Design of Suspended Slot Racetrack Microring Refractive Index Sensor Based on Polymer Nanocomposite.

Recently, polymer nanocomposites have attracted great interest due to their remarkable characteristics of high performance and enabling production of low-cost devices. This article explores the reflective index sensing application of the polymer nanocomposite IOC-133, which is a TiOx/polymer nanocomposite with a reflective index between 1.8 and 1.9. Considering the material properties of high reflective index, low absorption loss, and compatibility with nanoimprint lithography, a microring-based reflective index sensor with a suspended slot waveguide structure is proposed. We combined the sensing mechanism of slot waveguides with high reflective index polymer nanocomposites and designed the suspended structure to address the problem of decreasing sensitivity caused by residual layers. The sensing device was adopted as a microring resonator, which is conducive to large-scale integration. The finite-difference time-domain (FDTD) method was employed to analyze the effects of several key parameters. The results showed that the racetrack microring sensor we propose can achieve a high sensitivity of 436 nm/RIU (Refractive Index Units), about six times higher than the microring sensor with a ridge waveguide. The Q factor of the microring reaches 1.42 × 104, and the detection limit is 1.38 × 10-4 RIU. The proposed suspended slot microring sensor has potential value in the field of nanoprinted photonic integrated circuits.

Low Power Consumption Hybrid-Integrated Thermo-Optic Switch with Polymer Cladding and Silica Waveguide Core.

Taking advantage of the large thermo-optical coefficient of polymer materials, a hybrid-integrated thermo-optic switch was designed and simulated. It is also compatible with the existing silica-based planar light-wave circuit (PLC) platform. To further reduce the power consumption, we introduced the air trench structure and optimized the structural parameters of the heating region. This scheme is beneficial to solving the problem of the large driving power of silica-based thermo-optic switches at this stage. Compared with the switching power of all-silica devices, the power consumption can be reduced from 116.11 mW (TE) and 114.86 mW (TM) to 5.49 mW (TE) and 5.96 mW (TM), which is close to the driving power of the reported switches adopting polymer material as the core. For the TE mode, the switch's rise and fall times were 121 µs and 329 µs. For the TM mode, the switch times were simulated to be 118 µs (rise) and 329 µs (fall). This device can be applied to hybrid integration fields such as array switches and reconfigurable add/drop multiplexing (ROADM) technology.

Highly Sensitive Liquid M-Z Waveguide Sensor Based on Polymer Suspended Slot Waveguide Structure.

The slot structure has great advantages in improving the sensitivity of integrated waveguide optical sensors and reducing the detection limit. We propose a polymer Mach-Zehnder interferometer (MZI) optical sensor based on the slot structure and adopted the suspended structure to improve optical field interaction with the analyte, hence boosting the sensor's sensing accuracy. In this paper, the effects of the single waveguide width, slot width, and coupling structure of the slot waveguide on the performance of the sensor operating at a 1550 nm wavelength were analyzed. Under the premise of satisfying single-mode transmission, we designed an MZI with a branch spacing of 10 µm, arm length of 2045 µm, branch span of 700 µm, and slot region of 500 µm. The sensor's average sensitivity was 972.1 dB/RIU, and its average detection resolution was 1.6 × 10-6 RIU, which is approximately 1.5 times higher than that of the suspended strip waveguide, 1.6 times higher than that of the non-suspended slot structure, and 2.1 times higher than that of the non-suspended strip waveguide.

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases.

BACKGROUND: Overexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2). METHODS: HTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression. RESULTS: TY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase. CONCLUSIONS: These results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers.

Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic agents. Herein we report the design, synthesis, and phenotypic screening of a novel class of 3-aminopyrrolidinone-based hydroxamic acids as HDAC6 inhibitors. In particular, the α-methyl-substituted enantiomer 33 (3-S) showed significant in-cell tubulin acetylation (Tub-Ac) with an EC50 of 0.30 µM but limited impact on p21 levels at various concentrations. In enzyme inhibition assays, 33 demonstrated high selectivity for HDAC6 with an IC50 of 0.017 µM and selectivity indexes of 10 against HDAC8 and over 4000 against HDAC1-3 isoforms. Moreover, 33 has suitable drug metabolism and pharmacokinetics properties compared with other hydroxamic acid-based HDAC inhibitors, warranting further biological studies and development as a selective HDAC6 inhibitor.

