Palladium(II)-Catalyzed Tandem γ‑C(sp²)–H Arylation and Cyclization for the Construction of Natural Product-Like Polycyclic Fused <i>ortho</i>-Quinone Scaffolds

Here, we report a novel strategy for the direct construction of polycyclic fused ortho-quinone scaffolds through palladium(II)-catalyzed tandem γ-C(sp2)–H arylation and cyclization of arylglyoxals with aryl iodides. This transformation features unique tandem transient directing of γ-C(sp2)–H arylation and cyclization reaction mode, broad substrate scope, especially for the aromatic substrates containing oxygen and sulfur atoms, and avoiding the common issue of aromatization due to the construction of the hexatomic ring

TW-37 intravenous injection inhibits HCT-116 tumor growth <i>in vivo</i>.

<p>Stable HCT-116 cells, expressing lentiviral Beclin-1 shRNA [“shBec-1 (a)”] or scramble non-sense control shRNA (“shC”), were <i>s</i>.<i>c</i>. injected to the flanks of SCID mice. When the tumor volumes were about 100 mm³, mice were treated via intravenous injection of TW-37 (10 mg/kg body weight, daily for 15 days) or saline (“Vehicle”); Tumor volumes (A) and mice body weights (D) were recorded every 7 days for 35 days; Estimated daily tumor growth (in mm³ per day) was also calculated (B); At Day-35, mice were euthanized, tumors were removed and weighted individually (C). * <i>p</i>< 0.05 vs. “shC+Vehicle” group. ^#<i>p</i>< 0.05 vs. “shC+TW-37” group.</p

TW-37 provokes apoptosis in CRC cells.

<p>HCT-116 CRC cells (A-D), the primary human colon cancer cells (two lines, “Colon can-1/2”, E) and the primary human colon epithelial cells (“Colon Epi1”, E) were either left untreated (“C”) or stimulated with TW-37 at applied concentrations (10–1000 nM), cells were further cultured in TW-37-containing-medium for designated time; Cell apoptosis was tested by the listed assays mentioned in the text. Cleaved-Caspase-9 and Cleaved-PARP were quantified and normalized to β-Tubulin (B). Data were presented as mean (n = 5) ± standard deviation (SD). *<i>p</i><0.05 vs. “C”. Experiments in this figure were repeated three times, and similar results were obtained.</p

Beclin-1 shRNA sensitizes TW-37-induced killing of HCT-116 cells.

<p>Stable HCT-116 cells, expressing lentiviral Beclin-1 shRNA [two distinct ones with non-overlapping sequences, “shBec-1 (a)/(b)”], scramble non-sense control shRNA (“shC”), as well as the parental control cells (“Par”), were treated with/out TW-37 (300 nM) for applied time; Expression of listed proteins was shown (A, data were quantified), Cell survival (MTT assay, B) and apoptosis (ssDNA ELISA assay, C) were also tested. Data were presented as mean (n = 5) ± standard deviation (SD). *<i>p</i><0.05 vs. “C”. ^# <i>p</i><0.05 vs. “shC” cells. Experiments in this figure were repeated four times, and similar results were obtained.</p

Feedback autophagy activation counteracts TW-37.

<p>HCT-116 cells (A-D) and the primary human colon cancer cells (“Colon can-1”, E-G) were treated with TW-37 (300 nM), together with/out3-methyladenine (3-MA, 5 mM) or chloroquine (Cq, 100 μM), cells were further cultured for applied time; Expressions of listed proteins were shown (A and E, data were quantified); Cell survival (B and F) and apoptosis (C, D and G) were tested by the mentioned assays. Data were presented as mean (n = 5) ± standard deviation (SD). *<i>p</i><0.05 vs. “C” (untreated cells). ^# <i>p</i><0.05 vs. TW-37 only group. Experiments in this figure were repeated three times, and similar results were obtained.</p

Visible-Light-Induced External Radical-Triggered Annulation To Access CF₂‑Containing Benzoxepine Derivatives

A facile and diversified synthesis of functionalized CF₂-containing benzoxepine derivatives via photoredox catalysis was achieved in this work. This novel protocol features broad substrate scope, mild reaction conditions, operational simplicity, easy scale-up, and versatile derivatization, which would facilitate its practical and broad applications in the construction of valuable and synthetically challenging heterocycles

ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2

<p>Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene <i>BECN1</i> (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.</p

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection