Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

Heat Shock Proteins HSPA1 and HSP90AA1 Are Upregulated in Colorectal Polyps and Can Be Targeted in Cancer Cells by Anti-Inflammatory Oxicams with Arylpiperazine Pharmacophore and Benzoyl Moiety Substitutions at Thiazine Ring

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.

Synthesis and Characterization of Silver Nanoparticles Prepared with Carrasquilla Fruit Extract (Berberis hallii) and Evaluation of Its Photocatalytic Activity

In this study, silver nanoparticles (AgNPs) were obtained using a green-chemistry procedure. For this protocol, the Carrasquilla extract (CE) (Berberis hallii) and a AgNO3 solution were used as the reducing agent and the metal precursor, respectively. The as-prepared AgNPs after characterization were then used to evaluate the degradation of the methylene blue (MB), the safranin (SF), and the mixture of both dyes in the aqueous phase under solar light irradiation. The photocatalytic activity of AgNPs for the degradation of the MB (k = 0.0092 min−1) was higher than the SF (k = 0.00016 min−1) due to the susceptibility of the thiazine ring of the MB to photodegradation contrasted to the phenyl phenazine of the SF. However, SF was mostly removed by adsorption with a maximum uptake of 2907 mg/g. Overall, this eco-friendly and green conversion of silver ions to metallic elements avoids the use of toxic chemicals and could be applied for the degradation/adsorption of dyes used in several industrial processes.

On the Mechanism of the Caro Synthesis of Methylene Blue

The recent interest for new applications of methylene blue as a promising drug for several important ailments prompted us to fill unknown aspects related to this compound. Since there is no mechanism on the Caro synthesis of methylene blue, we provide the electron flow, step by step, from the starting N,N-dimethylphenylenediamine to the dibenzothiazine derivative. It is a free radical generation system due to the oxidizing properties of ferric chloride. We pointed out the alternative reactions that take place with hydrogen sulphide, the reducer from which the thiazine ring is formed.

STUDY OF THE INTERACTION BETWEEN OXICAM DERIVATIVES AND COX1 USING FINGERPRINT DESCRIPTORS AND MOLECULAR DOCKING

Oxicam derivatives play an important role in the treatment of pain and inflammation. The mechanism of action of these compounds consists in the inhibition of cyclooxygenase (COX) and the blockade of isoform 1 of this enzyme (COX-1) is considered to generate adverse effects. The aim of this paper is to establish which of the atoms in the oxicams molecules are responsible for their inhibitory activities, using electronegativity as fingerprint descriptor. Using this descriptor and molecular docking programs, the atoms in the molecule that have a greater contribution to COX-1 inhibition have been identified. In the case of the studied molecules, the oxygen atoms and the nitrogen atoms are highlighted. The oxygen atoms participate in the interaction as electron acceptors through U-MO molecular levels (74.1%) and the nitrogen atoms participate in the interaction both as a nucleophilic center through the molecular state of HOMO (13.7%) and as an electrophilic center through the molecular state of LUMO (13.2%). In the case of three out of four of the studied compounds, the 4-hydroxyl group of the thiazine ring participates in the interaction with COX-1. The results are also supported by the 2D and 3Ddiagrams of the applied docking method.

