Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

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 analog 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 darkrelaxed 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.

Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist

“…Unlike optogenetics, photopharmacology rely on the use of exogenous light-regulated small molecules that can photocontrol native targets and that could be tested and approved using standard drug development procedures. [8][9][10][11][12][13][14][15] These molecules can be used in combination with devices that deliver light to specific locations in the body 7,[16][17][18] in order to remotely control drug dosing and duration of action. Since the activity of drugs is structure-dependent, reversible photoresponsive drugs are obtained by the rational introduction of a molecular photoswitch into the structure of a bioactive compound.…”

Light‐Wavelength‐Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor

“…After the completion of the initial version of this manuscript, Gorostiza et al. reported an essentially identical molecular design for optical control of human DHFR activity . Their result, in which the Z isomer also inhibited the activity of human DHFR, is reasonable because the parent compound, MTX, is known as an inhibitor both of eDHFR and of human DHFR .…”

Photochromic antifolate for light-activated chemotherapy

“…Phototrexate was prepared as previously reported via a convergent 4-step synthesis starting from commercially available building blocks. 15,24 An essential requirement for using phototrexate as a photoswitchable antifolate is that it efficiently responds to light, which means that it can be promptly photoisomerized between its two different configurations with a relatively high degree of photoconversion (cis/trans ratio). UV/Vis absorption studies showed that phototrexate can be effectively isomerized from trans to cis with UVA light (375-395 nm) and back-isomerized from cis to trans with visible light (460-500 nm) ( Figure 2A).…”

“…8,9 Different ways to circumvent such limitations have been proposed, however, there have been limited applications in vivo so far. 10,11 Photopharmacology [12][13][14][15][16] represents a new and emerging approach in this regard since the energy of light is used to change the structure of a drug and hence to switch its pharmacological activity on and off on demand. [17][18][19] Light-regulated drug candidates can be obtained by modifying clinically approved drugs by the incorporation of photoresponsive molecular switches, thus enabling the reversible modulation of their biological properties upon illumination at specific wavelengths.…”

“…Herein, we report on the development and characterization of phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase and a promising candidate for an innovative photoactivated chemotherapy ( Figure 1A). 15…”