Photochromic antifolate for light-activated chemotherapy

Abstract

Although cytotoxic chemotherapy is one of the primary pharmacological treatments for chronic hyperproliferative diseases such as cancer and psoriasis, its efficacy and tolerability are in many cases dramatically limited by off-target toxicity. A promising approach to improve these therapies is to activate the drugs exclusively at their desired place of action. In fact, in those diseases that would benefit from a highly localized treatment, a precise spatiotemporal control over the activity of a chemotherapeutic agent would allow reducing the concentration of active compound outside the targeted region, improving the tolerability of the treatment. Light is a powerful tool in this respect: it offers unparalleled opportunities as a non-invasive regulatory signal for pharmacological applications because it can be delivered with high precision regarding space, time, intensity and wavelength. Photopharmacology represents a new and emerging approach in this regard since the energy of light is used to change the structure of the drug and hence to switch its pharmacological activity on and off on demand. We describe here phototrexate, the first light-regulated inhibitor of the human DHFR. Enzyme and cell viability assays demonstrated that phototrexate behaves as a potent antifolate in its cis configuration, obtained under UVA illumination, and that it is nearly inactive in its dark-relaxed trans form. Experiments in zebrafish confirmed that phototrexate can disrupt folate metabolism in a light-dependent fashion also in vivo. Overall, phototrexate represents a potential candidate towards the development of an innovative photoactivated antifolate chemotherapy.

Rational Design of Photochromic Analogues of Tricyclic Drugs

“…N-Chloroacetyl-2-nitroaniline was reduced to the corresponding amine (5) by treatment with iron in ammonium chloride and acetic acid. Oxidation with Oxone ® gave the nitroso derivative (6), which was then coupled to the chosen arylamine under Mills conditions to yield the arylazo intermediates (7a, 7b, 7c). Nucleophilic substitution of the chlorine with 1-methylpiperazine and subsequent treatment with hydrochloric acid afforded the three final compounds as dihydrochloride salts (1, 2, 3).…”

“…3,4 The latter is the most straightforward design strategy and is generally preferred because it requires minimal modifications of the original structure, thus maintaining the drug-likeness of the parent compound and largely preserving its pharmacokinetic and pharmacodynamic properties. 5,6 If azologization motifs are not present, in some cases the drug structure can be extended with a photoswitchable moiety while retaining the drug activity. 3,7 However, these versatile and complementary strategies are not applicable to all drugs.…”

Effects of enzyme-ligand interactions on the photoisomerization of a light-regulated chemotherapeutic drug

“…Thus, the PTX can reversibly inhibit the DHFR enzyme with high spatial-temporal precision under the control of light (Figure 1), 13 which can mitigate its side effect compared to the MTX. Despite the molecular photoswitches' successful applications in photopharmacology, their design often involves expensive trial-and-error experiments.…”

“…Despite the molecular photoswitches' successful applications in photopharmacology, their design often involves expensive trial-and-error experiments. 13 Therefore, the rational design of more effective photoswitchable drugs is necessary. However, several fundamental questions remain unanswered regarding the interactions among the protein, the photoswitchable ligand and the light.…”

Stability Indicating Method Development and Validation of Mitomycin and Fluorouracil by Using Uplc

“…Use of either form in pregnancy may harm the baby. Fluorouracil is in the antimetabolite [35] and pyrimidine analog families of medications. How it works is not entirely clear but believed to involve blocking the action of thymidylate synthase [36] and thus stopping the production of DNA.…”