Molecular dynamics simulations of CO₂ permeation through ionic liquids confined in γ-alumina nanopores

<p>CO₂ permeation through imidazolium-based ionic liquids (ILs, [BMIM][Ac], [EMIM][Ac], [OMIM][Ac], [BMIM][BF₄], and [BMIM][PF₆]) confined in 1.0, 2.0, and 3.5 nm γ-alumina pores was investigated using molecular dynamics simulation. It was found that the nanopore confinement effect influenced the structure of confined ILs greatly, resulting in a layered structure and anisotropic orientation of ILs. In the center of 2.0-nm pore, the long alkyl chain of [BMIM]⁺ tended to be parallel to the wall, providing a straight diffusion path benefiting the CO₂ permeation. The CO₂ diffusion coefficients in confined [EMIM][Ac], [BMIM][Ac], and [OMIM][Ac] were 2.3–4.1, 2.4–6.4, and 14.4–21.7 × 10⁻¹⁰ m² s⁻¹, respectively. This order was opposite to that in the bulk ILs, because the longer alkyl chain led to a more ordered structure, facilitating CO₂ diffusion. In addition, the CO₂ solubilities were 445–722 mol m⁻³ MPa⁻¹ for the five ILs confined in 1.0 nm pore, which were larger than those in 2.0 and 3.5 nm pores (196–335 mol·m⁻³ MPa⁻¹), due to the larger free volume. Both parallel orientation of alkyl chain and large free volume could increase the CO₂ permeability in confined ILs.</p

Cooperative Cu/Pd-Catalyzed 1,5-Boroacylation of Cyclopropyl-Substituted Alkylidenecyclopropanes

A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction

Cooperative Cu/Pd-Catalyzed 1,5-Boroacylation of Cyclopropyl-Substituted Alkylidenecyclopropanes

A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction

Discovery of a New Four-Leaf Clover-Like Ligand as a Potent <i>c‑MYC</i> Transcription Inhibitor Specifically Targeting the Promoter G‑Quadruplex

Downregulating transcription of the oncogene <i>c-MYC</i> is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the <i>c-MYC</i> promoter can suppress <i>c-MYC</i> transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the <i>c-MYC</i> G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called <b>IZCZ-3</b> was found to preferentially bind and stabilize the <i>c-MYC</i> G-quadruplex. Further intracellular studies indicated that <b>IZCZ-3</b> provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking <i>c-MYC</i> transcription through specific targeting of the promoter G-quadruplex structure. Notably, <b>IZCZ-3</b> effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent

Discovery of a New Four-Leaf Clover-Like Ligand as a Potent <i>c‑MYC</i> Transcription Inhibitor Specifically Targeting the Promoter G‑Quadruplex

Downregulating transcription of the oncogene <i>c-MYC</i> is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the <i>c-MYC</i> promoter can suppress <i>c-MYC</i> transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the <i>c-MYC</i> G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called <b>IZCZ-3</b> was found to preferentially bind and stabilize the <i>c-MYC</i> G-quadruplex. Further intracellular studies indicated that <b>IZCZ-3</b> provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking <i>c-MYC</i> transcription through specific targeting of the promoter G-quadruplex structure. Notably, <b>IZCZ-3</b> effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent

Discovery of a New Four-Leaf Clover-Like Ligand as a Potent <i>c‑MYC</i> Transcription Inhibitor Specifically Targeting the Promoter G‑Quadruplex

Downregulating transcription of the oncogene <i>c-MYC</i> is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the <i>c-MYC</i> promoter can suppress <i>c-MYC</i> transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the <i>c-MYC</i> G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called <b>IZCZ-3</b> was found to preferentially bind and stabilize the <i>c-MYC</i> G-quadruplex. Further intracellular studies indicated that <b>IZCZ-3</b> provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking <i>c-MYC</i> transcription through specific targeting of the promoter G-quadruplex structure. Notably, <b>IZCZ-3</b> effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent

Discovery of Novel Schizocommunin Derivatives as Telomeric G‑Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response

Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound <b>16</b> showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that <b>16</b> could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands

Three new schinortriterpenoids from the leaves of <i>Schisandra chinensis</i> (Turcz.) Baill

Three undescribed schinortriterpenoids, schinensilactones D-F (1–3), together with five known ones, namely, wuweizidilactone A (4), wuweizidilactone C (5), wuweizidilactone F (6), wuweizidilactone J (7) and wuweizidilactone N (8), were isolated from the leaves of Schisandra chinensis (Turcz.) Baill. The structures of new compounds were established by analysis of their spectroscopic data including MS, IR, 1D- and 2D-NMR spectra. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction and calculated electronic circular dichroism (ECD) spectra. All compounds were evaluated for their neuroprotective effects against H2O2-induced injury in human neuroblastoma SH-SY5Y cell lines. Cell viability was remarkably reduced to 52.33% in H2O2-treated cells. Compounds 5–7 exhibited moderate neuroprotective activities at 50 μM, with cell viability of 64.84%, 67.34% and 63.73%, respectively.</p

Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as <i>c‑MYC</i> Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction

<i>c-MYC</i> is one of the important human proto-oncogenes, and transcriptional factor NM23-H2 can activate <i>c-MYC</i> transcription by recognizing the G-quadruplex in the promoter of the gene. Small molecules that inhibit <i>c-MYC</i> transcription by disrupting the NM23-H2/G-quadruplex interaction might be a promising strategy for developing selective anticancer agents. In recent studies, we developed a series of isaindigotone derivatives, which can bind to G-quadruplex and NM23-H2, thus down-regulating <i>c-MYC</i> (J. Med. Chem. 2017, 60, 1292−1308). Herein, a series of novel isaindigotone derivatives were designed, synthesized, and screened for NM23-H2 selective binding ligands. Among them, compound <b>37</b> showed a high specific binding affinity to NM23-H2, effectively disrupting the interaction of NM23-H2 with G-quadruplex, and it strongly down-regulated <i>c-MYC</i> transcription. Furthermore, <b>37</b> induced cell cycle arrest and apoptosis, and it exhibited good tumor growth inhibition in a mouse xenograft model. This work provides a new strategy to modulate <i>c-MYC</i> transcription for the development of selective anticancer drugs

Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as <i>c‑MYC</i> Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction

<i>c-MYC</i> is one of the important human proto-oncogenes, and transcriptional factor NM23-H2 can activate <i>c-MYC</i> transcription by recognizing the G-quadruplex in the promoter of the gene. Small molecules that inhibit <i>c-MYC</i> transcription by disrupting the NM23-H2/G-quadruplex interaction might be a promising strategy for developing selective anticancer agents. In recent studies, we developed a series of isaindigotone derivatives, which can bind to G-quadruplex and NM23-H2, thus down-regulating <i>c-MYC</i> (J. Med. Chem. 2017, 60, 1292−1308). Herein, a series of novel isaindigotone derivatives were designed, synthesized, and screened for NM23-H2 selective binding ligands. Among them, compound <b>37</b> showed a high specific binding affinity to NM23-H2, effectively disrupting the interaction of NM23-H2 with G-quadruplex, and it strongly down-regulated <i>c-MYC</i> transcription. Furthermore, <b>37</b> induced cell cycle arrest and apoptosis, and it exhibited good tumor growth inhibition in a mouse xenograft model. This work provides a new strategy to modulate <i>c-MYC</i> transcription for the development of selective anticancer drugs