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To address the issue of mediocre separation efficiency of depressants in the copper-lead separation process, this article synthesized a macromolecular organic depressant, polymaleic anhydride-ethylenediaminetetraacetic acid (PMA–EDTC), using a polycarboxylic macromolecule as the backbone and also introducing –N–(C=S)–S– as the solidophilic group and employed as a galena depressant. The structure of PMA–EDTC was characterized using Fourier transform infrared (FT-IR). The effect of PMA–EDTC on the floatability of galena and chalcopyrite was investigated through micro-flotation and Contact angle measurements. The experimental results demonstrated that PMA–EDTC exhibited selectivity inhibition towards galena rather than chalcopyrite across a wide pH range. At a dose of 8 mg/L, there was effective separation between galena and chalcopyrite with a separation coefficient of 24.17, effectively altering the floatability of galena while having little impact on the floatability of chalcopyrite. The selective inhibition behavior and adsorption mechanism of PMA–EDTC on galena and chalcopyrite were investigated using FT-IR, Zeta potential, and X-ray photoelectron spectroscopy (XPS). FT-IR and Zeta potential studies indicated that PMA–EDTC formed chemical adsorption on the surface of galena. XPS confirmed the model of chemical adsorption of PMA–EDTC on lead atoms in the galena surface. The results indicate that PMA–EDTC adsorbs on the surface of galena via its –(C=S)–S–group, forming a hydrophilic complex and achieving selective depression of lead and the cleaning flotation of copper. [ABSTRACT FROM AUTHOR]

Abstract: Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure–activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines. [Copyright &y& Elsevier]

Abstract: Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure–activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2–p4 pockets of Mcl-1, Bcl-2 and Bcl-xL, and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC50 =10, 20 and 18nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives. [Copyright &y& Elsevier]

Abstract: Our previous work has shown that tanshinone IIA (Tan IIA) is a DNA minor groove binder instead of an intercalator as previously thought. In this study, we have further demonstrated that the molecular antitumor pharmacology of Tan IIA is dependent on its groove-binding capability. First, we investigated the structure damage to duplex DNA upon Tan IIA binding using circular dichroism spectra. Subsequently, we performed western blot, flow cytometry analysis, chromatin immunoprecipitation, and quantitative real-time PCR to illustrate the RNAPII degradation, phosphorylation, and distribution along the transcribed gene in H22 cells exposed to Tan IIA. In addition, p53 activation and apoptosis induction in both cultured H22 cells and in mice bearing the ascitic-type H22 were measured following Tan IIA treatment. It was revealed that Tan IIA decreases the level of RNAPII by altering DNA structure. At the low dose range (0.2–4μM) of Tan IIA exposure, the DNA structure damage results in the inhibition of RNAPII binding to DNA and the initiation of RNAPII phosphorylation, while higher concentrations of Tan IIA (4–20μM) cause complete phosphorylation and degradation of RNAPII followed by p53 activation and apoptosis. A similar apoptosis induction by RNAPII was observed in animals. Apoptosis of tumor cells from ascitic fluid was not detected until RNAPII levels were downregulated by Tan IIA, which requires 40mg/kg body weight of Tan IIA. It was concluded that DNA-conformational-damage-dependent RNAPII response upon groove binding is the molecular basis of the antitumor property of Tan IIA, in vivo and in vitro. [Copyright &y& Elsevier]