Targeting hematological malignancies with isoxazole derivatives.

Compounds with a heterocyclic isoxazole ring are well known for their diverse biologic activities encompassing antimicrobial, antipsychotic, immunosuppressive, antidiabetic and anticancer effects. Recent studies on hematological malignancies have also shown that some of the isoxazole-derived compounds feature encouraging cancer selectivity, low toxicity to normal cells and ability to overcome cancer drug resistance of conventional treatments. These characteristics are particularly promising because patients with hematological malignancies face poor clinical outcomes caused by cancer drug resistance or relapse of the disease. This review summarizes the knowledge on isoxazole-derived compounds toward hematological malignancies and provides clues on their mechanism(s) of action (apoptosis, cell cycle arrest, ROS production) and putative pharmacological targets (c-Myc, BET, ATR, FLT3, HSP90, CARM1, tubulin, PD-1/PD-L1, HDACs) wherever known.

A review of synthetic strategy, SAR, docking, simulation studies, and mechanism of action of isoxazole derivatives as anticancer agents.

Breast cancer (BC) is a global health concern and the leading cause of cancerous death among women across the world, BC has been characterized by fresh lump in the breast or underarm (armpit), thickened or swollen. Worldwide estimated 9.6 million deaths in 2018-2019. Numerous drugs have been approved by FDA for BC treatment but showed numerous adverse effects like bioavailability issues, selectivity issues, and toxicity issues. Therefore, there is an immediate need to develop new molecules that are non-toxic and more efficient for treating cancer. Isoxazole derivatives have gained popularity over the few years due to their effective antitumor potential. These derivatives work against cancer by inhibiting the thymidylate enzyme, inducing apoptosis, inhibiting tubulin polymerization, protein kinase inhibition, and aromatase inhibition. In this study, we have concentrated on the isoxazole derivative with structure-activity relationship study, various synthesis techniques, mechanism of action, docking, and simulation studies pertaining to BC receptors. Hence the development of isoxazole derivatives with improved therapeutic efficacy will inspire further progress in improving human health.Communicated by Ramaswamy H. Sarma.

Effect of immature tick-borne encephalitis virus particles on antiviral activity of 5-aminoisoxazole-3-carboxylic acid adamantylmethyl esters.

Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is common in Europe and Asia and causes a severe disease of the central nervous system. A promising approach in the development of therapy for TBEV infection is the search for small molecule antivirals targeting the flavivirus envelope protein E, particularly its ß-n-octyl-d-glucoside binding pocket (ß-OG pocket). However, experimental studies of candidate antivirals may be complicated by varying amounts and different forms of the protein E in the virus samples. Viral particles with different conformations and arrangements of the protein E are produced during the replication cycle of flaviviruses, including mature, partially mature, and immature forms, as well as subviral particles lacking genomic RNA. The immature forms are known to be abundant in the viral population. We obtained immature virion preparations of TBEV, characterized them by RT-qPCR, and assessed in vivo and in vitro infectivity of the residual mature virions in the immature virus samples. Analysis of the ß-OG pocket structure on the immature virions confirmed the possibility of binding of adamantylmethyl esters of 5-aminoisoxazole-3-carboxylic acid in the pocket. We demonstrated that the antiviral activity of these compounds in plaque reduction assay is significantly reduced in the presence of immature TBEV particles.

Influence of pH, ß-Cyclodextrin, and Metal Ions on the Solubility and Stability of the Medicinally Competent Isoxazole Derivative of Curcumin: A Photophysical Study.

