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Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2018 Nov 21; Vol. 140 (46), pp. 15764-15773. Date of Electronic Publication: 2018 Oct 22. - Publication Year :
- 2018
-
Abstract
- The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Humans
Methotrexate analogs & derivatives
Methotrexate chemistry
Models, Molecular
Molecular Structure
Photochemical Processes
Structure-Activity Relationship
Zebrafish
Antineoplastic Agents pharmacology
Enzyme Inhibitors pharmacology
Methotrexate pharmacology
Photochemotherapy
Tetrahydrofolate Dehydrogenase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 140
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 30346152
- Full Text :
- https://doi.org/10.1021/jacs.8b08249