Regorafenib and Ruthenium Complex Combination Inhibit Cancer Cell Growth by Targeting PI3K/AKT/ERK Signalling in Colorectal Cancer Cells.

Cancer is one of the leading cause of lethality worldwide, CRC being the third most common cancer reported worldwide, with 1.85 million cases and 850,000 deaths annually. As in all other cancers, kinases are one of the major enzymes that play an essential role in the incidence and progression of CRC. Thus, using multi-kinase inhibitors is one of the therapeutic strategies used to counter advanced-stage CRC. Regorafenib is an FDA-approved drug in the third-line therapy of refractory metastatic colorectal cancer. Acquired resistance to cancers and higher toxicity of these drugs are disadvantages to the patients. To counter this, combination therapy is used as a strategy where a minimal dose of drugs can be used to get a higher efficacy and reduce drug resistance development. Ruthenium-based compounds are observed to be a potential alternative to platinum-based drugs due to their significant safety and effectiveness. Formerly, our lab reported Ru-1, a ruthenium-based compound, for its anticancer activity against multiple cancer cells, such as HepG2, HCT116, and MCF7. This study evaluates Ru-1's activity against regorafenib-resistant HCT116 cells and as a combination therapeutic with regorafenib. Meanwhile, the mechanism of the effect of Ru-1 alone and with regorafenib as a combination is still unknown. In this study, we tested a drug combination (Ru-1 and regorafenib) against a panel of HT29, HCT116, and regorafenib-resistant HCT116 cells. The combination showed a synergistic inhibitory activity. Several mechanisms underlying these numerous synergistic activities, such as anti-proliferative efficacy, indicated that the combination exhibited potent cytotoxicity and enhanced apoptosis induction. Disruption of mitochondrial membrane potential increased intracellular ROS levels and decreased migratory cell properties were observed. The combination exhibited its activity by regulating PI3K/Akt and p38 MAP kinase signalling. This indicates that the combination of REG/Ru-1 targets cancer cells by modulating the PI3K/Akt and ERK signalling.

Pyrazolone incorporating bipyridyl metallointercalators as effective DNA, protein and lung cancer targets: Synthesis, characterization and in vitro biocidal evaluation.

Pyrazolone based metal complexes have strong bio-activity but the anti-cancer mechanism of these derivatives is not fully understood. In recent years, Cu(II) complexes have attracted the interest of researchers increasingly because of their high antitumor activities that are usually related to DNA binding. The reaction of three different derivatives (I) PPMP [3-methyl-1-phenyl-4-propionyl-1H-pyrazol-5(4H)-one], (II) TMCPMP [1-(3-chlorophenyl)-3-methyl-4-(4-methylbenzoyl)-1H-pyrazol-5(4H)-one] and (III) PPTPMP [3-methyl-4-propionyl-1-p-tolyl-1H-pyrazol-5(4H)-one] of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and 2.2' bipyridyl along with Cu(NO3)2·3H2O under methanolic condition allowed us to isolate and characterize a series of new mixed ligand complexes [Cu(TMCPMP) (Bipy)NCS] (1) [Cu(PPMP) (Bipy)NCS] (2) and [Cu(PPTPMP) (Bipy)NCS] (3). All complexes are well characterized by elemental analysis, metal estimation, molar conductivity, FT-IR and UV-Vis spectroscopy. The molecular geometry of these complexes has been determined by single crystal X-ray study. The single-crystal X-ray structures of complexes 1 and 2 exhibit square pyramidal geometry, while complex 3 revealed slightly distorted square-pyramidal geometry. The DNA binding of these compounds with Calf-Thymus DNA (CT-DNA) has been explored by emission titration methods, which revealed that 1-3 could interact with CT-DNA through intercalation mode. The complexes also exhibited a strong binding with Bovine Serum Albumin (BSA) over the ligands. Complexes were evaluated for their in vitro cytotoxic activities against lung cancer cell lines (A549) as well as noncancerous rat cardiomyocytes (H9C2) cell lines, which showed that all three complexes exhibited substantial cytotoxic activity with minimum effect on noncancerous cells. Complex 1 with more hydrophobic environment exhibited relatively high cytotoxic activity towards A549 cells. In summary, this new series of compounds belongs to a class of copper-pyrazolonate complexes that target many biochemical sites and with potential anti-cancer activity. All these results collectively suggested that complexes could serve as promising pharmacologically active substance against lung cancer.

(Z)-3-Methyl-4-[1-(4-methyl-anilino)propyl-idene]-1-phenyl-1H-pyrazol-5(4H)-one.

In the title mol-ecule, C20H21N3O, the central pyrazole ring forms dihedral angles of 4.75 (9) and 49.11 (9)°, respectively, with the phenyl and methyl-substituted benzene rings. The dihedral angle between the phenyl and benzene rings is 51.76 (8)°. The amino group and carbonyl O atom are involved in an intra-molecular N-H⋯O hydrogen bond. In the crystal, π-π inter-actions are observed between benzene rings [centroid-centroid seperation = 3.892 (2) Å] and pyrazole rings [centroid-centroid seperation = 3.626 (2) Å], forming chains along [111]. The H atoms of the methyl group on the p-tolyl substituent were refined as disordered over two sets of sites in a 0.60 (4):0.40 (4) ratio.

(Z)-3-Methyl-1-phenyl-4-[(p-tol-yl)(p-tolyl-amino)-methyl-idene]-1H-pyrazol-5(4H)-one.

In the title mol-ecule, C(25)H(23)N(3)O(2), the pyrazole ring forms dihedral angles of 28.56 (7), 80.35 (7) and 31.99 (7)° with the phenyl ring, the p-tolyl ring and the p-tolyl-amino ring, respectively. The N-H group attached to the exocyclic C=C bond is in a syn arrangement with respect to the C=O bond of the pyrazolone group and an intra-molecular N-H⋯O hydrogen bond is observed. In the crystal, weak C-H⋯π inter-actions link mol-ecules along [100].

Synthesis, spectroscopic characterization and DNA nuclease activity of Cu(II) complexes derived from pyrazolone based NSO-donor Schiff base ligands.

Two neutral mononuclear Cu(II) complexes have been prepared in EtOH using Schiff bases derived from 4-toluoyl pyrazolone and thiosemicarbazide. Both the ligands have been characterized on the basis of elemental analysis, IR, (1)H NMR, (13)C NMR and mass spectral data. The molecular geometry of one of these ligands has been determined by single crystal X-ray study. It reveals that these ligands exist in amine-one tautomeric form in the solid state. Microanalytical data, Cu-estimation, molar conductivity, magnetic measurements, IR, UV-Visible, FAB-Mass, TG-DTA data and ESR spectral studies were used to confirm the structures of the complexes. Electronic absorption and IR spectra of the complexes suggest a square-planar geometry around the central metal ion. The interaction of complexes with pET30a plasmid DNA was investigated by spectroscopic measurements. Results suggest that the copper complexes bind to DNA via an intercalative mode and can quench the fluorescence intensity of EB bound to DNA. The interaction between the complexes and DNA has also been investigated by agarose gel electrophoresis, interestingly, we found that the copper(II) complexes can cleave circular plasmid DNA to nicked and linear forms.