Recent publications by the Senge Group
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 (>70ߙ%) 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. ChemRxiv, https://doi.org/10.26434/chemrxiv.136339
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...
Grover, N.; Senge, M. O., Synthetic Advances in the C—H Activation of Rigid Scaffold Molecules, Synthesis, 2020, 52(22), 3295-3325
The remarkable structural and electronic properties of rigid non-conjugated hydrocarbons afford attractive opportunities to design molecular building blocks for both medicinal and material applications. The bridgehead positions provide the possibility to append diverse functional groups at specific angles and in specific orientations. The current review summarizes the synthetic development in CH functionalization of three rigid scaffolds namely: (a) cubane, (b) bicyclo[1.1.1]pentane (BCP), (c) adamantane.
Grover, N.; Emandi, G.; Twamley, B.; Khurana, B.; Sol, V.; Senge, M. O. Synthesis and Structure of meso-Substituted Dibenzihomoporphyrins Eur. J. Org. Chem. 2020, 2020(41) 6489-6496
Bench-stable meso-substituted di(p/m-benzi)homoporphyrins were synthesized through acid-catalyzed condensation of dipyrrole derivatives with aryl aldehydes. The insertion of a 1,1,2,2-tetraphenylethene (TPE) or but-2-ene-2,3-diyldi11 benzene unit in the porphyrin framework results in the formation of dibenzihomoporphyrins, merging the features of hydrocarbons and porphyrins. Single crystal X-ray analyses established the non-planar structure of these molecules, with the phenylene rings out of the mean plane, as defined by the dipyrromethene moiety and the two meso-carbon atoms. Spectroscopic and structural investigations show that the macrocycles exhibit characteristics of both TPE or but-2-ene-2,3-diyldibenzene and dipyrromethene units indicating the nonaromatic characteristics of the compounds synthesized. Additionally, the dibenzihomoporphyrins were found to generate singlet oxygen, potentially allowing their use as photosensitizers.
Flanagan, K. J.; Ryan, A. A.; Twamley, B.; Senge, M. O.; Influence of meso-linker attachment on the formation of core⋯ℼ interactions in urea-functionalized porphyrins. Zeitschrift für Naturforschung 2020, 75b, 755—764.
The ability to cover the face of a porphyrin macrocycle selectively is an attractive feature for concepts such as catalysis and anion binding that is reliant on porphyrin core interactions. Herein, we have synthesized a family of mono-urea functionalized porphyrin complexes with intent to investigate their potential to form core···Π interactions selectively to one face of the porphyrin macrocycle. By altering the distance between the urea moiety and the porphyrin through direct linkage or introducing a linker group we can control the formation of the core interactions.
Melissari, Z., Sample, H. C., Twamley, B., Williams, R. M. and Senge, M. O., Synthesis and spectral properties of gem-dimethyl chlorin photosensitizers, ChemPhotoChem, 2020, 4, 601-611.
Chlorins that bear a gem-dimethyl group, which attributes their resistance to oxidation, are of interest for applications in photomedicine. Herein, we present the synthesis and the photophysical properties of two geminal-dimethyl chlorins (dihydroporphyrins) and their free base counterparts that act as efficient singlet oxygen generators and thus exhibit potential for use in photodynamic therapy (PDT) as anticancer or antimicrobial agents upon further derivatization.
Grover, J.; Trujillo, C.; Saad, M.; Emandi, G.; Stipanišev, N.; Bernhard, S. S. R., Guédin, A.; Mergny, J.-L.; Senge, M. O.; Rozas, I.; Dual-binding conjugates of diaromatic guanidines and porphyrins for recognition of G-quadruplexes. Org. Biomol. Chem. 2020, 18, 5617—5624.
The first conceptualised class of dual-binding guanine quadruplex binders has been designed, synthesised and biophysically studied. These compounds combine diaromatic guanidinium systems and neutral tetra-phenylporphyrins (classical binding moiety for guanine quadruplexes) by means of a semi-rigid linker. An extensive screening of a variety of guanine quadruplex structures and double stranded DNA via UV-vis, FRET and CD experiments revealed the preference of the conjugates towards guanine quadruplexes.
