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5,6-Dihydropyrido[2,3-d]pyrimidin-7(8H)-ones are readily accessed by a variety of methods and are a good scaffold for the development of biologically active compounds. However, they are very reluctant to dehydrogenate to give C5-C6 unsaturated compounds, usually with higher activity. A serendipitous discovery has allowed us to develop an autocatalytic photochemical dehydrogenation process by irradiating at 450 or 365 nm in DMSO, in the presence of air, and at room temperature the corresponding 5,6-dihydro derivative (with a variety of substituents at C2, C4, C5, C6, and N8) without adding any external photosensitizer. A complete study including reactions in DMSO-d6 followed by NMR spectroscopy, EPR experiments, the use of radical quenchers, spin-trapping techniques, and reaction with methyl viologen, complemented with ab initio calculations has allowed us to propose a mechanistic rationalization for such a process.

Dual or multimodal imaging probes have emerged as powerful tools that improve detection sensitivity and accuracy in disease diagnosis by imaging techniques. Two imaging techniques that are complementary and do not use ionizing radiation are magnetic resonance imaging (MRI) and optical fluorescence imaging (OFI). Herein, we prepared metal-free organic species based on dendrimers with magnetic and fluorescent properties as proof-of-concept of bimodal probes for potential MRI and OFI applications. We used oligo(styryl)benzene (OSB) dendrimers core that are fluorescent on their own, and TEMPO organic radicals anchored on their surfaces, as the magnetic component. In this way, we synthesized six radical dendrimers and characterized them by FT-IR, 1H NMR, UV-Vis, MALDI-TOF, SEC, EPR, fluorimetry, and in vitro MRI. Importantly, it was demonstrated that the new dendrimers present two properties: on one hand, they are paramagnetic and show the ability to generate contrast by MRI in vitro, and, on the other hand, they also show fluoresce emission. This is a remarkable result since it is one of the very few cases of macromolecules with bimodal magnetic and fluorescent properties using organic radicals as the magnetic probe.

Quatsome nanovesicles, formed through the self-assembly of cholesterol (CHOL) and cetyltrimethylammonium bromide (CTAB) in water, have shown long-term stability in terms of size and morphology, while at the same time exhibiting high CHOL-CTAB intermolecular binding energies. We hypothesize that CHOL/CTAB quatsomes are indeed thermodynamically stable nanovesicles, and investigate the mechanism underlying their formation.

To develop metal-free magnetic resonance imaging (MRI) contrast agents, organic radical based contrast agents have been proposed as a promising alternative to obtain less toxic and safer MRI contrast agents. However, the low relaxivity and rapid in vivo reduction have limited the application of organic radicals as MRI contrast agents. As a special class of polymer, dendrimers with three-dimensional molecular structure and multiple tunable functional groups on surface, enable the facile chemical modification with organic radicals. With dendrimer as scaffold, a considerable amount of effort has been made to develop completely organic contrast agents. Herein, this mini review reports the recent advances of contrast agents with dendrimers as scaffold functionalized with radicals on the surface.

[EN] A dendrimer including a ring core moiety, a paramagnetic group, a linking moiety and a branching moiety for continuously probing and quantifying an analyte is provided together with methods, kits and devices for performing sensitive, accurate and durable measurements, [FR] L'invention concerne un dendrimère comprenant une fraction de noyau annulaire, un groupe paramagnétique, une fraction de liaison et une fraction de ramification permettant de sonder et de quantifier en continu un analyte, ainsi que des méthodes, des kits et des dispositifs permettant d'effectuer des mesures sensibles, précises et durables

