Nickel Complexes Bearing ONS Chelating Ligands: A Promising Contender for In Vitro Cytotoxicity Effects on Human Pancreatic Cancer MIA-PaCa‑2 Cells

The highly chronic human pancreatic cancer cell is one of the major reasons for cancerous death. Nickel complexes are recently gaining interest in anticancer activities on different types of cancer cells. Hence, in this study, we synthesized and characterized a series of ONS donor ligands [2-HO–C6H4–CHN–(C6H4)–SH] (L1), [2-OH-3-OMe–C6H3–CHN–(C6H4)–SH] (L2), [2-OH-3,5-(C(Me)3)2–C6H2–CHN–(C6H4)–SH] (L3), [2-OH–C6H4–CHN–(C6H4)–SMe] (L4), [2-OH-3-OMe–C6H3–CHN–(C6H4)–SMe] (L5), [2-OH-3,5-(C(Me)3)2–C6H2–CHN–(C6H4)–SMe] (L6) and their Ni(II) metal complexes [(MeOH)Ni(L1–L1–4H)] (1), [(MeOH)Ni(L2–L2–4H)] (2), [(MeOH)Ni(L3–L3–4H)] (3), [(L4–H)2Ni] (4), [(L5–H)2Ni] (5), and [(L6–H)2Ni] (6). The single-crystal X-ray diffraction data of complexes 1 and 4 were collected to elucidate the geometry around the metal center. The anticancer activity of complexes 1–6 was investigated on human pancreatic cancer cell line MIA-PaCa-2, which revealed that complexes 4 and 6 were the most significantly effective in decreasing the cell viability of cancer cells at the lowest dose. The structure parameters obtained from single-crystal X-ray diffraction data are found to be in good agreement with the data from density functional theory and Hirshfeld surface analysis for complex 1

Nickel Complexes Bearing ONS Chelating Ligands: A Promising Contender for In Vitro Cytotoxicity Effects on Human Pancreatic Cancer MIA-PaCa‑2 Cells

The highly chronic human pancreatic cancer cell is one of the major reasons for cancerous death. Nickel complexes are recently gaining interest in anticancer activities on different types of cancer cells. Hence, in this study, we synthesized and characterized a series of ONS donor ligands [2-HO–C6H4–CHN–(C6H4)–SH] (L1), [2-OH-3-OMe–C6H3–CHN–(C6H4)–SH] (L2), [2-OH-3,5-(C(Me)3)2–C6H2–CHN–(C6H4)–SH] (L3), [2-OH–C6H4–CHN–(C6H4)–SMe] (L4), [2-OH-3-OMe–C6H3–CHN–(C6H4)–SMe] (L5), [2-OH-3,5-(C(Me)3)2–C6H2–CHN–(C6H4)–SMe] (L6) and their Ni(II) metal complexes [(MeOH)Ni(L1–L1–4H)] (1), [(MeOH)Ni(L2–L2–4H)] (2), [(MeOH)Ni(L3–L3–4H)] (3), [(L4–H)2Ni] (4), [(L5–H)2Ni] (5), and [(L6–H)2Ni] (6). The single-crystal X-ray diffraction data of complexes 1 and 4 were collected to elucidate the geometry around the metal center. The anticancer activity of complexes 1–6 was investigated on human pancreatic cancer cell line MIA-PaCa-2, which revealed that complexes 4 and 6 were the most significantly effective in decreasing the cell viability of cancer cells at the lowest dose. The structure parameters obtained from single-crystal X-ray diffraction data are found to be in good agreement with the data from density functional theory and Hirshfeld surface analysis for complex 1

Design and synthesis of 1,4-benzothiazine derivatives with promising effects against colorectal cancer cells

<p>In this study, we designed and synthesized a series of 1,4-benzothiazine and evaluated them for anticancer activity toward HT-29 human colon cancer cells using SRB assay. Before the synthesis, docking studies were performed using various molecular targets of colon cancer including IL-2, IL-6, COX-2, caspase-3, and caspase-8. The molecular dynamic (MD) simulation was also executed to examine the stability of ligand-receptor complex of more stable dock conformation. Further computational study was carried out in order to predict the pharmacokinetic profile of titled compounds. Among 34 tested compounds, compounds <b>AR13</b> and <b>AR15</b> were found to be active against HT-29 cells (GI₅₀ < 10 μM)_. Moreover, Compounds <b>AR5</b>, <b>AR22</b>, and <b>AR34</b> showed the moderate activity with GI₅₀ < 70 μM. The binding energy was found to be > −5 kcal/mol for <b>AR13</b> and <b>AR15</b> with all the molecular targets and the ligand-protein complex was found stable after its formation. Again, computational analysis revealed that both molecules <b>AR13</b> and <b>AR15</b> had good ADMET profiling. These encouraging outcomes allowed us to conclude that both <b>AR13</b> and <b>AR15</b> may emerge as lead compounds against colon cancer.</p

