Recent publications by the Senge Group
Konrad, N.; Horetski, M.; Sihtmäe, M.; Truong, K.-N.; Osadchuk, I.; Burankova, T.; Kielmann, M.; Adamson, J.; Kahru, A.; Rissanen, K.; Senge, M.O.; Borovkov, V.; Aav, R.; Kananovich, D. Thiourea Organocatalysts as Emerging Chiral Pollutants: En Route to Porphyrin-Based (Chir)Optical Sensing. Chemosensors 2021, 9, 278
Environmental pollution with chiral organic compounds is an emerging problem requiring innovative sensing methods. Amino-functionalized thioureas, such as 2-(dimethylamino)cyclohexyl-(3,5-bis(trifluoromethyl)phenyl)thiourea (Takemoto′s catalyst), are widely used organocatalysts with virtually unknown environmental safety data. Ecotoxicity studies based on the Vibrio fischeri luminescence inhibition test reveal significant toxicity of Takemoto′s catalyst (EC50 = 7.9 mg/L) and its NH2-substituted analog (EC50 = 7.2—7.4 mg/L). The observed toxic effect was pronounced by the influence of the trifluoromethyl moiety. En route to the porphyrin-based chemosensing of Takemoto-type thioureas, their supramolecular binding to a series of zinc porphyrins was studied with UV-Vis and circular dichroism (CD) spectroscopy, computational analysis and single crystal X-ray diffraction. The association constant values generally increased with the increasing electron-withdrawing properties of the porphyrins and electron-donating ability of the thioureas, a result of the predominant ZnN cation—dipole (Lewis acid—base) interaction. The binding event induced a CD signal in the Soret band region of the porphyrin hosts—a crucial property for chirality sensing of Takemoto-type thioureas
Melissari, Z.; Williams, R. M.; Senge, M. O. Porphyrinoids for Photodynamic Therapy. In Applications of Porphyrinoids as Functional Materials; (H. Lang, T. Rüffer (eds.)). The Royal Society of Chemistry, 2021; 252—291
Heliotherapy (Greek etymology: ήΛΙΟ+ ΘΕΡΑΠΕίΑ= sun+ therapy) is the alleviating and therapeutic effect of natural sunlight that can be used to treat skin or muscle disorders. Phototherapy (PT)(Greek etymology: ΦώΤΟ+ ΘΕΡΑΠΕίΑ= light+ therapy) dates back thousands of years when Egyptians, Indians, Chinese, Romans, and Greeks were instinctively utilizing sunlight to treat several diseases, including vitiligo, tuberculosis, and psoriasis. 1 Many advances related to the clinical use and safety of PT have been made in the last 50 years, notably in the area of photodynamic therapy (PDT). PDT is an example of PT where light is used to alleviate and treat malignant diseases such as cancer and infections. In PDT, the so-called photosensitizer ...
Sample, H. C.; Emandi, G.; Twamley, B.; Grover, N.; Khurana, B.; Sol, V.; Senge, M. O. Synthesis and Properties of BODIPY Appended Tetraphenylethylene Scaffolds as Photoactive Arrays. European Journal of Organic Chemistry 2021, 2021, 4136—4143.
Tetraphenylethylene (TPE) and its derivatives exhibit excellent aggregation-induced emission (AIE) properties. The TPE unit is easily accessible, and many functional groups can be introduced in a facile manner to yield effective luminescent materials in both solution and the solid-state. It is because of this, several TPE-based compounds have been developed and applied in many areas, such as OLEDs and chemical sensors. Boron dipyrromethenes (BODIPYs) are a class of pyrrolic fluorophore of great interest with myriad application in both material science and biomedical applications. Through the combination of Pd-catalyzed cross-coupling reactions and traditional dipyrromethene chemistry, we present the syntheses of novel tetra-BODIPY-appended TPE derivatives with different distances between the TPE and BODIPY cores. The TPE-BODIPY arrays 6 and 9 show vastly differing AIE properties in THF/H2O systems, with 9 exhibiting dual-AIE, along with both conjugates being found to produce singlet oxygen (1O2). We presume the synthesized BODIPY-appended TPE scaffolds to be utilized for potential applications in the fields of light-emitting systems and theranostics.
