Free-Radical Copolymerization of Dibenzofulvene with (Meth)acrylates Leading to π-Stacked Copolymers

Copolymerizations of dibenzofulvene (DBF) with methyl methacrylate (MMA), 2-hydroxyethyl methacrylate (HEMA), methyl acrylate (MA), and 2-hydroxyethyl acrylate (HEA) were conducted under free radical conditions in toluene using α,α′-azobisisobutylonitrile (AIBN) as the initiator. In the copolymerizations, DBF indicated much higher reactivity than the comonomers, and the products comprised mainly of DBF units. NMR, UV, and fluorescence spectra, as well as electrochemical features indicated that the copolymers possess both isolated and rather short, sequential (meth)acrylate units, as well as π-stacked and unstacked DBF sequences. Isolated (meth)acrylate units are proposed to be sandwiched between DBF units. The ratios of π-stacked and unstacked side-chain fluorene groups of DBF units in excited states were accurately determined on the basis of fluorescent emission spectra; DBF units are mostly π-stacked in excited states as disclosed by fluorescence spectra. Two types of π-stacked sequences were suggested to be present in the ground state by electrochemical analysis. The copolymers exhibited higher solubility than pure poly(DBF)

Free-Radical Copolymerization of Dibenzofulvene with (Meth)acrylates Leading to π-Stacked Copolymers

Copolymerizations of dibenzofulvene (DBF) with methyl methacrylate (MMA), 2-hydroxyethyl methacrylate (HEMA), methyl acrylate (MA), and 2-hydroxyethyl acrylate (HEA) were conducted under free radical conditions in toluene using α,α′-azobisisobutylonitrile (AIBN) as the initiator. In the copolymerizations, DBF indicated much higher reactivity than the comonomers, and the products comprised mainly of DBF units. NMR, UV, and fluorescence spectra, as well as electrochemical features indicated that the copolymers possess both isolated and rather short, sequential (meth)acrylate units, as well as π-stacked and unstacked DBF sequences. Isolated (meth)acrylate units are proposed to be sandwiched between DBF units. The ratios of π-stacked and unstacked side-chain fluorene groups of DBF units in excited states were accurately determined on the basis of fluorescent emission spectra; DBF units are mostly π-stacked in excited states as disclosed by fluorescence spectra. Two types of π-stacked sequences were suggested to be present in the ground state by electrochemical analysis. The copolymers exhibited higher solubility than pure poly(DBF)

miR-424(322)-5p targets Ezh1 to inhibit the proliferation and differentiation of myoblasts

The proliferation and differentiation of myoblasts are considered the key biological processes in muscle development and muscle-related diseases, in which the miRNAs involved remain incompletely understood. Previous research reported that miR-424(322)-5p is highly expressed in mouse skeletal muscle. Therefore, C2C12 cells are used as a model to clarify the effect of miR-424(322)-5p on the proliferation and differentiation of myoblasts. The data show that miR-424(322)-5p exhibits a decreasing trend upon myogenic differentiation. Overexpression of miR-424(322)-5p inhibits the proliferation of myoblasts, manifested by downregulation of proliferation marker genes ( CCNB1, CCND2, and CDK4), decreased percentage of EdU + cells, and reduced cell viability. In contrast, these phenotypes are promoted in myoblasts treated with an inhibitor of miR-424(322)-5p. Interestingly, its gain of function inhibits the expression of myogenic regulators, including MyoD, MyoG, MyHC, and Myf5. Additionally, immunofluorescence staining of MyHC and MyoD shows that overexpression of miR-424(322)-5p reduces the number of myotubes and decreases the myotube fusion index. Consistently, inhibition of its function mediated by an inhibitor promotes the expressions of myogenic markers and myotube fusion. Mechanistically, gene prediction and dual-luciferase reporter experiments confirm that enhancer of zeste homolog 1 ( Ezh1) is one of the targets of miR-424(322)-5p. Furthermore, knockdown of Ezh1 inhibits the proliferation and differentiation of myoblasts. Compared with NC and inhibitor treatment, inhibitor+si- EZH1 treatment rescues the phenotypes of proliferation and differentiation mediated by the miR-424(322)-5p inhibitor. Taken together, these data indicate that miR-424(322)-5p targets Ezh1 to negatively regulate the proliferation and differentiation of myoblasts

Design, Synthesis, and Structure–Activity Relationship of Tetrahydropyrido[4,3‑<i>d</i>]pyrimidine Derivatives as Potent Smoothened Antagonists with <i>in Vivo</i> Activity

Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility. Many patients experience adverse events such as muscle spasms and weight loss. In addition, drug resistance often arises among tumor cells during treatment with vismodegib. There is clearly an urgent need to explore novel Smo antagonists with improved potency and efficacy. Through a scaffold hopping strategy, we have identified a series of novel tetrahydropyrido­[4,3-<i>d</i>]­pyrimidine derivatives, which exhibited effective inhibition of Hh signaling. Among them, compound <b>24</b> is three times more potent than vismodegib in the NIH3T3-GRE-Luc reporter gene assay. Compound <b>24</b> has a lower melting point and much greater solubility compared with vismodegib, resulting in linear PK profiles when dosed orally at 10, 30, and 100 mg/kg in rats. Furthermore, compound <b>24</b> showed excellent PK profiles with a 72% oral bioavailability in beagle dogs. Compound <b>24</b> demonstrated overall favorable <i>in vitro</i> safety profiles with respect to CYP isoform and hERG inhibition. Finally, compound <b>24</b> led to significant regression of subcutaneous tumor generated by primary Ptch1-deficient medulloblastoma cells in SCID mouse. In conclusion, tetrahydropyrido­[4,3-<i>d</i>]­pyrimidine derivatives represent a novel set of Smo inhibitors that could potentially be utilized to treat medulloblastoma and other Hh pathway related malignancies