SPECTRAL EVALUATION AND ANTIMICROBIAL ACTIVITY OF SYNTHESIZED 4H-1,4-BENZOTHIAZINES

Objective: 4H-1,4-Benzothiazines constitute an important class of heterocycles containing 1,4-thiazine ring fused to benzene ring. They are extensively used as tranquilizer, antispasmodic, central nervous system depressant, antiulcer, antibacterial, antifungal, antioxidant, anticancer agents, fungicides, etc. Therefore, these observations prompted us to synthesize substituted 4H-1,4-benzothiazines and investigate their antimicrobial activity against selected bacterial and fungal strains. Methods: In the present research work, 2-Amino-3,5,6-trichlorobenzenethiol condensed with β-diketones/β-ketoesters in the presence of dimethyl sulfoxide followed by oxidative cyclisation leading to the formation of 4H-1,4-benzothiazines. The spectral investigation confirmed the synthesis of these bioactive compounds. All synthesized compounds were screened for their antimicrobial activity (antibacterial and antifungal) using agar well diffusion method. Results: The minimum inhibitory concentration values of synthesized compounds gave excellent results against bacterial as well as fungal strains (Escherichia coli [Gram negative] MTCC 2939, 58–158 μg/mL, Bacillus subtilis [Gram positive] MTCC 441, 41–124 μg/mL, Streptomyces griseus [Gram negative] MTCC 1998, 85–128 μg/mL, Fusarium oxysporum MTCC 1755, 142–151 μg/mL, Aspergillus niger MTCC 281, 59–78 μg/mL, and Rhizopus stolonifer MTCC 2591, 85–118 μg/mL). Conclusion: Synthesized substituted benzothiazines have potential to be used as a new class of antibacterial and antifungal drugs. Further biomedical research is required to make 4H-1,4-benzothiazines related compounds as potential antibacterial and antifungal drugs.

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.

Synthetic Strategies of Benzothiazines: A Mini Review

Benzothiazine is a heterocyclic compound consisting of a benzene ring attached to the 6- membered thiazine ring. The benzothiazines constitute the group of heterocyclic compounds as they have found a variety of industrial uses and show promise as herbicides. Besides this, benzothiazines play an important role in the field of drug discovery as they have the potential to act as drug candidates for the treatment of a large number of diseases including, cancer, vasorelaxant, diabetic, hypertension, mycotic infection and microbial infection. The presence of nitrogen-sulphur axis and similarity in the structure with phenothiazine drugs help the benzothiazines to act as drugs for the treatment of a number of diseases. Herein, we represent different synthetic strategies for the simple and multi-component synthesis of benzothiazine heterocyclic derivatives. The strategies mostly involve the use of 2-aminothiophenol, 1, 3-dicarbonyl compounds or α-haloketones. In almost all the strategies, the potential yields have been obtained.

In Vitro Antiproliferative Evaluation of Synthetic Meroterpenes Inspired by Marine Natural Products

Several marine natural linear prenylquinones/hydroquinones have been identified as anticancer and antimutagenic agents. Structure-activity relationship studies on natural compounds and their synthetic analogs demonstrated that these effects depend on the length of the prenyl side chain and on the type and position of the substituent groups in the quinone moiety. Aiming to broaden the knowledge of the underlying mechanism of the antiproliferative effect of these prenylated compounds, herein we report the synthesis of two quinones 4 and 5 and of their corresponding dioxothiazine fused quinones 6 and 7 inspired to the marine natural product aplidinone A (1), a geranylquinone featuring the 1,1-dioxo-1,4-thiazine ring isolated from the ascidian Aplidium conicum. The potential effects on viability and proliferation in three different human cancer cell lines, breast adenocarcinoma (MCF-7), pancreas adenocarcinoma (Bx-PC3) and bone osteosarcoma (MG-63), were investigated. The methoxylated geranylquinone 5 exerted the highest antiproliferative effect exhibiting a comparable toxicity in all three cell lines analyzed. Interestingly, a deeper investigation has highlighted a cytostatic effect of quinone 5 referable to a G0/G1 cell-cycle arrest in BxPC-3 cells after 24 h treatment.

Crystal structure ofmeso-3,3′-(1,4-phenylene)bis(2-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one)

The crystal structure of the title compound –meso-C26H24N2O2S2with two stereocenters – has half the molecule in the asymmetric unit with the other half generated by a crystallographic center of inversion. The thiazine ring is in a conformation that is between half-chair and envelope [θ = 52.51 (17)°]. The phenyl ring on the 2-carbon atom of the thiazine ring is pseudo-axial. The central phenyl ring of the molecule is close to orthogonal to the phenyl rings on either side with an angle of 76.85 (11)° between those planes. In the crystal, pairwise, weak C—H...O hydrogen bonds between the central phenyl ring and the oxygen atoms of neighboring molecules result in continuous strips propagating along thea-axis direction. Hydrophobic interactions of the C—H...π type are also observed.