Ethyl 1,6-dimethyl-2-oxo-4-(quinolin-4-yl)-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

In the title compound, C18H19N3O3, the tetra­hydro­pyrimidone ring adopts a distorted boat conformation. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the mol­ecules into centrosymmetric dimers, which are further linked via inter­molecular C—H⋯π inter­actions. In addition, an intra­molecular C—H⋯O hydrogen bond occurs

Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPßCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p \u3c 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p \u3c 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p \u3c 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p \u3c 0.05). Our results indicate that HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPßCD-HET0016 significantly prolonged survival in PDX GBM811 model

Multi-kinase inhibitors can associate with heat shock proteins through their NH2-termini by which they suppress chaperone function

We performed proteomic studies using the GRP78 chaperone-inhibitor drug AR-12 (OSU-03012) as bait. Multiple additional chaperone and chaperone-associated proteins were shown to interact with AR-12, including: GRP75, HSP75, BAG2; HSP27; ULK-1; and thioredoxin. AR-12 down-regulated in situ immuno-fluorescence detection of ATP binding chaperones using antibodies directed against the NH2-termini of the proteins but only weakly reduced detection using antibodies directed against the central and COOH portions of the proteins. Traditional SDS-PAGE and western blotting assessment methods did not exhibit any alterations in chaperone detection. AR-12 altered the sub-cellular distribution of chaperone proteins, abolishing their punctate speckled patterning concomitant with changes in protein co-localization. AR-12 inhibited chaperone ATPase activity, which was enhanced by sildenafil; inhibited chaperone - chaperone and chaperone - client interactions; and docked in silico with the ATPase domains of HSP90 and of HSP70. AR-12 combined with sildenafil in a GRP78 plus HSP27 -dependent fashion to profoundly activate an eIF2α/ATF4/CHOP/Beclin1 pathway in parallel with inactivating mTOR and increasing ATG13 phosphorylation, collectively resulting in formation of punctate toxic autophagosomes. Over-expression of [GRP78 and HSP27] prevented: AR-12 -induced activation of ER stress signaling and maintained mTOR activity; AR-12 -mediated down-regulation of thioredoxin, MCL-1 and c-FLIP-s; and preserved tumor cell viability. Thus the inhibition of chaperone protein functions by AR-12 and by multi-kinase inhibitors very likely explains why these agents have anti-tumor effects in multiple genetically diverse tumor cell types

Synthesis of Taurine-Containing Peptides, Sulfonopeptides, and <i>N</i>- and <i>O</i>‑Conjugates

Taurine-containing water-soluble peptidomimetics were designed and synthesized. <i>N</i>-terminal taurine acylations allowed synthesis of a number of taurine-containing peptides. <i>N</i>-protection of taurine with Cbz and SO₂-activation with benzotriazole followed by coupling with various amino esters, dipeptides and nucleophiles provided taurine <i>N</i>- and <i>O</i>-conjugates and sulfonopeptides

Optical and Mechanical Properties of Thin PTFE Films, Deposited from a Gas Phase

Thin polytetrafluoroethylene (PTFE) films are produced by deposition from a gas phase by two methods: electron-enhanced vacuum deposition (EVD) and EVD + low-temperature plasma (LTP). Structure, morphology, and composition of the films are studied by IR spectroscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. They are close to the structure of bulk PTFE. The roughness of the films’ surface is changed with gas pressure and LTP power variations. Films are transparent from UV to near-infrared regions. Refractive and extinction indices and their anisotropy are measured by spectral ellipsometry. They are tuned by variations of deposition conditions. Hardness and Young modulus of the films are increased if EVD + low power LTP is used for film deposition. Use of EVD + LTP also increases thermal stability of the films. Contact angle of the films corresponds to the bulk PTFE. The PTFE molecules oriented are preferentially in perpendicular direction to the substrate surface

Changes in the tumor microenvironment and outcome for TME-targeting therapy in glioblastoma: A pilot study.

Glioblastoma (GBM) is a hypervascular and aggressive primary malignant tumor of the central nervous system. Recent investigations showed that traditional therapies along with antiangiogenic therapies failed due to the development of post-therapy resistance and recurrence. Previous investigations showed that there were changes in the cellular and metabolic compositions in the tumor microenvironment (TME). It can be said that tumor cell-directed therapies are ineffective and rethinking is needed how to treat GBM. It is hypothesized that the composition of TME-associated cells will be different based on the therapy and therapeutic agents, and TME-targeting therapy will be better to decrease recurrence and improve survival. Therefore, the purpose of this study is to determine the changes in the TME in respect of T-cell population, M1 and M2 macrophage polarization status, and MDSC population following different treatments in a syngeneic model of GBM. In addition to these parameters, tumor growth and survival were also studied following different treatments. The results showed that changes in the TME-associated cells were dependent on the therapeutic agents, and the TME-targeting therapy improved the survival of the GBM bearing animals. The current GBM therapies should be revisited to add agents to prevent the accumulation of bone marrow-derived cells in the TME or to prevent the effect of immune-suppressive myeloid cells in causing alternative neovascularization, the revival of glioma stem cells, and recurrence. Instead of concurrent therapy, a sequential strategy would be better to target TME-associated cells

Optical and Mechanical Properties of Thin PTFE Films, Deposited from a Gas Phase

Abstract Thin polytetrafluoroethylene (PTFE) films are produced by deposition from a gas phase by two methods: electron‐enhanced vacuum deposition (EVD) and EVD + low‐temperature plasma (LTP). Structure, morphology, and composition of the films are studied by IR spectroscopy, atomic force microscopy, and X‐ray photoelectron spectroscopy. They are close to the structure of bulk PTFE. The roughness of the films’ surface is changed with gas pressure and LTP power variations. Films are transparent from UV to near‐infrared regions. Refractive and extinction indices and their anisotropy are measured by spectral ellipsometry. They are tuned by variations of deposition conditions. Hardness and Young modulus of the films are increased if EVD + low power LTP is used for film deposition. Use of EVD + LTP also increases thermal stability of the films. Contact angle of the films corresponds to the bulk PTFE. The PTFE molecules oriented are preferentially in perpendicular direction to the substrate surface

CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy–Resistant Glioblastoma

BACKGROUND: Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors. METHODS: Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study. RESULTS: Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment. CONCLUSIONS: The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials

Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments.

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 a selective CYP450 inhibitor has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Tumor growth and vascular parameters (tumor blood volume, permeability and, extravascular and extracellular space volume) were determined by in vivo dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The pharmacokinetics of HPßCD-HET0016 were evaluated in plasma and tumor tissues using IV and IP routes of administration. IV treatment with HPßCD-HET0016 decreased tumor growth, tumor blood volume, permeability and, extravascular and extracellular space volume, when compared with the vehicle group (

Sweet-Tasting Ionic Conjugates of Local Anesthetics and Vasoconstrictors

Local anesthetics are widely utilized in dentistry, cosmetology, and medicine. Local anesthesia is essential to providing a pain-free experience during dental and local surgeries as well as cosmetic procedures. However, the injection itself may produce discomfort and be a source of aversion. A novel approach toward the taste modulation of local anesthetics is proposed, in which the anesthetics of the “-caine” family serve as cations and are coupled with anionic sweeteners such as saccharinate and acesulfamate. Ionic conjugates of vasoconstrictor epinephrine such as epinephrine saccharinate and epinephrine acesulfamate have also been synthesized. Novel ionic conjugates were developed using anion exchange techniques. Reported compounds are sweet-tasting and are safe to use both topically and as injections