Novel pyrano 1,3 oxazine based ligand inhibits the epigenetic reader hBRD2 in glioblastoma

Glioblastoma (GBM) is the most common primary brain malignancy, rarely amenable to treatment with a high recurrence rate. GBM are prone to develop resistance to the current repertoire of drugs, including the first-line chemotherapeutic agents with frequent recurrence, limiting therapeutic success. Recent clinical data has evidenced the BRD2 and BRD4 of the BET family proteins as the new druggable targets against GBM. In this relevance, we have discovered a compound (pyrano 1,3 oxazine derivative; NSC 328111; NS5) as an inhibitor of hBRD2 by the rational structure-based approach. The crystal structure of the complex, refined to 1.5 Å resolution, revealed that the NS5 ligand significantly binds to the N-terminal bromodomain (BD1) of BRD2 at the acetylated (Kac) histone binding site. The quantitative binding studies, by SPR and MST assay, indicate that NS5 binds to BD1 of BRD2 with a KD value of ∼1.3 µM. The cell-based assay, in the U87MG glioma cells, confirmed that the discovered compound NS5 significantly attenuated proliferation and migration. Furthermore, evaluation at the translational level established significant inhibition of BRD2 upon treatment with NS5. Hence, we propose that the novel lead compound NS5 has an inhibitory effect on BRD2 in glioblastoma.

Carpatizine, a novel bridged oxazine derivative generated by non-enzymatic reactions

Non-enzymatic reactions were used to improve the structurally diverse natural products.

A novel high performance oxazine derivative: design of tetrafunctional monomer, step-wise ring-opening polymerization, improved thermal property and broadened processing window

A novel tetrafunctional oxazine monomer containing benzoxazine and fluorene-oxazine was prepared for the first time using a Mannich condensation reaction of 2,7-dihydroxy-9,9-bis-(4-hydroxyphenyl)fluorene with paraformaldehyde and n-butylamine.

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is described. Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki cross-couplings. The key compound, a p-bromophenyl-substituted 1,2-oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE-allene. The Lewis acid-induced rearrangement of this heterocycle provided the corresponding bicyclic 1,2-oxazine derivative that may be regarded as internally protected amino sugar analogue. After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross-couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers.

δ-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia

In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role ofδ-tocotrienol and a semisyntheticδ-tocotrienol oxazine derivative, compound44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1αlevels, and combined treatment with compound44attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound44blocked this response. Additionalin vivostudies showed that intralesional treatment with compound44in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with theδ-tocotrienol oxazine derivative, compound44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors.