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Special Issue "Advances in Photopharmacology"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 15 December 2022 | Viewed by 7372

Special Issue Editors

Dr. Xavier Rovira Algans
E-Mail
Guest Editor
CSIC - Instituto de Quimica Avanzada de Cataluna (IQAC), Barcelona, Spain
Interests: G protein-coupled receptors; GPCR photopharmacology; cell signaling; spatiotemporal regulation; biased signaling; allosterism; mechanisms of activation; molecular modeling; mathematical modeling; molecular determinants of disease
Dr. Amadeu Llebaría
E-Mail Website
Guest Editor
CSIC - Instituto de Quimica Avanzada de Cataluna (IQAC), Barcelona, Spain
Interests: medicinal chemistry; chemical biology; molecular mechanisms in biology; allosteric modulation; photobiology; molecular probes; optical control of proteins; azobenzene synthesis; protein chemical labeling; enzyme inhibitors; GPCR ligands; drug photocontrol
Dr. Xavier Gomez-Santacana
E-Mail
Guest Editor
CSIC - Instituto de Quimica Avanzada de Cataluna (IQAC), Barcelona, Spain
Interests: G protein-coupled receptors; GPCR photopharmacology; photochromism; azo compounds; protein labeling; endogenous receptors; fluorescence; Föster resonance energy transfer

Special Issue Information

Dear Colleagues,

Photopharmacology is an emerging interdisciplinary field at the interface between physics, chemistry, biology, and medicine. The general goal of photopharmacology is to provide control over biological systems with a high degree of temporal and spatial precision using innovative light-regulated molecules and illumination devices. Indeed, drug action is currently recognized as a multidimensional process governed by molecular, spatial, and temporal components. Understanding the role of each of these dimensions is crucial to improving our knowledge of the mechanisms of action of drugs and how these mechanisms give rise to physiological effects. Along these lines, photopharmacology is opening new avenues to the regulation of biological systems in a precise manner using drugs. With the advent of new discoveries in this field, promising therapeutic applications for diseases with unmet needs and innovative research tools are being proposed. In this Special Issue, we aim to compile research contributions describing the most recent advances in photopharmacology in order to highlight the impact that it may have on a number of research.

Dr. Xavier Rovira Algans
Dr. Amadeu Llebaría
Dr. Xavier Gomez-Santacana
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • photopharmacology
  • light-regulated molecules
  • photochromism
  • molecular photoswitch
  • caged compounds
  • drug photodelivery
  • light delivery systems
  • targeted drug delivery
  • spatiotemporal precision
  • cell signaling
  • precision medicine

Published Papers (5 papers)

