Distinct Mechanisms of Cytotoxicity in Novel Nitrogenous Heterocycles: Future Directions for a New Anti-Cancer Agent

Electron-rich, nitrogenous heteroaromatic compounds interact more with biological/cellular components than their non-nitrogenous counterparts. The strong intermolecular interactions with proteins, enzymes, and receptors confer significant biological and therapeutic properties to the imidazole derivatives, giving rise to a well-known and extensively used range of therapeutic drugs used for infections, inflammation, and cancer, to name a few. The current study investigates the anti-cancer properties of fourteen previously synthesized nitrogenous heterocycles, derivatives of imidazole and oxazolone, on a panel of cancer cell lines and, in addition, predicts the molecular interactions, pharmacokinetic and safety profiles of these compounds. Method: The MTT and CellTiter-Glo^® assays were used to screen the imidazole and oxazolone derivatives on six cancer cell lines: HL60, MDA-MB-321, KAIMRC1, KMIRC2, MCF-10A, and HCT8. Subsequently, in vitro tubulin staining and imaging were performed, and the level of apoptosis was measured using the Promega ApoTox-Glo^® triplex assay. Furthermore, several computational tools were utilized to investigate the pharmacokinetics and safety profile, including PASS Online, SEA Search, the QikProp tool, SwissADME, ProTox-II, and an in silico molecular docking study on tubulin to identify the critical molecular interactions. Results: In vitro analysis identified compounds 8 and 9 to possess the most significant potent cytotoxic activity on the HL60 and MDA-MB-231 cell lines, supported by PASS Online anti-cancer predictions with pa scores of 0.413 and 0.434, respectively. In addition, compound 9 induced caspase 3/7 dependent-apoptosis and interfered with tubulin polymerization in the MDA-MB-231 cell line, consistent with in silico docking results, identifying binding similarity to the native ligand colchicine. All the derivatives, including compounds 8 and 9, had acceptable pharmacokinetics; however, the safety profile was suboptimal for all the tested derivates except compound 4. Conclusion: The imidazole derivative compound 9 is a promising anti-cancer agent that switches on caspase-dependent apoptotic cell death and modulates microtubule function. Therefore, it could be a lead compound for further drug optimization and development.     

火焰发射光谱对K元素激光诱导击穿光谱测量的影响

在煤和生物质燃烧过程中,燃料中的碱金属元素会发生气态释放,并在随烟气降温的过程中凝结,产生热力设备结渣、腐蚀、积灰等问题,影响设备的安全运行。激光诱导击穿光谱(LIBS)技术是测量煤/生物质火焰中碱金属元素分布的有效手段。建立了一套火焰场内K元素的LIBS测量系统,分别测量了不同ICCD门宽时间条件下火焰场内K元素的火焰发射光谱(FES)信号和LIBS信号,并计算、比较了二者的信号强度随测量系统ICCD门宽时间变化的规律。实验结果表明,相同ICCD门宽时间条件下,火焰场内K元素LIBS信号强度显著高于FES信号强度。随着ICCD门宽时间的增加,二者的信号强度均逐步增加,但是二者的增速变化规律并不相同:K元素LIBS信号强度的增加速度呈现出先快后慢的变化规律;K元素FES信号强度则呈现出线性增加的规律。同时,相同ICCD门宽时间条件下,K元素LIBS信号强度与FES信号强度的比值在ICCD门宽时间为0~8μs的范围内迅速升高至约4;之后,随着ICCD门宽时间的增加,该比值缓慢下降并逐步趋近于1。通过分析火焰场内K元素FES对LIBS测量影响的原理,提出了合理选取LIBS测量系统ICCD门宽时间,使得K元素LIBS信号强度与FES信号强度的比值最大化,从而降低K元素FES对LIBS测量影响,优化了提高火焰场内K元素LIBS信号测量准确度的方法。     

Surface wave propagation at the interface between lossy metamaterials medium and nonlinear media with arbitrary nonlinearity

The dispersion relation in a system that consists of a lossy metamaterials (MTMs) film surrounded by a linear substrate and a nonlinear cladding with an arbitrary nonlinearity is derived. The surface plasmonic (SP) wave at the interfaces between metamaterials (MTMs) and the nonlinear cover is recovered by taking certain limits. Lossy MTMs have simultaneously complex-negative permeability μ and complex-negative permittivity ε. Results are presented by plotting the SP frequency as a function of the nonlinearity at chosen damping factors. Both the real and imaginary parts are studied. Results also display the wave frequency as a function of plasma frequency. For comparison, the imaginary part is set to zero and curves are reproduced.     