Hasanin, M.S.; Abdelraof, M.; Fikry, M.; Shaker, Y.M.; Sweed, A.M.K.; Senge, M.O. Development of Antimicrobial Laser-Induced Photodynamic Therapy Based on Ethylcellulose/Chitosan Nanocomposite with 5,10,15,20-Tetrakis(m-Hydroxyphenyl)porphyrin. Molecules 2021, 26, 3551.
The development of new antimicrobial strategies that act more efficiently than traditional antibiotics is becoming a necessity to combat multidrug-resistant pathogens. Here we report the efficacy of laser-light-irradiated 5, 10, 15, 20-tetrakis (m-hydroxyphenyl) porphyrin (m THPP) loaded onto an ethylcellulose (EC)/chitosan (Chs) nanocomposite in eradicating multi-drug resistant Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans. Surface loading of the ethylcelllose/chitosan composite with m THPP was carried out and the resulting nanocomposite was fully characterized. The results indicate that the prepared nanocomposite incorporates m THPP inside, and that the composite acquired an overall positive charge. The incorporation of m THPP into the nanocomposite enhanced the photo-and thermal stability. Different laser wavelengths (458; 476; 488; 515; 635 nm), powers (5—70 mW), and exposure times (15—45 min) were investigated in the antimicrobial photodynamic therapy (aPDT) experiments, with the best inhibition observed using 635 nm with the m THPP EC/Chs nanocomposite for C. albicans (59±0.21%), P. aeruginosa (71.7±1.72%), and S. aureus (74.2±1.26%) with illumination of only 15 min. Utilization of higher doses (70 mW) for longer periods achieved more eradication of microbial growth.
Senge, M. O. Conformational Design of Enzyme-like Porphyrin Binding Pockets for Catalysis and Sensing. ECS Meeting Abstracts 2021, 16, 783
Porphyrins have long been recognized as sensors for various analytes. However, this involves mostly metalloporphyrins and there are still limitations with regard to discrimination and sensitivity. Here we illustrate that metal-free metal-free (′free base′) porphyrins can be re-engineered via conformational design to make the core N-H units accessible for interaction with substrates or analytes. This allows to utilize metal-free porphyrin free bases as organocatalysts. Highly conjugated porphyrin macrocyclic systems offer spectrophotometric sensitivity towards geometrical and/or electronic changes and thus, utilizing the porphyrin core for selective detection of substrates in solution offers significant potential for applications. As a proof-of-concept we describe how a combination of macrocycle distortion in conjunction with suitable functional groups in the porphyrin periphery allowed the design of the binding pocket in an …
Gierlich, P., Mata, A.I., Donohoe, C., Brito, R.M.M., Senge, M.O., Gomes-da-Silva, L.C., Ligand-Targeted Delivery of Photosensitizers for Cancer Treatment. Molecules 2020, 25(22), 5317.
Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers.
Elliott, R., Ryan, A.A., Aggarwal, A., Zhu, N., Steuber, F.W., Senge, M.O., Schmitt, W., 2D Porphyrinic Metal-Organic Frameworks Featuring Rod-Shaped Secondary Building Units. Molecules 2021, 26, 2955.
