BCAT2

The asymmetric unit of the title compound, catena-poly[[[aqua-bis-(pyridine-κN)cadmium(II)]-μ₂-4,4'-(1H-1,2,4-triazole-3,5-di-yl)dibenzoato-κ⁴ O,O':O'',O'''] 4.5-hydrate], {[Cd(C₁₆H₉N₃O₄)(C₅H₅N)₂(H₂O)]·4.5H₂O}_n or {[Cd(bct)(py)₂(H₂O)]·4.5H₂O}_n (I), consists of a Cd²⁺ cation coordinated to one bct^2- carboxyl-ate dianion, two mol-ecules of pyridine and a water mol-ecule as well as four and a half water mol-ecules of crystallization. The metal ion in I possesses a penta-gonal-bipyramidal environment with the four O atoms of the two bidentately coordinated carboxyl-ate groups and the N atom of a pyridine mol-ecule forming the O₄N equatorial plane, while the N atom of another pyridine ligand and the O atom of the water mol-ecule occupy the axial positions. The bct^2- bridging ligand connects two metal ions via its carb-oxy-lic groups, resulting in the formation of a parallel linear polymeric chain running along the [11] direction. The coordinated water mol-ecule of one chain forms a strong O-H⋯O hydrogen bond with the carboxyl-ate O atom of a neighboring chain, leading to the formation of double chains with a closest distance of 5.425 (7) Å between the cadmium ions belonging to different chains. Aromatic π-π stacking inter-actions between the benzene fragments of the anions as well as between the coordinated pyridine mol-ecules belonging to different chains results in the formation of sheets oriented parallel to the (01) plane. As a result of hydrogen-bonding inter-actions involving the water mol-ecules of crystallization, the sheets are joined together in a three-dimensional network.

Prevention/management of cachexia remains a critical issue in muscle wasting conditions. The branched-chain amino acids (BCAA) have anabolic properties in skeletal muscle, but their use in treating cachexia has minimal benefits. This may be related to altered BCAA metabolism consequent to the use of chemotherapy, a main cancer treatment. Since this topic is minimally studied, we investigated the effect of chemotherapy on BCAA concentrations, transporter expression and their metabolism. L6 myotubes were treated with vehicle (1.4μL/mL DMSO) or a chemotherapy drug cocktail, folfiri (CPT-11 (20μg/mL), leucovorin (10μg/mL), and 5-fluorouracil (50μg/mL)) for 24 - 48h. Chemotherapy reduced myotube diameter (-43%), myofibrillar protein content (-50%) and phosphorylation of the mTORC1 substrate S6K1^thr389 (-80%). Drug-treated myotubes exhibited decreased BCAA concentrations (-50%) and expression of their transporter, LAT1 (-67%). BCAA transaminase BCAT2 level was increased, but there was a reduction in PP2CM (-54%), along with increased inhibitory phosphorylation of BCKD^ser293 (+98%), corresponding with decreased BCKD enzyme activity (-23%) in chemotherapy-treated myotubes. Decreases in BCAA concentrations were a later response, preceded by decreases in LAT1 and BCKD activity. While supplementation with the BCAA restored myotube BCAA levels, it had minimal effects on preventing the loss of myofibrillar proteins. However, RNAi-mediated depletion of NEdd4, the protein ligase responsible for ubiquitin-dependent degradation of LAT1, attenuated the effects of chemotherapy on BCAA concentrations, anabolic signaling, protein synthesis and myofibrillar protein abundance. Thus, if our findings are validated in preclinical models, interventions regulating muscle amino acid transporters might represent a promising strategy to treat cachexia.

Most photosensitizers of interest for photodynamic therapy-especially porphyrinoids and chlorins-are hydrophobic. To circumvent this difficulty, the use of nanocarriers is an attractive strategy. In this perspective, we have developed highly water-soluble and biocompatible fluorescent organic nanoparticles (FONPs) made from citric acid and diethyltriamine which are then activated by ethlynene diamine as nanoplatforms for efficient photosensitizers (PSs). Purpurin 18 (Pp18) was selected as a biosourced chlorin photosensitizer combining the efficient single oxygen generation ability and suitable absorption in the biological spectral window. The simple reaction of activated FONPs with Pp18, which contains a reactive anhydride ring, yielded nanoparticles containing both Pp18 and Cp6 derivatives. These functionalized nanoparticles combine solubility in water, high singlet oxygen generation quantum yield in aqueous media (0.72) and absorption both in the near UV region (FONPS) and in the visible region (Soret band approximately 420 nm as well as Q bands at 500 nm, 560 nm, 660 nm and 710 nm). The functionalized nanoparticles retain the blue fluorescence of FONPs when excited in the near UV region but also show deep-red or NIR fluorescence when excited in the visible absorption bands of the PSs (typically at 520 nm, 660 nm or 710 nm). Moreover, these nanoparticles behave as efficient photosensitizers inducing colorectal cancer cell (HCT116 and HT-29 cell lines) death upon illumination at 650 nm. Half maximal inhibitory concentration (IC50) values down to, respectively, 0.04 and 0.13 nmol/mL were observed showing the potential of FONPs[Cp6] for the PDT treatment of cancer. In conclusion, we have shown that these novel biocompatible nanoparticles, which can be elaborated from biosourced components, both show deep-red emission upon excitation in the red region and are able to produce singlet oxygen with high efficiency in aqueous environments. Moreover, they show high PDT efficiency on colorectal cancer cells upon excitation in the deep red region. As such, these functional organic nanoparticles hold promise both for PDT treatment and theranostics.