Simultaneously being a nonradiative and noninvasive technique makes magnetic resonance imaging (MRI) one of the highly required imaging approaches for the early diagnosis and follow-up of tumors, specifically for brain cancer. Paramagnetic gadolinium (Gd)-based contrast agents (CAs) are the most widely used ones in brain MRI acquisitions with special interest when assessing blood-brain barrier (BBB) integrity, a characteristic of high-grade tumors. However, alternatives to Gd-based contrast agents (CAs) are highly required to overcome their established toxicity. Organic radicals anchored on a dendrimer macromolecule surface (radical dendrimers) are promising alternatives since they also exhibit paramagnetic properties and can act as T1 CAs like Gd-based CAs while being organic species (mitigating concerns about toxic metal accumulation). Here, we studied the third generation of a water-soluble family of poly(phosphorhydrazone) radical dendrimers, with 48 PROXYL radical units anchored on their branches, exploring their potential of ex vivo and in vivo contrast enhancement in brain tumors (in particular, of immunocompetent, orthotopic GL261 murine glioblastoma (GB)). Remarkably, this radical species provides suitable contrast enhancement on murine GL261 GB tumors, which was comparable to that of commercial Gd-based CAs (at standard dose 0.1 mmol/kg), even at its 4 times lower administered dose (0.025 mmol/kg). Importantly, no signs of toxicity were detected in vivo. In addition, it showed a selective accumulation in brain tumor tissues, exhibiting longer retention within the tumor, which allows performing imaging acquisition over longer time frames (≥2.5 h) as opposed to Gd chelates. Finally, we observed high stability of the radicals in biological media, on the order of hours instead of minutes, characteristic of the isolated radicals. All of these features allow us to suggest that the G3-Tyr-PROXYL-ONa radical dendrimer could be a viable alternative to metal-based M

The fabrication of multifunctional switches is a fundamental step in the development of nanometer-scale molecular spintronic devices. The anchoring of active organic radicals on gold nanoparticles (AuNPs) surface is little studied and the realization of AuNPs-based switches remains extremely challenging. We report the first demonstration of a surface molecular switch based on AuNPs decorated with persistent perchlorotriphenylmethyl (PTM) radicals. The redox properties of PTM are exploited to fabricate electrochemical switches with optical and magnetic responses, showing high stability and reversibility. Electronic interaction between the radicals and the gold surface is investigated by UV-vis, showing a very broad absorption band in the near-infrared (NIR) region, which becomes more intense when PTMs are reduced to anionic phase. By using multiple experimental techniques, we demonstrate that this interaction is likely favored by the preferentially flat orientation of PTM ligands on the metallic NP surface, as confirmed by first-principles simulations.

The search for new biomedical applications of dendrimers has promoted the synthesis of new radical-based molecules. Specifically, obtaining radical dendrimers has opened the door to their use in various fields such as magnetic resonance imaging, as anti-tumor or antioxidant agents, or the possibility of developing new types of devices based on the paramagnetic properties of organic radicals. Herein, we present a mini review of radical dendrimers based on polyphosphorhydrazone, a new type of macromolecule with which, thanks to their versatility, new metal-free contrast agents are being obtained, among other possible applications.

The present invention discloses a third generation polyphosphorhydrazone (PPH) dendrimer peripherally functionalized with PROXYL radical units, by using a tyrosine amino acid (Tyr) as linker. The present invention also relates to the process of obtainment of said dendrimer and the use thereof as a magnetic resonance imaging (MRI) contrast agent.

An organic free radical is a molecule with one or more unpaired electrons. Although most free radicals are highly reactive, chemists have developed a few families of so-called persistent organic radicals with high kinetic stabilities. Polychlorinated trityl radicals, also known as polychlorotriphenylmethyl (PTM) radicals, are particularly chemically stable due to the high steric hindrance provided by the chlorine atoms in ortho positions which protect their single unpaired electron localised on the central carbon atom. In addition to their inherent magnetic spin due to the unpaired electron, PTMs exhibit other appealing properties such as a rich electrochemistry and characteristic optical properties (absorption and emission). Moreover, it has been shown that these properties can be tuned through the preparation of a large library of PTM-based derivatives. Here, we review recent developments employing PTM radicals, which include their implementation in molecular electronic junctions/switches, as building blocks for the preparation of magnetic networks and opto-electronic devices/materials and their exploitation in bio-applications.

The chance to have persistent organic radicals in combination with metals has attracted much interest since it offers the possibility of having new functional molecules with multiple open-shell elements. In this study, we report the synthesis of two tripodal tris(2-pyridyl)methylamine ligands (TPMA) functionalized with nitronyl nitroxide persistent radicals. The newly formed ligands have been used to coordinate zinc(II), copper(II), iron(II) and cobalt(II). The resulting complexes have been investigated by means of electron paramagnetic resonance (EPR), ESI-MS, FT-IR spectroscopy and X-ray diffraction. An electron reduction of the N–O radical moiety has been observed, depending on the metal used for the formation of the complex and the reaction conditions. We have observed small differences in the EPR spectra depending on the meta or para position of the radical moiety in the complex structure and some antiferromagnetic interactions between the paramagnetic M(II) ions and the radical species.

