Design, Synthesis, and Cytotoxicity and Topoisomerase I/IIα Inhibition Activity of Pyrazolo[4,3-f]quinoline Derivatives.

With the several targets of cancer treatment, inhibition of DNA topoisomerase activity is one of the well-known focuses in cancer chemotherapy. Here, we describe the design and synthesis of a novel series of pyrazolo[4,3-f]quinolines with potential anticancer/topoisomerase inhibition activity. Forty newly designed pyrazolo[4,3-f]quinoline derivatives were synthesized via inverse imino Diels-Alder reaction. The antiproliferative activity of the synthesized derivatives was initially measured in the human NUGC-3 cancer cell line. Then, the selected compounds 1B, 1C, 1M, 2A, 2D, 2E, 2F, and 2R with higher activity among tested compounds were screened against six cancer cell lines, including ACHN, HCT-15, MM231, NCI-H23, NUGC-3, and PC-3. The results demonstrated that the compounds 1M, 2E, and 2P were most effective in all cancer cell lines exhibiting GI50 below 8 µM. Among them, 2E showed an equivalent inhibition pattern of topoisomerase IIα activity to that of etoposide, positive control at a 100 µM dose.

The Lower-Risk Cannabis Use Guidelines' (LRCUG) recommendations: How are Canadian cannabis users complying?

Canada, alongside other jurisdictions, implemented non-medical cannabis legalization in 2018, partly towards improving public health. Evidence-based 'Lower-Risk Cannabis Use Guidelines' (LRCUG), including recommendations for cannabis users on how to decrease risk-behaviors for harms, have been developed and widely disseminated in Canada since 2017. However, knowledge on users' compliance with the LRCUG is limited. We identified four major Canadian (three national, one provincial) population surveys presenting key data on cannabis-related behaviors: the National Cannabis Survey, Canadian Cannabis Survey, Canadian Tobacco, Alcohol & Drugs Survey, and CAMH Monitor. We scanned each survey for indicator data mapping onto either of the LRCUG's recommendations for the years 2017 to 2019. Relevant indicator data, albeit with varying operationalizations, were found for six of the ten LRCUG's recommendation clusters in at least some of the surveys, and were extracted and summarized. For results, substantial -- but declining -- majorities of users consumed cannabis by smoking, yet with shifts towards other use modes. Between one- to two-in-five users engaged in the risk-behaviors of using high-potency cannabis products, frequent cannabis use and cannabis-impaired driving, respectively. A small proportion of pregnant or breastfeeding women continued cannabis use during the study period. The data identified found suggested a heterogeneous picture regarding cannabis users' compliance with the LRCUG's recommendations. Non-compliance is highest for recommendations regarding modes-of-use, and applies to minorities of users for other risks factors. These sub-groups are at elevated risk for acute (e.g., accidents) or long-term (e.g., dependence) cannabis-related harms contributing to the public health burden. Appropriate targeted interventions in these areas require improvement.

Synthesis of N-arylindazole-3-carboxamide and N-benzoylindazole derivatives and their evaluation against α-MSH-stimulated melanogenesis.

We have designed and synthesized twenty-six N-arylindazole-3-carboxamide (3a-p) and N-benzoylindazole (6a-j) derivatives to discover with excellent inhibition activities of α-MSH-stimulated melanogenesis. In the bio evaluation studies of these compounds, we discovered eighteen compounds, out of twenty-six exhibited more potent inhibition than the positive control arbutin. From the SAR studies, we identified 3k and 6g as lead compounds which displayed almost 5 and 9 times more potent inhibition of α-MSH-stimulated melanogenesis respectively than the reference arbutin. It is also evident the presence of electron withdrawing group at para position (R3) for the compounds (3a-p) and presence of +M group at ortho position (R5) for the compounds (6a-j) were crucial for their excellent inhibition activities of α-MSH-stimulated melanogenesis.

Microscale droplets covered by amphiphilic gold nanoparticles with various ligand ratios and concentrations.

We describe a simple and reliable route for forming microscale droplets covered with amphiphilic gold nanoparticles (AuNPs) functionalized with mixed hydrophilic and hydrophobic ligands on the AuNP surface. When an aqueous solution of amphiphilic AuNPs was mixed with hexane, the hexane (or water) droplets covered with amphiphilic AuNPs in the water (or hexane) phase were created, in which amphiphilic AuNPs in water phase migrated to the hexane-water interface. The extent of AuNP migration to the interface could be tuned by the ratio of the hydrophobic to hydrophilic ligands on the AuNP surface and the overall concentration of AuNPs. Importantly, the extent of the AuNP migration to the interface depending on the AuNP concentration followed the Langmuir isotherm model well. The equilibrium constant and maximum uptake of AuNPs at the interface were estimated using the Langmuir isotherm model. To the best of our knowledge, this is the first report of the equilibrium constant determination of amphiphilic AuNPs at the liquid-liquid interface. Based on the maximum uptake of AuNPs at the hexane-water interface, we demonstrated that the AuNPs could be closely packed at the interface.

Development of 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and their salts as potent cytotoxic agents and topoisomerase I/IIα inhibitors.

A novel series of 35 angularly fused pentacyclic 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 28, 30, 34, 35, 46, 48, 52, and 53 compounds exhibited potent cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and IIα inhibition. Among them, the compound 48 exhibited dual Topoisomerase I and IIα inhibition especially at 20 µM concentrations the compound 48 exhibited 1.25 times more potent Topoisomerase IIα inhibitory activity (38.3%) than the reference drug etoposide (30.6%). The compound 52 also exhibited excellent (88.4%) topoisomerase I inhibition than the reference drug camptothecin (66.7%) at 100 µM concentrations. Molecular docking studies of the compounds 48 and 52 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 48 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 52 have with Arg364, Thr718, and Asn722 residues. Both the compounds 48 and 52 have π-π stacking interactions with the stacked DNA bases. The docking studies of the compound 48 with topo IIα explored that it was bound to the topo IIα DNA cleavage site where etoposide was situated. The benzo[f]chromeno[4,3-b][1,7]naphthyridine ring of the compound 48 was stacked between the DNA bases of the cleavage site with π-π stacking interactions and there were no hydrogen bond interactions with topo IIα.

Three cases of complications after high-intensity focused ultrasound treatment in unmarried women.

High-intensity focused ultrasound (HIFU) has been regarded as a non-surgical, minimally invasive therapeutic option for patients who prioritize uterus-conservation. Although many studies have shown that HIFU therapy is a safe and effective treatment of uterine fibroid, not all fibroids are suitable for HIFU due to risks of serious complications. We experienced three cases of complications after the HIFU ablation for huge uterine fibroids, including two cases of rapid myoma enlargement and one case of heavy vaginal bleeding.