Development of Poly(acrylate-<i>co</i>-benzyl maleate) Copolymers as Wax Deposition Inhibitors for Crude Oil

Wax precipitation and deposition during crude oil transportation through pipelines pose significant flow assurance challenges. Therefore, the present work focuses on synthesizing a range of poly(C22Ac-co-BM) copolymers (P1, P2, and P3) derived from fatty alcohol acrylate (C22Ac) and benzyl maleate (BM) through free radical polymerization (FRP). These copolymers were designed to serve as efficient wax inhibitor (WI) additives for crude oil. The detailed characterization of these additives was carried out using structure-sensitive techniques, such as 1H–13C nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and gel permeation chromatography. The paraffin inhibition efficiency (% PIE) of these additives was investigated using pour point, coldfinger, and flow loop experiments. The findings revealed a pour point reduction of branched line crude oil (BLCO) doped with P1, P2, and P3 ranging from 17 to 67% and wax inhibition between 40 and 68% at an optimal dosage of 400 ppm. Among the synthesized poly(C22Ac-co-BM) copolymers, P2 displayed the most promising performance, demonstrating a 67% reduction in the pour point and a substantial 69% reduction in BLCO wax deposition

NMR-Based Serum Metabolomics Reveals Reprogramming of Lipid Dysregulation Following Cyclophosphamide-Based Induction Therapy in Lupus Nephritis

Lupus nephritis (LN) is a major cause of morbidity and mortality in lupus. Renal biopsy is the gold standard for classification of nephritis, but because of its impracticality, new approaches for improving patient prognostication and monitoring treatment efficacy are needed. We aimed to evaluate the potential of metabolic profiling in identifying biomarkers to distinguish disease and monitor treatment efficacy in patients with LN. Serum samples from patients with LN (<i>n</i> = 18) were profiled on NMR-based metabolomics platforms at diagnosis and after 6 months of treatment. LN patients had a different metabolomic fingerprint as compared with healthy controls, with increased lipoproteins and lipids and reduced acetate and amino acids. Using multivariate statistical analysis, we found that the metabolic changes observed in naïve LN patients at diagnosis displayed a variation in the opposite direction upon responding to treatment. Increased levels of lipid metabolites including low- and very-low-density lipoproteins (LDL/VLDL) in LN patients significantly decreased after 6 months of treatment, whereas the serum levels of acetate increased. These levels correlated significantly with SLE Disease Activity Index (SLEDAI 2K), renal SLEDAI, and serum C3 and C4 levels. The result presented in this pilot longitudinal study revealed the reprogramming of metabolome in LN patients on immunosuppressive therapy using NMR-based metabolomics, and thus this approach may be used to monitor the response to treatment

OligonucleotidesAssembled Au Nanorod-Assisted Cancer Photothermal Ablation and Combination Chemotherapy with Targeted Dual-Drug Delivery of Doxorubicin and Cisplatin Prodrug

External stimuli responsive dual drugs carrier was synthesized with Au nanorods (NRs) as the platform. On Au NRs, single stranded DNAs were assembled using 5′ thiol end. Following this, complementary DNA (cDNA) strands were hybridized. This hybridized double stranded DNA facilitated doxorubicin (Dox) intercalation into the duplexes. The cDNA designed with the 5′ amine functional group assisted to tether platinum [Pt­(IV)] prodrugs by establishing amide bond with the acid group at the axial ligand. The other axial acid group in Pt­(IV) prodrugs was conjugated with the folic acid (FA) to target folate receptors overexpressed in the cancer cells. This targeting vehicle provided remote-controlled delivery of this high toxic cargo cocktail at the tumor site, ensuring extra specificity that can avoid acute toxicity, where release of Dox and Pt­(IV) was achieved upon NIR 808 nm diode laser irradiation. The dehybridization set the Dox free to bind the cell nucleus and cellular reductants reduced Pt­(IV) to yield toxic Pt­(II), becoming an active drug. The in vitro and in vivo studies revealed that this external stimulus responsive combination drug delivery was significantly effective

Optimization of Sphingosine-1-phosphate‑1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P₁ receptors, while a variety of side effects have been ascribed to its S1P₃ receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P₁ receptor agonism. Here we describe a study of the tolerance of the S1P₁ and S1P₃ receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in <i>in vitro</i> and <i>in vivo</i> pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P₁ receptor agonists with good selectivity vs S1P₃ receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development

Discovery of Tetrahydropyrazolo­pyridine as Sphingosine 1‑Phosphate Receptor 3 (S1P₃)‑Sparing S1P₁ Agonists Active at Low Oral Doses

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing–remitting multiple sclerosis. It is a potent agonist of the S1P₁ receptor, but its lack of selectivity against the S1P₃ receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P₃-sparing S1P₁ agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolo­pyridines