Finding alternatives to gadolinium (Gd)-based contrast agents (CA) with the same or even better paramagnetic properties is crucial to overcome their established toxicity. Herein we describe the synthesis and characterization of entirely organic metal-free paramagnetic macromolecules based on biocompatible oligoethylene glycol dendrimers fully functionalized with 5 and 20 organic radicals (OEG Gn-PROXYL (n = 0, 1) radical dendrimers) with the aim to be used as magnetic resonance imaging (MRI) contrast agents. Conferring high water solubility on such systems is often a concern, especially in large generation dendrimers. Our approach to overcome such an issue in this study is by synthesizing dendrimers with highly water-soluble branches themselves. In this work, we show that the highly water-soluble OEG Gn-PROXYL (n = 0, 1) radical dendrimers obtained showed properties that convert them in good candidates to be studied as contrast agents for MRI applications like diagnosis and follow-up of infectious diseases, among others. Importantly, with the first generation radical dendrimer, a similar r1 relaxivity value (3.4 mM−1s−1) in comparison to gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) used in clinics (3.2 mM−1s−1, r.t. 7T) has been obtained, and it has been shown to not be cytotoxic, avoiding the toxicity risks associated with the unwanted accumulation of Gd in the body.

The COVID-19 pandemic has spread throughout the world at great speed, however, its capacity for expansion and therefore its impact on a country's health system and its economy is not the same in the different areas of the world. In this work, we present a study on the influence of temperature on the speed of virus transmission. The study has been carried out with data collected in a narrow time window, one month, and from a reduced geographical area such as a single country, as Spain, or a cruise such as the Diamond Princess. The objective is to have the data as homogeneous as possible and try to minimize the influence of factors that are not strictly environmental. The result is that there is a clear relationship between the temperature and the speed of virus spread.

The finding of alternative imaging probes to Gadolinium (Gd) and other metal based contrast agents (CA) is crucial to overcome their established toxicity. Herein we describe the synthesis and characterization of an entirely organic metal-free magnetic resonance imaging (MRI) contrast agent based on polyphosphorhydrazone (PPH) dendrimers, fully functionalized with up to 48 organic nitroxide radical units. We propose an innovative synthetic procedure based on the use of an amino acid linker (Tyr) coupled to each dendrimer′s branch that permits the anchoring of the radicals and at the same time makes possible the control over their water solubility. We demonstrate that the negatively charged resulting PPH GnTyr-PROXYL (n = 0−3) radical dendrimers are excellent candidates to be used as MRI contrast agents, suited for biomedical applications as they show high water solubility, no aggregation problems, and low cytotoxicity, as well as good stability in highly reducing environments. It is achieved a remarkable r1 relaxivity, ca. four times higher (13 mM−1 s −1 ) than the gold-standard Gd-DTPA used in clinics. Furthermore, the r1 and r2 relaxivity per unit of radical showed an increase with the increase in generation of dendrimers.

Nowadays there is a great interest in using individual molecules as nanometer-scale switches and logic devices, with the aim of reaching higher power and smaller size. Demonstrating that one molecular switch can be turned on and off at room temperature simply by applying a current to a neighboring molecule has interesting implications. Herein, we report the synthesis, characterization, and behavior of three generations of polyphosphorhydrazone dendrimers, fully functionalized with 6, 12, and 24 redox-active perchlorotriphenylmethyl (PTM) radicals in the periphery, capable of undergoing an electrochemical reversible switching by multielectron reduction and oxidation. An electrical input was used to trigger the physical properties of these radical dendrimers in a reversible way, modifying their optical, magnetic, and electronic properties. Our Gn(PTM• )x radical dendrimers are paramagnetic, exhibit an absorbance band at 386 nm, and have a red fluorescence emission, if in the radical state. When they are switched to their anion state, these dendrimers convert to diamagnetic species with a maximum absorbance band at ca. 520 nm and no fluorescence emission. Due to two different molecular states, the switch undergoes a reversible and important color change, from light brown for G0(PTM• )6 and bright yellow for G1(PTM• )12 and G2(PTM• )24 dendrimers, when in the radical state, to either a deep wine color for G0(PTM−)6 or purple colors for G1(PTM−)12 and G2(PTM−)24 dendrimers, when in the anion state. Furthermore, there exists a viable opportunity to control the exact number of electrons transferred during the switching process, which could lead not only to a two-state but also to a multistate switch in the near future. This is the first molecular switch based on organic radical dendrimers, to our best knowledge. Moreover, these species can act as electron accumulative molecules able to accept and release up to 24 electrons per molecule at very accessible potentials and in