Photochromic antifolate for light-activated chemotherapy

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

PHOTOISOMERIZABLE DERIVATIVES OF DIHYDROFOLATE REDUCTASE INHIBITORS

The present invention relates a compound of formula (I) in Z-isomer form (Z-(l)) or a compound of formula (I) in E-isomer form (E-(l)) wherein: R2 is a radical of formula (II) and of formula (III); X1, X2, X3, X4 and X5 are CR3 and N; Y1 is NH, O and S; each R1, each R3 and R7 are H, halogen, -OH, -O-(C1-C8)alkyl, -N((C1-C8)alkyl)3, -NH((C1-C8)alkyl)2, and -NH2(C1-C8)alkyl; R4, R5 and R6 are H and (C1-C8)alkyl; - - - line indicates the position of R2 radical by which R2 is attached to the adjacent N; and the asterisk indicates a stereogenic carbon atom being in R-isomer, S-isomer and a mixture of R-isomer and S-isomer. It also relates to the compound Z-(l) for use as a medicament; and the compound E-(l) for use in the treatment of a disease or condition mediated by the dihydrofolate reductase, wherein the treatment comprises exposing a compound E-(I) to light irradiation to obtain the compound Z-(l)

Phototrexate : a novel drug candidate for cancer and psoriasis

Antifolates are structural analogs of folates, essential one-carbon donors in the synthesis of DNA in mammalian cells, and they work as inhibitors of key enzymes in folate metabolism, such as dihydrofolate reductase and thymidylate synthetase. Methotrexate (MTX) was one of the first agents of this class and is still extensively used in the treatment of a variety of tumors, including acute lymphocytic leukemia, breast cancer, osteosarcoma, primary central nervous system lymphoma, and head and neck cancer. Above all, it is also commonly used in certain autoimmune diseases, such as rheumatoid arthritis or psoriasis. However, the clinical efficacy of MTX is often limited and compromised by toxic dose-related side effects, which leads to morbidity, interruption of the treatment, and occasional mortality. A promising approach to tackle this problem is to activate the drug exclusively at its 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 target tissue, improving the tolerability and hence the efficacy 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. We have recently developed Phototrexate, the first photoswitchable antifolate, by incorporation of a photochromic unit into the structure of MTX. Phototrexate was designed to be constitutively inactive in its thermodynamically stable configuration (E isomer), while it can be activated with light (Z isomer) to locally provide the pharmacological effects of the parent drug, as confirmed in our earlier experiments in vitro and in zebrafish larvae. Studies are currently underway to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and efficacy of our compound in vitro and in preclinical animal models. All current results indicate that Phototrexate is a drug candidate with high potential for development as an innovative light-regulated antifolate for cancer and psoriasis

Pharmacological inactivation of the prion protein by targeting a folding intermediate

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression

Female sexuality and vaginal health across the menopausal age

Objective:The primary aim was to evaluate changes in female sexuality across the menopausal period, and the secondary objective was to test the associations of female sexuality domains with vaginal atrophy and its symptoms.Methods:A cross-sectional multicenter study was performed involving 518 women, 40 to 55 years of age, consulting outpatient gynecological services at 30 centers across Italy. Vaginal atrophy was identified by the contemporaneous presence of a pH >5, subjective vaginal dryness, and an objective sign. The relationships between vaginal atrophy and its main symptoms (vaginal dryness and dyspareunia), and Female Sexual Function Index (FSFI) score and its domains (desire, arousal, orgasm, dyspareunia, lubrication, and sexual satisfaction) were analyzed.Results:The prevalence of sexual dysfunction, as defined by a FSFI score <26.55, was 70.6%, increasing from 55% in the years 40 to 45, to 82.8% (P<0.01) in the years 52 to 55 of age. Mean FSFI score decreased from 40 to 45, to 46 to 48 years of age (23.13±9.76 vs 19.49±9.88; P<0.05), and from 48 to 51, to 52 to 55 years of age (21.3±8.06 to 17.59±9.11; P<0.01). Independent determinants of FSFI were age, vaginal atrophy, and the presence of vaginal dryness and dyspareunia (R2 0.208; P=0.011). FSFI score was independently correlated (R2 0.116) with weight (CR -0.067; 95% confidence interval [CI] -0.126, -0.006; P<0.032), menopausal status (CR -2.406; 95% CI -4.180, -0.63; P<0.008), and vaginal dryness (CR -5.647; 95% CI -7.677, -3.618; P<0.0001). Vaginal dryness was the only variable correlated independently with each FSFI domain, including desire (also correlated with menopausal status), arousal (with age and menopausal status), lubrication (with age), orgasm (with age), satisfaction (with vaginal atrophy and being an ex-smoker), and dyspareunia (with age and spontaneously referred dyspareunia).Conclusions:In the perimenopausal years, FSFI score decreases and sexual dysfunction increases by about 30%. Vaginal dryness is the symptom of vaginal atrophy most closely related to all domains of female sexuality