The ß-diketo-modified isoxazole derivative of curcumin (IOC) is well renowned for its anticancer, antioxidant, antimalarial, antiproliferative, and many other biological activities. With the aim of obtaining fundamental knowledge on the photophysics of IOC, the present work was directed toward delineating those at different pH environments and studying the degradation profiles of IOC at five different pH values. Because one of the primary drawbacks of curcumin is its rapid degradation at physiological conditions, the studies showed that the problem could be resolved, as the IOC molecule was extremely stable even in a highly alkaline medium. Further, in order to encounter the problems associated with the low solubility of IOC in aqueous media, ß-CD (ß-cyclodextrin) was used and calculations of the thermodynamic parameters revealed that the process of development of the host-guest inclusion complex was highly spontaneous in nature. The synthesis of the IOC:ß-CD inclusion complex has also been accomplished in the solid state, and the solid formed has been characterized using various physicochemical techniques. Finally, while variations in the pH as well as addition of foreign metal ions in +1 and +2 oxidation states showed minimal effect on the photophysics of the IOC:ß-CD inclusion complex, antiproliferative studies performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed their nontoxic nature on fibroblast L929 normal cell lines and extremely toxic activity on human lung cancer A549 cell lines.

Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives.

3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl] kaempferol is a novel lead compound to discover anti-diabetic and anti-obesity drugs. The present study reported the scaffold hopping of the lead compound to obtain a new isoxazole derivative, C45, which has improved glucose consumption at the nanomolar level (EC50 = 0.8 nM) in insulin resistant (IR) HepG2 cells. Western blotting showed that C45 markedly enhanced the phosphorylation of AMPK (AMP-activated protein kinase) and reduced the levels of the gluconeogenesis key enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose 6-phosphatase) in HepG2 cells. The potential molecular mechanism of C45 may be activation of the AMPK/PEPCK/G6Pase pathways. We concluded that C45 might be a valuable candidate to discover anti-diabetic drugs.

An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC50; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation.

Crystal structure and Hirshfeld surface analysis of ethyl 5-phenyl-isoxazole-3-carboxyl-ate.

The title compound, C12H11NO3, is an inter-mediate used in the synthesis of many drug-like mol-ecules. The mol-ecule is almost planar, with the phenyl ring inclined to the isoxazole ring by 0.5 (1)°. The ester moiety has an extended conformation and is almost in the same plane with respect to the isoxazole ring, as indicated by the O-C-C-N torsion angle of -172.86 (18)°. In the crystal, mol-ecules are linked via pairs of C-H⋯O hydrogen bonds with the same acceptor atom, forming inversion dimers with two R21(7) ring motifs. The mol-ecules stack in layers lying parallel to (10-3). Analysis using Hirshfeld surface generation and two-dimensional fingerprint plots explores the distribution of weak inter-molecular inter-actions in the crystal structure.

The effect of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide on lymphocyte subsets and humoral immune response in SRBC-immunized mice.

5-Amino-3-methyl-4-isoxazolecarboxylic acid hydrazide is a non-cytotoxic synthetic isoxazole derivative with considerable immunomodulatory properties demonstrated in in vitro experiments. The aim of this study was to investigate the influence of this compound, depending on the dosage and schedule of treatment, on lymphocyte subsets in non-immunized mice and humoral immune response in SRBC (sheep red blood cells)-immunized mice. An analysis of lymphocyte subsets was carried out by flow cytometry, using specific monoclonal antibodies stained with fluorescein isothiocyanate (FITC) or phycoerythrin (PE). In the SRBC-immunized mice, the influence of the compound on the humoral response was determined, depending on the time of administration relative to the antigen. The number of plaque forming cells (PFC) was determined by a local hemolysis technique in an agar gel. Total and 2-mercaptoethanol resistant serum agglutination titers were defined by active hemagglutination test carried out on microplates. The investigated hydrazide was able to modulate the percentage and absolute number of T lymphocyte subsets in the thymus, and T and B lymphocytes in the peripheral lymphatic organs. It also enhanced humoral immune response in SRBC-immunized mice by increasing the number of cells producing hemolytic anti-SRBC antibodies (PFC) and by augmenting the level of total and 2-mercaptoethanol resistant hemagglutinin. The present study showed modulatory effects of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide on lymphocyte subsets and humoral immune response in mice. This compound could be potentially useful for the treatment of autoimmune diseases, infections or as an adjuvant for boosting the efficacy of vaccines.