Atropisomers of <i>meso</i> Tetra(<i>N</i>‐Mesyl Pyrrol‐2‐yl) Porphyrins: Synthesis, Isolation and Characterization of All‐Pyrrolic Porphyrins

Zhu, Lianjie; Himmel, Leonard; Merkes, Jean Michél; Kießling, Fabian; Rueping, Magnus; Banala, Srinivas

doi:10.1002/chem.201905637

Cited by 4 publications

(2 citation statements)

References 36 publications

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“…Atropisomers of meso -arylporphyrin derivatives investigated as PDT photosensitizers have been isolated and characterized. − Isomers with similar photophysical properties are expected to give similar ROS quantum yields because neither energy nor electron transfer reactions require close contact with oxygen . Hence, conventional wisdom is that individual photosensitizer isomers should display similar behavior as isomer mixtures.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization

et al. 2022

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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 α 4 atropisomer, where meso -phenyl sulfonamide substituents are on the same side of the tetrapyrrole macrocycle, exhibits the highest cellular uptake and phototoxicity. This is the most amphipathic atropisomer with a conformation that optimizes hydrogen bonding (H-bonding) with polar head groups of membrane phospholipids. Consequently, α 4 binds to the phospholipids on the surface of the membrane, flips into the membrane to adopt the orientation of a surfactant, and eventually diffuses to the interior of the cell (bind-flip mechanism). We observed increased α 4 internalization by cells of the tumor microenvironment in vivo and correlated this to the response of photodynamic therapy when tumor illumination was performed 24 h after α 4 administration. These results show that properly orientated aryl sulfonamide groups can be incorporated into drug design as efficient cell-penetrating motifs in vivo and reveal the unexpected biological consequences of atropisomerism.

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Section: Introductionmentioning

confidence: 99%

Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization

et al. 2022

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“…[52] However, it must also be noted that six membered rings are not a strict requirement for separable atropisomers, with many reports of atropisomeric porphyrins arising from five membered rings at the meso-position. To date, atropisomeric N-mesyl-pyrrol-2-yl porphyrins [53] and N-protected-imidazol-2-yl porphyrins [54,55] have been reported in literature.…”

Section: Atropisomerism In Porphyrinsmentioning

confidence: 99%

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis

Maguire,

Strachan,

Norvaiša

et al. 2024

Chemistry A European J

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Porphyrin atropisomerism, which arises from restricted σ‐bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20‐tetrakis(o‐hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

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Atropisomers of meso Tetra(N‐Mesyl Pyrrol‐2‐yl) Porphyrins: Synthesis, Isolation and Characterization of All‐Pyrrolic Porphyrins

Zhu

Himmel

Merkes

et al. 2020

Chemistry A European J

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Atropisomerism has been observed in a variety of biaryl compounds and meso‐aryl substituted porphyrins. However, in porphyrins, this phenomenon had been shown only with o‐substituted 6‐membered aromatic groups at the meso‐position. We show herein that a 5‐membered heteroaromatic (N‐mesyl‐pyrrol‐2‐yl) group at the meso‐position leads to atropisomerism. In addition, we report a ‘one‐pot’ synthetic route for the synthesis of ‘all‐pyrrolic’ porphyrin (APP) with several N‐protection groups (Boc, Cbz, Ms and Ts). Among these groups, we found that only the Ms group gave four individually separable atropisomers of meso‐tetra(N‐Ms‐pyrrol‐2‐yl) porphyrin. Furthermore, the reductive removal of Cbz‐ was achieved to obtain meso‐tetra(pyrrol‐2‐yl) porphyrin. Thus, our synthetic procedure provides an easy access to a group of APPs and stable atropisomers, which is expected to expand the application of novel APP‐based materials.

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Atropisomers of meso Tetra(N‐Mesyl Pyrrol‐2‐yl) Porphyrins: Synthesis, Isolation and Characterization of All‐Pyrrolic Porphyrins

Cited by 4 publications

References 36 publications

Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization

Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis

Atropisomers of meso Tetra(N‐Mesyl Pyrrol‐2‐yl) Porphyrins: Synthesis, Isolation and Characterization of All‐Pyrrolic Porphyrins

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