IR, 1HNMR, 13CNMR and mass spectral Analytical data from Synthesis and molecular docking studies of some novel Schiff bases incorporating 6-butylquinolinedione moiety as potential topoisomerase 2β inhibitors

A series of novel pyranoquinolinone-based Schiff's bases were designed and synthesized. A molecular docking study was employed to investigate their binding and functional properties as Topoisomerase 2β inhibitors, using the Discovery Studio 2.5 software, where they showed very interesting ability to intercalate the DNA–topoisomerase complex. Compounds <b>2a</b>, <b>2c</b> and <b>2f</b> showed high docking score values (82.36% −29.98 kcal mol⁻¹ for compound <b>2a</b>, 78.18% −26.98 kcal mol⁻¹ for compound <b>2c</b> and 78.65, −28.11 kcal mol⁻¹ for compound <b>2f</b>) and revealed the highest enzyme inhibition activity. The best hit compounds exhibited highly potent topoisomerase 2β inhibitors with submicromolar IC50 at 5 μM compared to the reference doxorubicin

Molecular design, synthesis and biological evaluation of novel 1,2,5-trisubstituted benzimidazole derivatives as cytotoxic agents endowed with ABCB1 inhibitory action to overcome multidrug resistance in cancer cells

Multidrug resistance (MDR) is a leading cause for treatment failure in cancer patients. One of the reasons of MDR is drug efflux by ATP-binding cassette (ABC) transporters in eukaryotic cells especially ABCB1 (P-glycoprotein). In this study, certain novel 1,2,5-trisubstituted benzimidazole derivatives were designed utilising ligand based pharmacophore approach. The designed benzimidazoles were synthesised and evaluated for their cytotoxic activity towards doxorubicin-sensitive cell lines (CCRF/CEM and MCF7), as well as against doxorubicin-resistant cancer cells (CEM/ADR 5000 and Caco-2). In particular, compound VIII showed a substantial cytotoxic effect in all previously mentioned cell lines especially in doxorubicin-resistant CEM/ADR5000 cells (IC50 = 8.13 µM). Furthermore, the most promising derivatives VII, VIII and XI were tested for their ABCB1 inhibitory action in the doxorubicin-resistant CEM/ADR 5000 subline which is known for overexpression of ABCB1 transporters. The results showed that compound VII exhibited the best ABCB1 inhibitory activity at three tested concentrations (22.02 µM (IC50), 50 µM and 100 µM) in comparison to verapamil as a reference ABCB1 inhibitor. Such inhibition resulted in a synergistic effect and a massive decrease in the IC50 of doxorubicin (34.5 µM) when compound VII was used in a non-toxic dose in combination with doxorubicin in doxorubicin-resistant cells CEM/ADR 5000 (IC50(Dox+VII) = 3.81 µM). Molecular modelling studies were also carried out to explain the key interactions of the target benzimidazoles at the ABCB1 binding site. Overall the obtained results from this study suggest that 1,2,5-trisubstituted benzimidazoles possibly are promising candidates for further optimisation and development of potential anticancer agents with ABCB1 inhibitory activity and therefore overcome MDR in cancer cells.</p

Click and Release: SO₂ Prodrugs with Tunable Release Rates

Employing an intramolecular cycloaddition reaction, we have developed a series of SO₂ prodrugs with tunable release rates with half-lives ranging from minutes to days

A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells

Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as d-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled d-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate d-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against 18F-labeled d-fructose-based probe 6-[18F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells