, as well as varied packing types. The merits of collecting data beyond the standard resolution usually reported for small molecules are discussed.
The Shape of Porphyrins
Kingsbury, C. J., Senge, M. O., The shape of porphyrins, Coord. Chem. Rev, 2021, 431, 213760
Porphyrin molecules are a widely exploited biochemical moiety, with uses in medicinal chemistry, sensing and materials science. The shape of porphyrins, as an aromatic unit, is reductively imagined to be approximately flat, with regular, rigid shape, owing to the popular depiction as a simplified skeletal model. While this regular conformation does exist, the array of substitution patterns in synthetic porphyrins or interactions with the apoprotein in biochemical moieties often induce distortions both in-plane and out-of-plane. Structural deviation reduces symmetry from the ideal D4h and can introduce changes in the physical and electronic structure; physical changes can introduce pockets for favorable intermolecular interactions, and electronic distortion can introduce new electronic transitions and properties. A quantification of porphyrin distortion is presented based on the Normal-coordinate Structural Decomposition method (NSD) pioneered by Shelnutt. NSD transforms crystallographically-determined atomic positions of each porphyrin into a summation of common concerted atom vectors, allowing for quantification of porphyrin anisotropy by symmetry. This method has been used previously for comparison of small data sets of synthetic and biological porphyrins. In the twenty-five years since the method was pioneered, the volume and variety of available crystal structure data has ballooned, and data analysis tools available have become more sophisticated, while the method has languished. Using modern data-science methods, clusters of porphyrin distortions are grouped to show the average effect that a substitution pattern has on porphyrin shape. Aiming to provide an overview on the shape and conformation of these key macrocycles we here provide context to the strategies employed for introducing porphyrin distortion and to provide a quantitative comparative basis for analysis of novel structures. This is achieved by demonstrating that porphyrin molecules often have a predictable NSD pattern, and therefore solid-state conformation, based on chemical arguments. This quantification allows for assessment of predicted structures and forms the basis of a symmetry-by-design motif for a range of porphyrinoids. A modernized computer program used in this structural determination is provided for analysis, with this treatise acting as a guide to the interpretation of results in new structure determinations. New features include simple report generation, prediction of symmetry and assessment of cluster behavior for a range of porphyrin moieties, as well as convenient plotting functions and data reductions.
An Insight into Non-Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold
Grover, N., Flanagan, K. J., Trujillo, C., Kingsbury, C. J. and Senge, M.O. An Insight into Non-Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold. Eur. J. Org. Chem. 2021 7, 1113 - 1122
The effect of bridgehead substitutions on non-covalent interactions was investigated for seven BCP derivatives. The X-ray analyses show 3D-structures and a combination of non-covalent interactions including HB, XB, and CH...HC contacts. QTAIM analysis and MEP graphs show the presence of bond critical points and Σ-holes.
Dipyrrinato-Iridium(III) Complexes for an Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation
Hohlfeld, B..F., Gitter, B., Kingsbury, C..J., Flanagan, K..J., Steen, D., Wieland, G..D., Kulak, N., Senge, M..O. and Wiehe, A. Dipyrrinato-Iridium(III) Complexes for an Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation. Chem. Eur. J. 2021, 27, 6440 —6459
The generation of bio-targetable photosensitisers is of utmost importance to the emerging field of photodynamic therapy and antimicrobial (photo-)therapy. A synthetic strategy is presented in which chelating dipyrrin moieties are used to enhance the known photoactivity of iridium(III) metal complexes. Formed complexes can thus be functionalized in a facile manner with a range of targeting groups at their chemically active reaction sites. Dipyrrins with N- and O-substituents afforded (dipy)iridium(III) complexes via complexation with the respective Cp*-iridium(III) and ppy-iridium(III) precursors (dipy = dipyrrinato, Cp* = pentamethyl-Η 5 -cyclopentadienyl, ppy = 2-phenylpyridyl). Similarly, electron-deficient Ir III (dipy)(ppy) 2 complexes could be used for post- functionalization, forming alkenyl, alkynyl and glyco-appended iridium(III) complexes. The phototoxic activity of these complexes has been assessed in cellular and bacterial assays with and without light; the Ir III (Cl)(Cp*)(dipy) complexes and the glyco-substituted iridium(III) complexes showing particular promise as photomedicine candidates. Representative crystal structures of the complexes are also presented.