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Research

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Article
A Novel Photoswitchable Azobenzene-Containing Local Anesthetic Ethercaine with Light-Controlled Biological Activity In Vivo
Int. J. Mol. Sci. 2022, 23(10), 5352; https://doi.org/10.3390/ijms23105352 - 11 May 2022
Viewed by 1135
Abstract
Pain is a common symptom that impairs the quality of life for people around the world. Local anesthetics widely used for pain relief have a number of side effects, which makes the development of both new drugs and new ways to control their [...] Read more.
Pain is a common symptom that impairs the quality of life for people around the world. Local anesthetics widely used for pain relief have a number of side effects, which makes the development of both new drugs and new ways to control their activity particularly important. Photopharmacology makes it possible to reduce the side effects of an anesthetic and control its biological activity in the body. The purpose of this work was to create a new light-controlled local anesthetic and study its biological activity in animals. A compound with a simple scheme of synthesis was chosen to shift the UV-Vis absorption band towards the visible range of the spectrum and was synthesized for the first time. Some computer calculations were performed to make sure that the aforementioned changes would not lead to loss of biological activity. The micellar form of the new compound was prepared, and in vivo biological studies were carried out in rabbits. The existence of a local anesthetic effect, which disappeared almost completely on irradiation with light (λ = 395 nm), was shown using the surface anesthesia model. Moreover, the possibility of multiple reversible changes in the biological activity of ethercaine under the action of light was demonstrated. The latter compound manifests no local irritating effect, either. The data obtained indicate the prospects for the development of new compounds based on azobenzene for light-controlled local anesthesia. Full article
(This article belongs to the Special Issue Advances in Photopharmacology)
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Article
Light-Control over Casein Kinase 1δ Activity with Photopharmacology: A Clear Case for Arylazopyrazole-Based Inhibitors
Int. J. Mol. Sci. 2022, 23(10), 5326; https://doi.org/10.3390/ijms23105326 - 10 May 2022
Viewed by 1123
Abstract
Protein kinases are responsible for healthy cellular processes and signalling pathways, and their dysfunction is the basis of many pathologies. There are numerous small molecule inhibitors of protein kinases that systemically regulate dysfunctional signalling processes. However, attaining selectivity in kinase inhibition within the [...] Read more.
Protein kinases are responsible for healthy cellular processes and signalling pathways, and their dysfunction is the basis of many pathologies. There are numerous small molecule inhibitors of protein kinases that systemically regulate dysfunctional signalling processes. However, attaining selectivity in kinase inhibition within the complex human kinome is still a challenge that inspires unconventional approaches. One of those approaches is photopharmacology, which uses light-controlled bioactive molecules to selectively activate drugs only at the intended space and time, thereby avoiding side effects outside of the irradiated area. Still, in the context of kinase inhibition, photopharmacology has thus far been rather unsuccessful in providing light-controlled drugs. Here, we present the discovery and optimisation of a photoswitchable inhibitor of casein kinase 1δ (CK1δ), important for the control of cell differentiation, circadian rhythm, DNA repair, apoptosis, and numerous other signalling processes. Varying the position at which the light-responsive azobenzene moiety has been introduced into a known CK1δ inhibitor, LH846, revealed the preferred regioisomer for efficient photo-modulation of inhibitory activity, but the photoswitchable inhibitor suffered from sub-optimal (photo)chemical properties. Replacement of the bis-phenyl azobenzene group with the arylazopyrazole moiety yielded a superior photoswitch with very high photostationary state distributions, increased solubility and a 10-fold difference in activity between irradiated and thermally adapted samples. The reasons behind those findings are explored with molecular docking and molecular dynamics simulations. Results described here show how the evaluation of privileged molecular architecture, followed by the optimisation of the photoswitchable unit, is a valuable strategy for the challenging design of the photoswitchable kinase inhibitors. Full article
(This article belongs to the Special Issue Advances in Photopharmacology)
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Article
Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate
Int. J. Mol. Sci. 2021, 22(23), 13171; https://doi.org/10.3390/ijms222313171 - 06 Dec 2021
Cited by 1 | Viewed by 1889
Abstract
Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow [...] Read more.
Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications. Full article
(This article belongs to the Special Issue Advances in Photopharmacology)
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Article
Photopharmacological Applications for Cherenkov Radiation Generated by Clinically Used Radionuclides
Int. J. Mol. Sci. 2021, 22(16), 9010; https://doi.org/10.3390/ijms22169010 - 20 Aug 2021
Cited by 1 | Viewed by 1306
Abstract
Translational photopharmacological applications are limited through irradiation by light showing wavelengths within the bio-optical window. To achieve sufficient tissue penetration, using wavelengths >500 nm is mandatory. Nevertheless, the majority of photopharmacological compounds respond to irradiation with more energetic UV light, which shows only [...] Read more.
Translational photopharmacological applications are limited through irradiation by light showing wavelengths within the bio-optical window. To achieve sufficient tissue penetration, using wavelengths >500 nm is mandatory. Nevertheless, the majority of photopharmacological compounds respond to irradiation with more energetic UV light, which shows only a minor depth of tissue penetration in the µm range. Thus, we became interested in UV light containing Cherenkov radiation (CR) induced as a by-product by clinically employed radionuclides labeling specific tissues. Therefore, CR may be applicable in novel photopharmacological approaches. To provide evidence for the hypothesis, we verified the clinically established radionuclides 68Ga and 90Y but not 18F in clinically used activities to be capable of generating CR in aqueous solutions. We then investigated whether the generated CR was able to photoactivate the caged kinase inhibitor cagedAZD5438 as a photoresponsive model system. Herein, 21% uncaging of the model system cagedAZD5438 occurred by incubation with 90Y, along with a non-specific compound decomposition for 68Ga and partly for 90Y. The findings suggest that the combination of a clinically employed radionuclide with an optimized photoresponsive agent could be beneficial for highly focused photopharmacological therapies. Full article
(This article belongs to the Special Issue Advances in Photopharmacology)
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Review