Metal-organic frameworks (MOFs) encompass a rapidly expanding class of materials with diverse potential applications including gas storage, molecular separation, sensing and catalysis. So-called ′rod MOFs′, which comprise infinitely extended 1D secondary building units (SBUs), represent an underexplored subclass of MOF. Further, porphyrins are considered privileged ligands for MOF synthesis due to their tunable redox and photophysical properties. In this study, the CuII complex of 5,15-bis(4-carboxyphenyl)-10,20-diphenylporphyrin (H2L-CuII, where H2 refers to the ligand′s carboxyl H atoms) is used to prepare two new 2D porphyrinic rod MOFs PROD-1 and PROD-2. Single-crystal X-ray analysis reveals that these frameworks feature 1D MnII- or CoII-based rod-like SBUs that are coordinated by labile solvent molecules and photoactive porphyrin moieties. Both materials were characterised using infrared (IR) spectroscopy, powder X-ray diffraction (PXRD) spectroscopy and thermogravimetric analysis (TGA). The structural attributes of PROD-1 and PROD-2 render them promising materials for future photocatalytic investigations.
Flanagan, K.J., Paradiz Dominguez, M., Melissari, Z., Eckhardt, H.-G., Williams, R.M., Gibbons, D., Prior, C., Locke, G.M., Meindl, A., Ryan, A.A., Senge, M.O., Structural Effects of meso-Halogenation on Porphyrins, Beilstein J. Org. Chem. 2021, 17, 1149-1170.
The use of halogens in the crystal engineering of supramolecular porphyrin assemblies has been a topic of strong interest over the past decades. With this in mind we have characterized a series of direct meso-halogenated porphyrins using single crystal X-ray crystallography. This is accompanied by a detailed conformational analysis of all deposited meso-halogenated porphyrins in the CSD. In this study we have used the Hirshfeld fingerprint plots together with normal-coordinate structural decomposition and determined crystal structures to elucidate the conformation, present intermolecular interactions, and compare respective contacts within the crystalline architectures. Additionally, we have used density functional theory calculations to determine the structure of several halogenated porphyrins. This contrasts conformational analysis with existing X-ray structures and gives a method to characterize samples that are difficult to crystallize. By using the methods outlined above we were able to deduce the impact a meso halogen has on a porphyrin, for example, meso-halogenation is dependent on the type of alternate substituents present when forming supramolecular assemblies. Furthermore, we have designed a method to predict the conformation of halogenated porphyrins, without need of crystallization, using DFT calculations with a high degree of accuracy.
Senge, M.O., Sergeeva, N.N., Hale, K.J., Classic highlights in porphyrin and porphyrinoid total synthesis and biosynthesis, Chem. Soc. Rev. 2021, 50, 4730-4789.
Porphyrins feature prominently in nature, be it as enzymatic cofactors, electron and exciton shuffles, as photoactive dyes, or as signaling substances. Their involvement in the generation, storage and use of oxygen is pivotal to life, while their photochemical properties are central to the biochemical functioning of plants. When complexed to metals, porphyrins can engage in a multitude of contemporary applications ranging from solar energy generation to serving as catalysts for important chemical reactions. They are also able to function as useful theranostic agents, and as novel materials for a wide range of applications. As such, they are widely considered to be highly valuable molecules, and it almost goes without saying that synthetic organic chemistry has dramatically underpinned all the key advances made, by providing reliable access to them. In fact, strategies for the synthesis of functionalized porphyrins have now reached a state of refinement where pretty well any desired porphyrin can successfully be synthesized with the approaches that are available, including a cornucopia of related macrocycle-modified porphyrinoids. In this review, we are going to illustrate the development of this exciting field by discussing a number of classic syntheses of porphyrins. Our coverage will encompass the natural protoporphyrins and chlorophylls, while also covering general strategies for the synthesis of unsymmetrical porphyrins and chlorins. Various industrial syntheses of porphyrins will also be discussed, as will other routes of great practical importance, and avenues to key porphyrinoids with modified macrocycles. A range of selected examples of contemporary functionalization reactions will be highlighted. The various key syntheses will be described and analyzed from a traditional mechanistic organic chemistry perspective to help student readers, and those who are new to this area. The aim will be to allow readers to mechanistically appreciate and understand how many of these fascinating ring-systems are built and further functionalized.