Weak Interactions and Conformational Changes in Core-Protonated A2- and Ax-Type Porphyrin Dications
Kingsbury, C.J.; Flanagan, K.J.; Eckhardt, H.-G.; Kielmann, M.; Senge, M.O. Weak Interactions and Conformational Changes in Core-Protonated A2- and Ax-Type Porphyrin Dications, Molecules 2020, 25, 3195
Individual chemical motifs are known to introduce structural distortions to the porphyrin macrocycle, be it in the core or at the periphery of the macrocycle. The interplay when introducing two or more of these known structural motifs has been scarcely explored and is not necessarily simply additive; these structural distortions have a chance to compound or negate to introduce new structural types. To this end, a series of compounds with complementary peripheral (5,15-disubstitution) and core (acidification) substitution patterns were investigated. The single-crystal X-ray structures of 18 5,15-diphenylporphyrin, 5,15-diphenylporphyrindi-ium diacid, and related compounds are reported, including the first example of a 5,15-dialkylporphyrindi-ium. Normal-coordinate structural decomposition (NSD) analysis is used for a detailed analysis of the conformation of the porphyrin subunit within the crystal structures.
Exploring the Relationship Between Structure and Activity in BODIPYs Designed for Antimicrobial Phototherapy
Hohlfeld, B. F., Gitter, B., Flanagan, K., Kingsbury, C. J., Kulak, N., Senge, M. O., & Wiehe, A., Exploring the Relationship Between Structure and Activity in BODIPYs Designed for Antimicrobial Phototherapy. Org. Biomol. Chem., 2020, 18, 2416-2431.
A synthetic strategy to BODIPY dyes is presented giving access to a range of new compounds relevant in the context of antimicrobial photodynamic therapy (aPDT). BODIPYs with the 8-(4-fluoro-3-nitrophenyl) and the 8-pentafluorophenyl substituents were used for the synthesis of new mono- and dibrominated BODIPYs.
Crystal structures of 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(pentafluorophenyl)porphyrin as the chloroform monosolvate and tetrahydrofuran monosolvate
Kingsbury, C. J., Flanagan, K. J., Kielmann, M., Twamley, B. and Senge, M.O.; Crystal structures of 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(pentafluorophenyl)porphyrin as the chloroform monosolvate and tetrahydrofuran monosolvate; Acta Cryst. 2020, E76, 214-220.
The crystal structures of the title compounds, two solvates (CHCl3 and THF) of a symmetric and highly substituted porphyrin, C44H2Br8F20N4 or OBrTPFPP, are described.
Square Grid Metal—Chloranilate Networks as Robust Host Systems for Guest Sorption
Kingsbury, C. J., Abrahams, B. F., Auckett, J. E., Chevreau, H., Dharma, A. D., Duyker, S., He, Q., Hua, C., Hudson, T. A., Murray, K. S., Phonsri, W., Peterson, V. K., Robson, R., White, K. F.; Square Grid Metal—Chloranilate Networks as Robust Host Systems for Guest Sorption. Chem. Eur. J. 2019, 25 (20) , 5222-5234.
