Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

J Am Chem Soc. 2018 Nov 21;140(46):15764-15773. doi: 10.1021/jacs.8b08249. Epub 2018 Oct 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Methotrexate / analogs & derivatives
  • Methotrexate / chemistry
  • Methotrexate / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Photochemical Processes
  • Photochemotherapy*
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / metabolism*
  • Zebrafish

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Tetrahydrofolate Dehydrogenase
  • Methotrexate