Larowska, D.; O′Brien, J. M.; Senge, M. O.; Burdzinski, G.; Marciniak, B.; Lewandowska-Andralojc, A.; Graphene Oxide Functionalized with Cationic Porphyrins as Materials for the Photodegradation of Rhodamine B. J. Phys. Chem. C 2020, 124, 15769—15780
Two noncovalent nanohybrids between cationic porphyrin (free-base TMPyP and zinc(II) ZnTMPyP) bearing cationic (N-methylpyridyl) groups and graphene oxide (GO) were constructed with the aim of generating a photocatalyst active for rhodamine B (RhB) degradation. The obtained materials were thoroughly characterized by steady-state and time-resolved absorption and emission methods, which indicated that metalation of the porphyrin with Zn(II) increases the affinity of the porphyrin toward the GO surface. Photocurrent experiment together with femtosecond transient absorption spectroscopy clearly showed the existence of electron transfer from the photoexcited porphyrin to GO.
Hajiashrafi, T.; Salehi, S.; Kubicki, M.; Flanagan, K. J.; Senge, M. O.; Synthesis, characterization, and crystal structure analysis of Zn(II) and Cd(II) coordination compounds containing 4-((pyridin-4-ylmethylene)amino)phenol Schiff-base ligand. J. Mol. Struc. 2020, 1221, 128846.
Zn(II) and Cd(II) coordination compounds containing 4-((pyridin-4-ylmethylene)amino)phenol ligands were synthesized and then characterized using spectroscopic techniques and single crystal X-ray crystallography.
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.
Norvaiša, K., Kielmann, M. and Senge, M. O., Porphyrins as Colorimetric and Photometric Biosensors in Modern Bioanalytical Systems, ChemBioChem, 2020, 21, 1793-1807.
Chlorins that bear a gem-dimethyl group, which attributes their resistance to oxidation, are of interest for applications in photomedicine. Herein, we present the synthesis and the photophysical properties of two geminal-dimethyl chlorins (dihydroporphyrins) and their free base counterparts that act as efficient singlet oxygen generators and thus exhibit potential for use in photodynamic therapy (PDT) as anticancer or antimicrobial agents upon further derivatization...
Kielmann, M.; Flanagan, K. J.; Senge, M. O. Targeted Synthesis of Regioisomerically Pure Dodecasubstituted Type I Porphyrins through the Exploitation of Peri-interactions. J. Org. Chem. 2020, 85, 7603—7610
A targeted synthesis of dodecasubstituted type I porphyrins that utilizes the reaction of unsymmetrical 3,4-difunctionalized pyrroles and sterically demanding aldehydes was developed. This way, type I porphyrins could be obtained as the only type isomers, likely due to a minimization of the steric strain arising from peri-interactions. Uniquely, this method does not depend on lengthy precursor syntheses, the separation of isomers, or impractical limitations of the reaction scale. In addition, single crystal X-ray analysis elucidated the structural features of the macrocycles.
Sitte, E. and Senge, M. O., The Red Color of Life Transformed - Synthetic Advances and Emerging Applications of Protoporphyrin IX in Chemical Biology, Eur. J. Org. Chem., 2020, 22, 3171-3191
The use of the heme precursor protoporphyrin IX for biological applications has experienced a steep increase in recent years. Herein, we review possibilities for synthetic modification of this porphyrin scaffold and discuss its emerging key uses in the field of chemical biology.
Callaghan, S.; Flanagan, K. J.; O'Brien, J. E. and Senge, M. O., Short-Chained Anthracene Strapped Porphyrins and their Endoperoxides, Eur. J. Org. Chem., 2020, 2020 18, 2735-2744.
Herein, we report the synthesis of three short-chained anthracene strapped porphyrins and their corresponding endoperoxides, formed by a cycloaddition reaction between in situ generated singlet oxygen and the anthracene moiety. We also synthesized Zn(II)complexes of the strapped porphyrins. X-ray crystallography and UV/Vis analysis confirmed macrocyclic distortion in the strapped systems.
Locke, G.M.; Flanagan, K.J. and Senge, M.O., Towards triptycene functionalization and triptycene-linked porphyrin arrays, Beilstein J. Org. Chem. 2020, 16, 763-777.
Herein, 9,10-diethynyltriptycene is investigated for its use as a rigid isolating unit in the synthesis of multichromophoric arrays. Sonogashira cross-coupling conditions are utilized to attach various porphyrins and boron dipyrromethenes (BODIPYs) to the triptycene scaffold. While there are previous examples of triptycene porphyrin complexes, this work reports the first example of a linearly connected porphyrin dimer, linked through the bridgehead carbons of triptycene.
