Synthesis, Assessment of Antineoplastic Activity, and Molecular Docking of Novel 2-Thioxo-oxazolidin-4-one Derivatives.

BACKGROUND: Oxazolidinones display several biological effects, including anticancer activity. The purpose of this present work was to investigate a series of novel oxazolidinone derivatives with potential antineoplastic activity. Their mechanisms of death induction and effects in the cell cycle were also evaluated. A molecular docking study was accomplished through proteins of the Cyclin-Dependent Kinases family (CDK). The new compound LPSF/NBM-2 was appeared to promote cell cycle arrest at the G2/M phase and increase the percentage of apoptotic cells. METHODS: Oxazolidinone derivatives were obtained through Knoevenagel condensation. The cytotoxic assay was evaluated through the MTT method. Moreover, flow cytometry was performed in order to investigate the effects of the new compounds on the cell cycle, induction of cell death, and apoptosis. A blind docking was performed through the SwissDock online server and the analysis of the results was performed using the UCSF Chimera and Biovia discovery studio software. RESULTS: LPSF/NBM-1 and LPSF/NBM-2 displayed the most cytotoxic activity against HL-60 (IC50 = 54.83 µM) and MOLT-4 (IC50 = 51.61 µM) cell lines. LPSF/NBM-2 showed an increased percentage of cell population at the G2/M phase. Molecular-docking results of LPSF/NBM-1 and LPSF/NBM-2 suggested a binding affinity with the evaluated CDK proteins. CONCLUSION: LPSF/NBM-1 and LPSF/NBM-2 displayed cytotoxic profiles against Hl-60 and MOLT-4. LPSF/NBM-2 increased cell population percentage at the G2/M phase and promoted cell death compared to non-treated cells in the MOLT-4 cell line. Based on these findings, oxazolidinone derivatives could be highlighted as possible cytostatic agents against lymphoma cells. Molecular docking results suggested the action of LPSF/NBM-1 and LPSF/NBM-2 compounds on enzymes of cyclin-dependent kinases family, however, more studies are needed to establish this correlation.

Stereoselective synthesis of (-)-cytoxazone and its unnatural congener (+)-5-epi-cytoxazone.

An interesting protocol for stereoselective synthesis of (-)-cytoxazone and its unnatural stereoisomer (+)-5-epi-cytoxazone from d-4-hydroxyphenylglycine in overall yields of 10% and 16%, respectively, is described. The stereoselective addition of cyanide to an N-Boc protected aminoaldehyde (tert-butyl ((R)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate) (5) constitutes the key step in this approach, producing a mixture of cyanohydrins 6a and b (1,2-anti and 1,2-syn tert-butyl (2-cyano-2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate) in 89% yield, with reasonable stereoselectivity (1.0:1.8) in favor of the anti-Felkin product (1,2-syn). A one-pot sequence of three successive steps from this mixture produced the oxazolidinone isomers 9a and b ((4R,5R)- and (4R,5S)-4-(4-methoxyphenyl)-2-oxooxazolidine-5-carboxylate). Chromatographic column separation and reduction of the ester function of both precursors led to (-)-cytoxazone and (+)-5-epi-cytoxazone.

Kresoxim-methyl and famoxadone as activators of toxigenic potential of Aspergillus carbonarius.

Ochratoxin A (OTA) is a secondary metabolite produced by filamentous fungi species belonging to the genera Penicillium and Aspergillus. The contamination of grapes by ochratoxigenic species occurs worldwide in regions of tropical and temperate climates. Better control of fungal growth is achieved through good cultural practice and proper selection of fungicides. Kresoxim-methyl and famoxadone are the most common fungicides used in vineyards. This study aimed at analysing the OTA production and toxigenic potential of Aspergillus carbonarius under fungicide treatment with famoxadone and kresoxim-methyl. The growth rate of A. carbonarius was evaluated by measuring the glucosamine content and the diameter of the fungal colonies. OTA production was quantified by HPLC analysis. The treatment with fungicides, kresoxim-methyl and famoxadone, significantly reduced the fungal growth, by 76% and 60%, respectively. However, the mycotoxin production was greater in the fungicide-treated groups than the control group, showing that even though the fungicides were effective in controlling fungal growth, they were ineffective against mycotoxin production.

Synthesis and in vitro anticancer activity of new 2-thioxo-oxazolidin-4-one derivatives.

BACKGROUND: Oxazolidinones derivatives exhibit different biological properties, including anticancer activity. This work aimed to investigate the anticancer potential of five novel 2-Thioxo-oxazolidin-4-one derivatives. METHODS: Cytotoxicity assays were performed in human peripheral blood mononuclear cells (PBMCs) from healthy individuals and seven tumor cell lines. Apoptosis detection and cell cycle were evaluated by flow cytometry and the expression of genes involved in cell death processes by Real-Time PCR. RESULTS: All oxazolinedione derivatives were not cytotoxic in PBMCs. NB-5 showed the best results in cancer cells, inhibiting the growth of all tumor cell lines tested. NB-4 exhibited the highest cytotoxicity in Jurkat cells (IC50=15.19µM) and NB-3 showed better anticancer effects in HL-60 (17.84µM). Only NB-4 significantly induced apoptosis in acute leukemia cells (p=0.001). All compounds caused a significant increase in expression of pro-apoptotic gene BID (p<0.05) and BECN1 (p<0.05). NB-3 significantly modulated the expression of RIPK3 (p=0.02) and DDIT3 (p=0.014), while NB-2 induced an increase of CDKN1A (p=0.03) and NB-4 induced PPARγ gene (p=0.0006). CONCLUSION: NB-5 showed antitumor effects in solid and hematopoietic cancer cells, while other derivatives produced higher activity against hematopoietic cells. In acute leukemia cells, oxazolidinone derivatives modulated the expression of genes involved in apoptosis, ER stress, necroptosis and inflammation.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections.

Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48-72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Crystal structure of 4-methyl-N-{(E)-meth-yl[(3aR,8aS)-2-oxo-3,3a,8,8a-tetra-hydro-2H-indeno-[1,2-d][1,3]oxazol-3-yl]-λ(4)-sulfanyl-idene}benzene-sulfonamide.

The formulation that the title compound, C18H18N2O4S2, adopts is a zwitterionic core with the charge separated to the sulfilimine S and N atoms and is supported by the two different S-N bond distances about the sulfinimine N atom [1.594 (2) and 1.631 (2) Å, respectively] that are typical for such bonds. The notably unusual bond is S-N(oxazolidinone) [1.692 (2) Å] that is longer than a typical S-N bond [1.603 (18) Å, Mogul analysis; Macrae et al. (2008 ▸). J. Appl. Cryst. 41, 466-470]. The bond-angle sum about sulfilimine sulfur (308.35°) reflects the trigonal-pyramidal geometry of this atom. Two of the angles are less than 100°. Despite the pyramidalization of this sulfur, there are no significant inter-molecular inter-actions, beyond usual van der Waals contacts, in the crystal packing.

Crystal structure of (4R,5S)-4-methyl-3-methyl-sulfinyl-5-phenyl-1,3-oxazolidin-2-one.

The absolute structure of the chiral asymmetric indole precursor title compound, C11H13NO3S, was confirmed by refinement of the Flack and Hooft parameters and is that expected based on the starting materials for the synthesis. The phenyl group subtends a dihedral angle of 56.40 (5)° with the mean plane of the oxazolidinone ring, which adopts an envelope conformation, with the C atom bearing the methyl group as the flap. In the crystal, no significant directional inter-actions beyond van der Waals contacts are observed.