12 research outputs found
Molecular dynamics simulations of CO<sub>2</sub> permeation through ionic liquids confined in γ-alumina nanopores
<p>CO<sub>2</sub> permeation through imidazolium-based ionic liquids (ILs, [BMIM][Ac], [EMIM][Ac], [OMIM][Ac], [BMIM][BF<sub>4</sub>], and [BMIM][PF<sub>6</sub>]) 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]<sup>+</sup> tended to be parallel to the wall, providing a straight diffusion path benefiting the CO<sub>2</sub> permeation. The CO<sub>2</sub> 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<sup>−10</sup> m<sup>2</sup> s<sup>−1</sup>, respectively. This order was opposite to that in the bulk ILs, because the longer alkyl chain led to a more ordered structure, facilitating CO<sub>2</sub> diffusion. In addition, the CO<sub>2</sub> solubilities were 445–722 mol m<sup>−3</sup> MPa<sup>−1</sup> 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<sup>−3</sup> MPa<sup>−1</sup>), due to the larger free volume. Both parallel orientation of alkyl chain and large free volume could increase the CO<sub>2</sub> 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