Buglak, A.A., Charisiadis, A., Sheehan, A., Kingsbury, C.J., Senge, M.O., Filatov, M.A., Quantitative Structure-Property Relationship Modelling for the Prediction of Singlet Oxygen Generation by Heavy-atom-free BODIPY Photosensitizers, Chem. Eur. J. Accepted Author Manuscript, 2021.
Heavy-atom-free sensitizers forming long-living triplet excited states via the spin-orbit charge transfer intersystem crossing (SOCT-ISC) process have potential to replace transition metal complexes in photonic applications. The efficiency of SOCT-ISC in BODIPY donor-acceptor dyads can be tuned by structural modification. Predicting the triplet state yields and reactive oxygen species generation quantum yields in a particular solvent is challenging due to a lack of quantitative structure-property relationship (QSPR) models. We analyzed data on 1O2 generation quantum yields (ΦΔ) for >70 heavy-atom-free BODIPY in toluene, acetonitrile, and THF. To build reliable QSPR models, we synthesized new BODIPYs containing different electron donating groups, studied their optical and structural properties and the solvent dependence of 1O2, which confirmed the formation of triplet states via SOCT-ISC. More than 5000 quantum-chemical descriptors were calculated including descriptors using DFT, namely M06-2X functional. QSPR models predicting ΦΔ values were developed using multiple linear regression (MLR), which perform significantly better than other machine learning methods and show sufficient statistical parameters (R = 0.88-0.91 and q2 = 0.62-0.69) for all three solvents. A small root mean squared error of 8.2% was obtained for ΦΔ values predicted using MLR model in toluene. QSPR and machine learning techniques can be useful for predicting ΦΔ values in different media and virtual screening of new heavy-atom-free BODIPYs with improved photosensitizing ability.
Fergus, C., Al-qasem, M., Cotter, M., McDonnell, C.M., Sorrentino, E., Chevot, F., Hokamp, K., Senge, M.O., Southern, J.M., Connon, S.J., Kelly V.P., The human tRNA-guanine transglycosylase displays promiscuous nucleobase preference but strict tRNA specificity, Nucleic Acids Research. 2021, 49(9), 4877-4890.
Base-modification can occur throughout a transfer RNA molecule; however, elaboration is particularly prevalent at position 34 of the anticodon loop (the wobble position), where it functions to influence protein translation. Previously, we demonstrated that the queuosine modification at position 34 can be substituted with an artificial analogue via the queuine tRNA ribosyltransferase enzyme to induce disease recovery in an animal model of multiple sclerosis. Here, we demonstrate that the human enzyme can recognize a very broad range of artificial 7-deazaguanine derivatives for transfer RNA incorporation. By contrast, the enzyme displays strict specificity for transfer RNA species decoding the dual synonymous NAU/C codons, determined using a novel enzymeRNA capture-release method. Our data highlight the broad scope and therapeutic potential of exploiting the queuosine incorporation pathway to intentionally engineer chemical diversity into the transfer RNA anticodon.
Hohlfeld, B.F., Gitter, B., Kingsbury, C.J., Flanagan, K.J., Steen, D., Wieland, G.D., Kulak, N., Senge, M.O., Wiehe, A. Dipyrrinato-Iridium(III) Complexes for Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation. Chem. Eur. J. 2021, 27, 6440-6459.
The generation of bio-targetable photosensitizers 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-η5-cyclopentadienyl, ppy=2-phenylpyridyl). Similarly, electron-deficient [IrIII(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 [IrIII(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.
Kingsbury, C. J., Sample, H., 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.
The 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—H⋯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.
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, 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.