Reaction of the chloranilate dianion with Y(NO3)3 in the presence of Et4N+ in the appropriate proportions results in the formation of (Et4N)[Y(can)2], which consists of anionic square-grid coordination polymer sheets with interleaved layers of counter-cations. These counter-cations, which serve as squat pillars between [Y(can)2] sheets, lead to alignment of the square grid sheets and the subsequent generation of square channels running perpendicular to the sheets. The crystals are found to be porous and retain crystallinity following cycles of adsorption and desorption. This compound exhibits a high affinity for volatile guest molecules, which could be identified within the framework by crystallographic methods. In situ neutron powder diffraction indicates a size-shape complementarity leading to a strong interaction between host and guest for CO2 and CH4. Single-crystal X-ray diffraction experiments indicate significant interactions between the host framework and discrete I2 or Br2 molecules. A series of isostructural compounds (cat)[MIII(X-an)2] with M=Sc, Gd, Tb, Dy, Ho, Er, Yb, Lu, Bi or In, cat=Et4N, Me4N and X-an=chloranilate, bromanilate or cyanochloranilate bridging ligands have been generated. The magnetic properties of representative examples (Et4N)[Gd(can)2] and (Et4N)[Dy(can)2] are reported with normal DC susceptibility but unusual AC susceptibility data noted for (Et4N)[Gd(can)2].
Metal-anilate coordination polymers
Kingsbury, C. J.,Metal-anilate coordination polymers. Ph.D. Thesis,University of Melbourne, Parkville, 2018
Crystalline coordination polymers are a class of materials which hold promise as adsorbents, sensors, electronic materials and magnets, as catalysts and separation matrices, or as batteries and electro-catalysts. Many of these applications depend on materials which offer an unusual combination of properties, resulting from the combination of a ligand and metal in a periodic lattice. These properties include stability and permanent porosity upon desolvation, crystallinity, monodisperse pores, open metal sites, flexibility, uptake of and interaction with guest molecules. Coordination polymers derived from redox-active ′anilate′ ligands such as 2,5-dihydroxy-p-benzoquinone (H2dhbq) and chloranilic acid (H2can) have been studied as a possible mechanism for the introduction of electroactive properties into coordination polymers. No systematic study of the coordination polymers derived from substituted anilate ligands has previously been undertaken. In Chapter 2, the syntheses and crystal structures of novel anilate molecules and derived mononuclear and dinuclear compounds are reported. Ligand syntheses are achieved in one or two steps from commercially available starting materials, achieving sufficient purity upon recrystallisation, and many are observed to form isostructural dinuclear metal complexes. The bond distances within these compounds and similar compounds in the literature are observed to be dependent on oxidation state, and are independent of metal coordination geometry, allowing for the assignment of oxidation state from crystallographic data. In Chapter 3, a number of novel one-dimensional coordination polymers are described with metal centres linked by anilate ligands. These one-dimensional chains are shown to have a few different shapes, dependent on the relative coordination geometries around sequential metal centres in a chain. Two strategies for the formation of porous materials by cross-linking of one-dimensional chains are described, but synthetic attempts ultimately resulted in the formation of non-porous materials. In Chapter 4, structures are shown in which each metal centre links to three bridging anilate ligands, forming two- and three-dimensional coordination polymers, the majority of which showed a two-dimensional hexagonal grid network structure. Of these compounds, anionic coordination polymers of the form [M2(anilate)3]2- were found to show open-type structure, and were investigated for host-guest properties via gas adsorption. Reversible, gas-specific structural transformations were observed with the loading of CO2 and N2O into some of these compounds; by changing the cation, the structure was rigidified and did not collapse on desolvation. Compounds containing iron exhibited metal-to-ligand charge transfer, resulting in enhanced conductivity. This MLCT was found to be a temperature-dependent process in some cases. In Chapter 5, structures are shown in which each metal centre links to four bridging anilate ligands, forming two- dimensional square-grid coordination polymers and three-dimensional diamond-type coordination polymers. The square grid compound (Et4N)[Y(can)2] is shown to maintain structure on loss of solvent, and is investigated for interactions with solid, liquid and gaseous intercalants. Particularly strong interactions with hydrogen, methane and CO2 are investigated further via in situ crystallographic methods. Finally, this thesis is concluded, and these individual results are examined as a whole, including commentary on the limitations of this work and potential future work in this area. Appendices 1—5 contain additional data that supplement the thesis.
