The
recent crystal structures of CC chemokine receptors 2 and 9
(CCR2 and CCR9) have provided structural evidence for an allosteric,
intracellular binding site. The high conservation of residues involved
in this site suggests its presence in most chemokine receptors, including
the close homologue CCR1. By using [3H]CCR2-RA-[R], a high-affinity, CCR2 intracellular ligand, we report
an intracellular binding site in CCR1, where this radioligand also
binds with high affinity. In addition, we report the synthesis and
biological characterization of a series of pyrrolone derivatives for
CCR1 and CCR2, which allowed us to identify several high-affinity
intracellular ligands, including selective and potential multitarget
antagonists. Evaluation of selected compounds in a functional [35S]GTPγS assay revealed that they act as inverse agonists
in CCR1, providing a new manner of pharmacological modulation. Thus,
this intracellular binding site enables the design of selective and
multitarget inhibitors as a novel therapeutic approach.
Tripentones represent an interesting class of compounds due to their significant cytotoxicity against different human tumor cells in the submicro-nanomolar range. New tripentone analogs, in which a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowed with anticancer activity viz 8H-thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four steps with fair overall yields (34–57%). All tripentone derivatives were tested in the range of 0.1–100 μM for cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 µM and 20.73 µM for HCT-116 and MCF-7 cells, respectively, did not affect the viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of its cytotoxic action. The same compound was further investigated in order to study its mode of action. Results showed that it did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis. Flow cytometric analysis demonstrated that this compound caused cell cycle alteration, inhibiting its progression in S and G2/M phases.
Lignins have shown remarkable antioxidant properties; acting as “scavengers” of free radicals physiologically produced by cell metabolisms; and exerting a protective action caused by the strong ability of these molecules to absorb UV radiation. Through preliminary Molecular Modeling studies and experimental studies in vivo and in vitro, a lignin hydrolysate compound has been shown to be an extremely versatile active ingredient, presenting soothing, anti-inflammatory, anti-itch, anti-oxidant, anti-aging and anti-pollution properties. The possible fields of application are therefore multiple; making this lignin hydrolysate a particularly interesting ingredient for topical dermatological compositions in the treatment of various skin disorders such as inflammation, edema, swelling, rash, redness, itching, chrono- and photo-induced skin aging. These manifestations are also the basis of more or less serious skin problems, making lignin hydrolysate capable of being used in cosmetic products for the eternal challenge of fighting skin aging, but also in medical devices that can be used to fight more painful and annoying symptoms, like those caused by dermatitis or psoriasis.
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