Callaghan, S., Vindstad, B.E., Flanagan, K.J., Melø, T.B., Lindgren, M., Grenstad, K., Gederaas, O.A. and Senge, M.O., Structural, Photophysical, and Photobiological Studies on BODIPY-Anthracene Dyads. ChemPhotoChem. 2020 5(2), 131-141
We report the structural, photophysical, and photobiological properties of a promising BODIPY-anthracene dyad (BAD) that was previously shown to induce a therapeutic effect against MDA-MB-468ߕcells. The BODIPY was synthesized and its crystal structure was elucidated. We further investigate the potential of this molecule as a versatile photosensitizer for photodynamic therapy against AY27 and F98 cancer cell models. Both necrosis and apoptosis were found to play a role in cell death and G1 phase arrestation was observed following PDT. From time-resolved spectroscopic analysis of absorbance and luminescence, it was found that the singlet oxygen quantum yield of the most promising BODIPY-anthracene dyad is high (>70 %) and originates from a triplet state. Interestingly, despite the efficient PDT effect, long-lived triplet states or singlet oxygen formation were not observed when water (or D2O) was used as the solvent but were readily observed in solvents such as MeOH and EtOH.
Norvaiša, K., Yeow, K., Twamley, B., Roucan, M., Senge. M. O., Strategic Synthesis of ′Picket Fence′ Porphyrins Based on Nonplanar Macrocycles. Eur. J. Org. Chem. 2021, 1871-1882
Traditional ′picket fence′ porphyrin systems have been a topic of interest for their capacity to direct steric shielding effects selectively to one side of the macrocycle. Sterically overcrowded porphyrin systems that adopt macrocycle deformations have recently drawn attention for their applications in organocatalysis and sensing. Here we explore the combined benefits of nonplanar porphyrins and the old molecular design to bring new concepts to the playing field.
Sitte, E., Twamley, B., Grover, N., Senge, M. O., Investigation of the Reactivity of 1-Azido-3-iodobicyclo[1.1.1]pentane under ″Click″ Reaction Conditions, J. Org. Chem 2021, 86, 1238-1245.
The bicyclo[1.1.1]pentane (BCP) unit is under scrutiny as a bioisostere in drug molecules. We employed methodologies for the synthesis of different BCP triazole building blocks from one precursor, 1-azido-3-iodobicyclo[1.1.1]pentane, by ″click″ reactions and integrated cycloaddition—Sonogashira coupling reactions. Thereby, we accessed 1,4-disubstituted triazoles, 5-iodo-1,4,5-trisubstituted triazoles, and 5-alkynylated 1,4,5-trisubstituted triazoles. This gives entry to the synthesis of multiply substituted BCP triazoles on either a modular or a one-pot basis. These methodologies were further utilized for appending porphyrin moieties onto the BCP core.
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.
Norvaiša, K., O'Brien, J. E., Gibbons, J. D. and Senge, M. O., Elucidating Atropisomerism in Nonplanar Porphyrins with Tunable Supramolecular Complexes, Chem. Eur. J., 2020, 27, 331-339
Atropisomerism is a fundamental feature of substituted biaryls resulting from rotation around the biaryl axis. Different stereoisomers are formed due to restricted rotation about the single bond, a situation often found in substituted porphyrins. Previously NMR determination of porphyrin atropisomers proved difficult, if not almost impossible to accomplish, due to low resolution or unresolvable resonance signals that predominantly overlapped. Here, we shed some light on this fundamental issue found in porphyrinoid stereochemistry. Using benzenesulfonic acid (BSA) for host—guest interactions and performing 1D, 2D NMR spectroscopic analyses, we were able to characterize all four rotamers of the nonplanar 5,10,15,20-tetrakis(2-aminophenyl)-2,3,7,8,12,13,17,18- octaethylporphyirin as restricted H-bonding complexes.
Sample, H. C., Senge, M. O., Nucleophilic Aromatic Substitution (SNAr) and Related Reactions of Porphyrinoids: Mechanistic and Regiochemical Aspects, Eur. J. Org. Chem., 2021, (1), 7-42
The nucleophilic substitution of aromatic moieties (SNAr) has been known for over 150 years and found wide use for the functionalization of (hetero)aromatic systems. At current, several ′types′ of SNAr reactions have been established and notably the area of porphyrinoid macrocycles has seen many uses thereof. Herein we detail the SNAr reactions of seven types of porphyrinoids...