Role of NEt4+ in Orienting and Locking Together [M2lig3]2- (6,3) Sheets (H2lig = Chloranilic or Fluoranilic Acid) to Generate Spacious Channels Perpendicular to the Sheets
Kingsbury, C. J., Abrahams, B. F., D'Alessandro, D. M., Hudson, T. A., Murase, R., Robson, R., White, K. F.; Role of NEt4+ in Orienting and Locking Together [M2lig3]2- (6,3) Sheets (H2lig = Chloranilic or Fluoranilic Acid) to Generate Spacious Channels Perpendicular to the Sheets; Cryst. Growth Des. 2017, 17, 4, 1465—1470
In the presence of the Et4N+ cation the chloranilate dianion (can2—) associates with a range of divalent cations, M2+, to yield an isomorphous series of crystalline compounds of composition (Et4N)2[M2(can)3] (M = Mg, Mn, Fe, Co, Ni, Cu, and Zn). The fluoranilate dianion (fan2—) likewise affords the closely related (Et4N)2[Zn2(fan)3]. The structures of (Et4N)2[Zn2(can)3], (Et4N)2[Fe2(can)3], and (Et4N)2[Zn2(fan)3] were determined by single crystal X-ray diffraction. Powder X-ray diffraction indicates that all the members of the can2— series are isomorphous. The structure of (Et4N)2[Zn2(fan)3] is very closely related to the structures of the can2— compounds. The [M2(can)32—]n component is present as chicken-wire-like sheets with (6,3) topology. The Et4N+ cation binds sheet to sheet and aligns them so that the large holes within the sheets are arranged one above another, thereby generating spacious channels running perpendicular to the sheets. The solvent molecules present in the channels are ill-defined and easily removed. The (Et4N)2[M2(can)3] structure remains intact after desolvation. The void spaces are calculated to be ∼39% in the case of the can2— compounds and ∼43% in (Et4N)2[Zn2(fan)3]. Substantial amounts of CO2 are sorbed at 273 K by (Et4N)2[Zn2(can)3] and (Et4N)2[Zn2(fan)3]. Spectroscopic evidence supports the presence of at least some of the chloranilate in the radical trianion form in (Et4N)2[Fe2(can)3].
An indirect generation of 1D MII-2,5-dihydroxybenzoquinone coordination polymers, their structural rearrangements and generation of materials with a high affinity for H2, CO2 and CH4
Abrahams, B. F., Dharma, A. D., Dyett, B., Hudson, T. A., Maynard-Casely, H., Kingsbury, C. J., McCormick, L. J., Robson, R., Sutton, A. L., and White, K. F.; An indirect generation of 1D MII-2,5-dihydroxybenzoquinone coordination polymers, their structural rearrangements and generation of materials with a high affinity for H2, CO2 and CH4; Dalton Trans., 2016,45, 1339-1344
A series of solid-state structural transformations are found to accompany desolvation of relatively simple coordination polymers to yield materials that exhibit unexpected gas sorbing properties. Reaction of 1,2,4,5-tetrahydroxybenzene with MII salts (M = Mg, or Zn) in an alcohol/water solution in the presence of air affords cis-MII(C6H2O4-II)(H2O)2·2H2O·xROH, (M = Mg, or Zn), crankshaft-like chains in which the absolute configurations of the chiral metal centres follow the pattern ef;Δ Δ Λ Λ Δ Δ Λ Λef;, and are hydrogen bonded together to generate spacious channels. When crystals of the crankshaft chain are air dried the crystals undergo a single crystal-to-powder rearrangement to form linear trans-MII(C6H2O4-II)(H2O)2 chains. Further dehydration yields microporous solids that reversibly sorb H2, CH4 and CO2 with high sorption enthalpies.
Coordination polymers of chloranilate and nitranilate
Kingsbury, C. J., Coordination polymers of chloranilate and nitranilate. Unpublished Master's Thesis,University of Melbourne, Parkville, 2013
Master's Thesis