Identification of a novel aminotetralin class of HDAC6 and HDAC8 selective inhibitors.

Herein we report the identification of a novel class of HDAC6 and HDAC8 selective inhibitors through a unique chemistry and phenotypic screening strategy. Tetrahydroisoquinoline 12 was identified as a potent HDAC6 and HDAC8 dual inhibitor from a focused library through cellular tubulin acetylation and p21 induction screening assays. Scaffold hopping from 12 led to the discovery of an aminotetralin class of HDAC inhibitors. In particular, the 3-R stereoisomer 32 showed highly potent inhibition against HDAC6 and HDAC8 with IC50 values of 50 and 80 nM, respectively. Treatment of neuroblastoma BE(2)C cells with 32 resulted in elevated levels of acetylated tubulin, TrkA, and neurite outgrowth with only marginal effects on p21 induction and histone H3 acetylation. Consistent with its weak enzymatic inhibition of HDAC1, 32 showed significantly less cytotoxicity than SAHA and moderately inhibited the growth of myeloma NCI-H929 and OPM-2 cells.

Small molecule R1498 as a well-tolerated and orally active kinase inhibitor for hepatocellular carcinoma and gastric cancer treatment via targeting angiogenesis and mitosis pathways.

Protein kinases play important roles in tumor development and progression. Lots of kinase inhibitors have entered into market and show promising clinical benefits. Here we report the discovery of a novel small molecule, well-tolerated, orally active kinase inhibitor, R1498, majorly targeting both angiogenic and mitotic pathways for the treatment of hepatocellular carcinoma (HCC) and gastric cancer (GC). A series of biochemical and cell-based assays indicated that the target kinase cluster of R1498 included Aurora kinases and VEGFR2 et al. R1498 showed moderate in vitro growth inhibition on a panel of tumor cells with IC50 of micromole range. The in vivo anti-tumor efficacy of R1498 was evaluated on a panel of GC and HCC xenografts in a parallel comparison with another multikinase inhibitor sorafenib. R1498 demonstrated superior efficacy and toxicity profile over sorafenib in all test models with >80% tumor growth inhibition and tumor regression in some xenogratfts. The therapeutic potential of R1498 was also highlighted by its efficacy on three human GC primary tumor derived xenograft models with 10-30% tumor regression rate. R1498 was shown to actively inhibit the Aurora A activity in vivo, and decrease the vascularization in tumors. Furthermore, R1498 presented good in vivo exposure and therapeutic window in the pharmacokinetic and dose range finding studies. Theses evidences indicate that R1498 is a potent, well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic and antiproliferative profile, and provide strong confidence for further development for HCC and GC therapy.

Pharmacokinetic optimization of class-selective histone deacetylase inhibitors and identification of associated candidate predictive biomarkers of hepatocellular carcinoma tumor response.

Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC50 = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.

A novel Bcl-2 small molecule inhibitor 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB)-induced apoptosis in leukemia cells.

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.

Nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-XL, (-)-Gossypol, enhances biological effect of genistein against BxPC-3 human pancreatic cancer cell line.