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.
Abdel-Mohsen, H. T.; Abood, A.; Flanagan, K. J.; Meindl, A.; Senge, M. O. and El Diwani, H. I., Synthesis, crystal structure, and ADME prediction studies of novel imidazopyrimidines as antibacterial and cytotoxic agents, Arch. Pharm. Chem. Life Sci., 2020, 353, 3, 1900271.
In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a-u and 9a-d were efficiently constructed by a domino reaction between 2-imino-6-substituted-2,3-dihydropyrimidin-4(1H)-ones 4a-d or 8a-c and 2-bromoacetophenones 5a-i under mild basic conditions. The synthesized series were screened for their antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive (+) bacteria, as well as against Gram-negative (-) bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi.
Andexer, J. N.; Beifuss, U.; Beuerle, F.; Brasholz, M.; Breinbauer, R.; Ernst, M.; Greb, J.; Gulder, T.; Hüttel, W.; Kath-Schorr, S.; Kordes, M.; Lehmann, M.; Lindel, T.; Luy, B.; Mück-Lichtenfeld, C.; Muhle, C.; Narine, A.; Niemeyer, J.; Paradies, J.; Pfau, R.; Pietruszka, J.; Schaschke, N.; Senge, M. O.; Straub, B. F.; Werner, T.; Werz, D. B.; Winter, C. Organische Chemie. Nachrichten aus der Chemie, 2020, 68, 42—72.\
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Grover, N.; Locke, G. M.; Flanagan, K. J.; Beh, M. H. R.; Thompson, A.; Senge, M. O. Chem. Eur. J. 2020, 26, 2405-2416.
Connecting two porphyrin units in a rigid linear fashion, without any undesired electron delocalization or communication between the chromophores, remains a synthetic challenge. Herein, a broad library of functionally diverse multi-porphyrin arrays that incorporate the non-traditional rigid linker groups cubane and bicyclo[1.1.1]pentane (BCP) is described. A robust, reliable, and versatile synthetic procedure was employed to access porphyrin-cubane/BCP-porphyrin arrays, representing the largest non-polymeric structures available for cubane/BCP derivatives.
Abdel-Mohsen, H. T.; Abdullaziz, M. A.; El Kerdawy, A. M.; Ragab, F. A. F.; Flanagan, K. J.; Mahmoud, A. E. E.; Ali, M. M.; El Diwani, H. I.; Senge, M. O. Targeting Receptor TyrosineKinase VEGFR-2 in Hepatocellular Cancer:Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles. Molecules, 2020, 25, 770
In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 ΜM in comparison to sorafenib (IC50 = 10.99 ΜM).
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.
Gamm, P.; Sheridan, M. V.; Van Wyck, S.J.; Meindl, A.; Senge, M.O. and Geiger, W.E.; Ethynylphenyl-Derivatized Free Base Porphyrins: Anodic Oxidation Processes and Covalent Grafting onto Glassy Carbon Electrodes, Langmuir, 2020, 36, 1, 96-108.
In six of seven cases, direct anodic oxidation of the ethynyl group of an ethynylphenyl-derivatized free-base porphyrin gave modified glassy carbon electrodes in which the porphyrin was strongly surface-bound, most likely in a perpendicular geometry through covalent attachment of the ethynyl group to a surface carbon atom.
Flanagan, K. J., Twamley, B. and Senge, M. O., Investigating the Impact of Conformational Molecular Engineering on the Crystal Packing of Cavity Forming Porphyrins, Inorg. Chem., 2019, 58, 23, 15769-15787.
Herein we report the synthesis of 5,10,15,20-tetraaryl-(X)-substituted-2,3,7,8,12,13,17,18-octaethylporphyrins (OETArXPs) and a structural investigation of their solid-state properties via small molecule X-ray diffraction. A series of halogen (fluorine to iodine), nitrogenous (azido, cyano), alkyl (TMS-acetylene and acetylene), and chained (benzyloxy) porphyrins were chosen as the initial target molecules. Following this, a selection of tetravalent metal complexes [Cu(II), Ni(II), and Pd(II)] based on these porphyrins were synthesized to allow for an investigation of the effects of metal complexes on the structural properties of these highly substituted porphyrins.
