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G‐quadruplex (G4), present in the c‐Myc promoter, has emerged as an attractive cancer‐specific molecular target for drug development. So, the discovery of small molecules to stabilize c‐Myc‐G4 to inhibit transcription of c‐Myc protein is of great significance. Herein, a combined molecular docking‐based virtual screening strategy, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing L6000 Natural Compound Library. Four natural compounds, including Licoflavone B, Demethyleneberberine, Ginkgetin, and Mulberroside C, were predicted to have preferable binding affinities to c‐Myc G4 and then selected for commercial purchase and experimental evaluation. Compounds Licoflavone B and Ginkgetin can significantly inhibit myeloma cell proliferation, with IC50 values <8 μM against the RPMI‐8226 cell line. Moreover, our data demonstrated that the two compounds could simultaneously downregulate c‐Myc transcription and expression. Collectively, compounds Licoflavone B and Ginkgetin might be regarded as new candidates for the development of the more potent c‐Myc‐G4 stabilizers in the future. [ABSTRACT FROM AUTHOR]

• Identification of benzimidazolyl isoxazole derivatives as new potent c-Myc G4 stabilizers. • Compound 3-(1-(2-(3,5-dimethylphenoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(4-fluorophenyl)isoxazole (EP12) exhibited better RPMI-8226 cell inhibition activity (IC 50 = 6.16 µM). • Compound EP12 induced apoptosis and inhibited the expression of c-Myc mRNA and c-Myc protein at 5 µM.. • Circular dichroism (CD) and molecular dynamics (MD) simulation studies indicated that compound EP12 could firmly stabilize c-Myc G4. The c-Myc oncogene is one of the most frequently deregulated driver genes in human cancer, and its rearrangement is closely associated with the development of multiple myeloma (MM). However, c-Myc is a disordered protein that lacks adequate binding pockets on its surface and has a half-life of only 20 to 30 minutes, so it is challenging to design small-molecule inhibitors. The guanine-rich nuclease hypersensitive element III 1 (NHEIII 1) upstream of the P1 promoter of the c-Myc gene can form intramolecular parallel G-quadruplexes (G4) structures. It has been established that c-Myc G4 controls 85-90% of the transcriptional activation of the c-Myc, which represents one of the most sought-after drug targets in cancer. Therefore, targeting c-Myc G4 to inhibit c-Myc protein would be a potential strategy for the treatment of MM. Herein, a series of benzimidazolyl isoxazole derivatives (EP1-EP19) were designed and synthesized. Among them, compound EP12 exhibited better RPMI-8226 cell inhibition activity (IC 50 = 6.16 µM). Moreover, compound EP12 induced apoptosis and inhibited the expression of c-Myc mRNA and c-Myc protein at 5 µM. Circular dichroism (CD) and molecular dynamics (MD) simulation studies indicated that compound EP12 could firmly stabilize c-Myc G4. Accordingly, compound EP12 displayed potent anti-MM activities in vitro and might be a potential c-Myc G4 small molecular stabilizer to warrant further investigation. [Display omitted] [ABSTRACT FROM AUTHOR]

Myc is a master transcriptional regulator that controls almost all cellular processes, whose function is dependent on dimerization with its obligate partner Max. Stabilization of Max homodimer by small molecules (such as compound NSC13728) has proven an effective way to reduce the availability of Myc-Max dimer. Omomyc, a peptide inhibitor of Myc, is able to form Omomyc homodimer, which can competitively inhibit the binding of Myc-Max to the E-box of DNA. Considering the high amino acid sequence homology between Omomyc and Max, we put forward the hypothesis that Max-Max stabilizers could stabilize the Omomyc homodimer. Hence, through molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation, we discovered that the stability of Omomyc-Omomyc is remarkably higher than that of Max-Max. Moreover, after adding the compound NSC13728 into the well-defined "Site 3," the binding affinity between two Omomyc monomers can be further increased. Compound NSC13728 has stronger binding interaction to Omomyc-Omomyc than to Max-Max. "Site 3" of Omomyc is more hydrophobic than that of Max, which enlightens us that the more potent Omomyc-Omomyc stabilizers may be hydrophobic in structure. [ABSTRACT FROM AUTHOR]

We report a facile method to synthesize a series of WO 3 microfibers with three-dimensional architectures of nanoparticles and/or microplates through an infiltration and calcination process by taking cotton as template. The crystal structures, morphologies and optical properties of the WO 3 microfibers have been investigated systematically leading to the finding that the WO 3 microfibers show mixed phases and delicate micro/nano-structures which can be controlled by calcination temperature and rate. Furthermore, we also find that the WO 3 microfibers calcined at 500 °C under a calcination rate of 1 °C/min exhibit an intense photoluminescence emission around 452 nm. [ABSTRACT FROM AUTHOR]

SIRT1, namely silent information regulator 1, is a kind of NAD + dependent deacetylase, the activators of which have potential therapeutic applications. Previous studies revealed that two resveratrol molecules (RSV1 and RSV2) bound to SIRT1, and were mainly responsible for strengthening the binding of p53-AMC peptide to SIRT1 so as to activating SIRT1. Thus, we constructed four novel RSV1-RSV2 type SIRT1 activators (i.e., RSV_m1, RSV_m2, RSV_m3 and RSV_m4) by linking the structures of RSV1 and RSV2, and further evaluated their binding affinities and dynamics properties using molecular dynamics simulations. Compared with RSV1, 2, compounds RSV_m1 and RSV_m3 not only had higher binding interaction with SIRT1, but promoted the bindings of p53-AMC peptide to SIRT1 obviously. While the other two compounds were proved to be comparable to RSV1, 2. The four RSV1-RSV2 type compounds might give some valuable clues for the rational design of more promising SIRT1 activators in the near future. [ABSTRACT FROM AUTHOR]