A new efficient adsorbent in the preconcentration studies of the Cr(III) and Fe(III) ions

In this study, the imine‐graphene hybrid material (HM) was used as an adsorbent for removal of Fe(III) and Cr(III) metal ions from the drinking waters. The adsorbent material (HM) was prepared at three steps. At the first step, the graphite was oxidized by Hummer's method for preparation of graphene oxide (GO), in the second step, the silanization derivative (GO‐APTES) was obtained from the reaction of the 3‐(trimethoxysilyl) propylamine and GO. In the final step, the hybrid material (HM) was synthesized from the reaction of the 3,5‐diiodosalicylaldehyde and GO‐APTES. The chemical structures of three materials GO, GO‐APTES and HB were characterized by using the FT‐IR, XRD, EDX, SEM, TEM and UV‐vis methods. Thermal properties of the materials GO, GO‐APTES and HB were investigated by TGA/DTA methods in the 25–1000°C temperature range. Adsorption and desorption studies of the hybrid material toward Fe(III) and Cr(III) metal ions were investigated using the Batch method. The effect of pH, contact time, temperature, concentration on the adsorption properties of the hybrid material were investigated by ICP‐OES. The Fe(III) and Cr(III) ions have the maximum adsorption at the pH 7. The adsorption capacity decreases with the increase in pH values because above pH 9 the adsorption decreases due to the precipitation of metal hydroxide.     

Bursatella leachii Purple Ink Secretion Concentrate Exerts Cytotoxic Properties against Human Hepatocarcinoma Cell Line (HepG2): In Vitro and In Silico Studies

Liver cancer is a leading cause of cancer death globally. Marine mollusc-derived drugs have gained attention as potential natural-based anti-cancer agents to overcome the side effects caused by conventional chemotherapeutic drugs during cancer therapy. Using liquid chromatography-mass spectrometry, the main biomolecules in the purple ink secretion released by the sea hare, named Bursatella leachii (B. leachii), were identified as hectochlorin, malyngamide X, malyngolide S, bursatellin and lyngbyatoxin A. The cytotoxic effects of B. leachii ink concentrate against human hepatocarcinoma (HepG2) cells were determined to be dose- and time-dependent, and further exploration of the underlying mechanisms causing the programmed cell death (apoptosis) were performed. The expression of cleaved-caspase-8 and cleaved-caspase-3, key cysteine-aspartic proteases involved in the initiation and completion of the apoptosis process, appeared after HepG2 cell exposure to the B. leachii ink concentrate. The gene expression levels of pro-apoptotic BAX, TP53 and Cyclin D1 were increased after treatment with the B. leachii ink concentrate. Applying in silico approaches, the high scores predicted that bioactivities for the five compounds were protease and kinase inhibitors. The ADME and cytochrome profiles for the compounds were also predicted. Altogether, the B. leachii ink concentrate has high pro-apoptotic potentials, suggesting it as a promising safe natural product-based drug for the treatment of liver cancer.     

Aldose reductase inhibitory activity studies of THERACURMIN

THERACURMIN a commercially available nano-dispersion of curcumin used to treat after effects of alcohol has been evaluated for in vitro ARI activity on Aldose reductase isolated from the bovine lens. As envisaged, the product displays better ARI activity with IC₅₀ value of 3 μM. The observed ARI activity of THERACURMIN is of therapeutic significance as the limited bioavailability of curcumin limits its clinical use.     

Vector least-squares solutions for coupled singular matrix equations

The weighted least-squares solutions of coupled singular matrix equations are too difficult to obtain by applying matrices decomposition. In this paper, a family of algorithms are applied to solve these problems based on the Kronecker structures. Subsequently, we construct a computationally efficient solutions of coupled restricted singular matrix equations. Furthermore, the need to compute the weighted Drazin and weighted Moore–Penrose inverses; and the use of Tian's work and Lev-Ari's results are due to appearance in the solutions of these problems. The several special cases of these problems are also considered which includes the well-known coupled Sylvester matrix equations. Finally, we recover the iterative methods to the weighted case in order to obtain the minimum D-norm G-vector least-squares solutions for the coupled Sylvester matrix equations and the results lead to the least-squares solutions and invertible solutions, as a special case.     

Analysis of vitamin E derivatives in serum using coordinated ion spray mass spectrometry

A method for the extraction and analysis of tocopherols from serum using coordinated ion spray (CIS) mass spectrometry was developed and tested. The tocopherols were extracted from serum and analyzed by direct infusion into the mass spectrometer, bypassing the need for a liquid chromatography step. CIS is a method for improving the ionization efficiency of non-polar compounds by adding metal ions to the electrospray solvent. The non-polar analytes appear as metal adducts in the resulting mass spectrum. Silver was used as the metal ion for the CIS, causing analyte masses to be increased by 107 and 109 Da from the two main silver isotopes. Vitamin E succinate was added to the samples before extraction and was used as an internal standard to compensate for any variations in the extraction efficiency or mass spectrometric response. alpha-Tocopherol and an ether-linked analogue known as alpha-TEA were analyzed in concentrations from 1.25-40 microg/mL (1.9-60 pg consumed). The response curve was constructed by comparing the response of the analytes to the internal standard and gave linear results with r2 values greater than 0.98. This new method was shown to be sensitive, reproducible, fast and required very small amounts of analyte.