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Review
Photopharmacology of Antimitotic Agents
Int. J. Mol. Sci. 2022, 23(10), 5657; https://doi.org/10.3390/ijms23105657 - 18 May 2022
Cited by 2 | Viewed by 770
Abstract
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell [...] Read more.
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents. Full article
(This article belongs to the Special Issue Advances in Photopharmacology)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Photopharmacological Applications for Cherenkov Radiation Generated by Clinically Used Radionuclides
Authors: Melanie Krebs; Alexander Döbber; Theo Rodat; Ulf Lützen; Yi Zhao; Maaz Zuhayra; Christian Peifer
Affiliation: Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany
Abstract: Translational photopharmacological applications are limited through irradiation by light showing wavelengths within the biooptical window. To achieve sufficient tissue penetration, using wavelengths > 500 nm is mandatory. Nevertheless, the majority of photopharmacological compounds are responding to irradiation with more energetic UV light, which shows only minor depth of tissue penetration in µm range. Thus, we became interested in UV-light containing Cherenkov radiation (CR) induced as by-product by clinically employed radionuclides. Here, the generation of CR selectively originates already within a specific tissue labelled by the nuclides, and the short-ranged Cherenkov Effect could potentially overcome the need of an external irradiation. Therefore, this CR may be applicable towards novel photopharmacological approaches. To provide evidence for the hypothesis, we investigated whether the clinically established radionuclides 18F, 68Ga and 90Y or a linear particle accelerator are capable of generating CR in aqueous solution, thus being able to photoactivate a caged kinase inhibitor as a model system. Our primary results show a generation of CR for all tested nuclides to a different extent and a partial activation of the model system with 90Y. This suggests that the combination of a clinically employed radionuclide with a photoresponsive agent could be beneficial towards highly focused photopharmacological therapies.

Title: Light-control over Casein Kinase 1delta activity with photopharmacology: a clear case for arylazopyrazole-based inhibitors
Authors: Albert Schulte; Dušan Kolarski; Vidya Sundaram; Ashutosh Srivastava; Florence Tama; Ben L. Feringa; Wiktor Szymanski
Affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Abstract: Protein kinases are responsible for healthy cellular processes and signalling pathways, and their dysfunction is the basis of many pathologies. There are numerous small molecule inhibitors of protein kinases that systemically regulate dysfunctional signalling processes. However, attaining selectivity in kinase inhibition within the complex human kinome is still a challenge that inspires unconventional approaches. One of those approaches is photopharmacology, which uses light-controlled bioactive molecules to selectively activate drugs only at the intended space and time, thereby avoiding side effects outside of the irradiated area. Still, in the context of kinase inhibition, photopharmacology has thus far been rather unsuccessful in providing light-controlled drugs. Here, we present the discovery and optimisation of a photoswitchable inhibitor of Casein Kinase 1delta (CK1delta), important for the control of cell differentiation, circadian rhythm, DNA repair, apoptosis and numerous other signalling processes. Varying the position at which the light-responsive azobenzene moiety has been introduced into a known CK1delta inhibitor LH846, revealed the preferred regioisomer for efficient photo-modulation of inhibitory activity, but the photoswitchable inhibitor suffered from sub-optimal (photo)chemical properties. Replacement of the bis-phenyl azobenzene group with the arylazopyrazole moiety yielded a superior photoswitch with very high photostationary state distributions, increased solubility and a 10-fold difference in activity between irradiated and thermally adapted samples. The reasons behind those findings are explored with molecular docking and Molecular Dynamics simulations. Results described here show how the evaluation of privileged molecular architecture, followed by the optimisation of the photoswitchable unit, is a valuable strategy for the challenging design of the photoswitchable kinase inhibitors.

Title: Azobenzene/tetraethyl ammonium photochromic potassium channel blockers: scope and limitations for design of para-substituted derivatives with specific absorption band maxima and thermal isomerization rate
Authors: Daniil M. Strashkov; Vladimir N. Mironov; Dmitrii M. Nikolaev; Maxim S. Panov; Stanislav A. Linnik; Andrey S. Mereshchenko; Vladimir A. Kochemirovsky; Andrey V. Vasin; Mikhail N. Ryazantsev
Affiliation: Saint Petersburg State University, 7/9 Universitetskaya nab., 199034 St. Petersburg, Russia
Abstract: Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of cis and trans isomers of ATPLs, the thermal lifetime of their cis form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications.

Title: Photopharmacology of antimitotic agents
Authors: Susanne Kirchner; Zbigniew Pianowski
Affiliation: Karlsruhe Institute of Technology
Abstract: Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and therefore belong to the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intra-cellular transport, inhibit cell proliferation, and promote cell death. Because these drugs target biological processes that are essential to all cells they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing com-pounds that can be applied globally to cells in their inactive form and inducing bioactivity selec-tively in targeted cells or tissue during a defined time window. This review discusses pho-toswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or -destabilizing agents.

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