OBJECTIVES: In pancreatic cancer, several important survival molecules such as EGFR, NF-kappaB, and Bcl-2 or Bcl-XL are highly activated. Thus, agents that inhibit NF-kappaB activation, together with agents that directly inhibit Bcl-2 or Bcl-XL protein function, may lead to enhanced cell killing. (-)-Gossypol, a natural polyphenolic compound isolated from cottonseeds, is a dual and potent small-molecule inhibitor of Bcl-2 and Bcl-XL proteins, with a Ki value in the 300-600 nM range for both proteins. METHODS: : The BxPC-3 human pancreatic cell line was used in this study. (-)-Gossypol was dissolved in DMSO at 20 mmol/L as stock solution, and genistein was dissolved in 0.1 M Na2CO3 to make a 10 mM stock solution. For cell viability, apoptosis, and NF-kappaB studies, MTT assay, histone/DNA ELISA, and Electrophoretic Mobility Shift Assay (EMSA) were used, respectively. Coimmunoprecipitation experiments were designed to study Bcl-XL/Bim heterodimerization, and Western blots to study cytochrome c release. RESULTS: (-)-Gossypol showed a concentration-dependent growth inhibition effect against BxPC-3 pancreatic cancer cell line and induced apoptosis with no effect on normal peripheral blood lymphocytes. Results from coimmunoprecipitation experiments indicate that the effect of (-)-gossypol is mediated, at least, in part via disrupting the heterodimerization of Bcl-XL with Bim in BxPC-3 pancreatic cancer cells. (-)-Gossypol completely disrupts Bcl-XL/Bim heterodimerization with no change in the total Bcl-XL or Bim protein, indicating that (-)-gossypol treatment does not affect the levels of Bcl-XL and Bim proteins. We have previously shown that genistein, a prominent soy isoflavone, transcriptionally down-regulates Bcl-2, Bcl-XL, VEGF, MMP-9, and uPAR via inhibiting NF-kappaB activity. In this study, genistein down-regulated NF-kappaB DNA binding activity and inhibited the growth of BxPC-3 pancreatic cancer cells. In addition, the combination of (-)-gossypol with genistein showed significantly greater growth inhibition compared with either agent alone. CONCLUSION: From these results, we conclude that inhibition of NF-kappaB activity and direct inhibition of Bcl-2 or Bcl-XL function should serve as a novel strategy for pancreatic cancer therapy.

Novel indole alpha-methylene-gamma-lactones as potent inhibitors for AKT-mTOR signaling pathway kinases.

In an effort to generate novel anticancer agents, a series of hybrids of alpha-methylene-gamma-lactones and 2-phenyl indoles has been synthesized and evaluated for inhibition activities on the phosphorylation of AKT, mTOR, p70S6 kinase, and 4E-BP1. The results indicate that substitutes on the gamma-position of lactones have a rather significant influence on inhibition activities.

Benzothieno[3,2-b]indole derivatives as potent selective estrogen receptor modulators.

A series of estrogen receptor ligands based on benzothieno[3,2-b]indole were synthesized and their binding affinity for estrogen receptor subtypes (ERalpha and ERbeta) and effects on mouse uterus and bone were evaluated. Some of these compounds showed strong binding affinity to ER and significantly increased the bone mineral density of ovariectomized mice.

Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands.

We report the design and synthesis of a series of enantiomerically pure hexahydropyrazinoquinolines as potent and selective ligands for the dopamine 3 subtype receptor using a newly developed synthetic method and using in vitro pharmacological evaluation. Our efforts yielded optically pure ligands with high affinities for the D(3) receptor and outstanding selectivity over closely related D(1)-like and D(2)-like receptors. For example, compound 38a has a K(i) value of 5.7 nM to the D(3) receptor and selectivity greater than 10000- and 1600-fold over the D(1)-like and D(2)-like receptors, respectively, and thus is one of the most selective D(3) ligands reported to date.

Syntheses of quinolone hydrochloride enantiomers from synthons (R)- and (S)-2-methylpiperazine.

A series of R and S enantiomers of 7-(3-methylpiperazin-1-yl) quinolone derivatives were synthesized from (R)- and (S)-tert-butyl 2-methylpiperazine-1-carboxylate and tested for their antibacterial activities on 14 kinds of bacteria. Although no distinct difference in in vitro antibacterial activities was observed, 2-64-fold difference between R and S enantiomers was observed in approximately 52% of cases.

Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands.

A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D3 ligand with a moderate binding affinity to the D3 receptor (Ki=304 nM) but no selectivity over the D1-like and D2-like receptors. In this study, we wish to report the design, synthesis and structure-activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in new compounds with improved binding affinity and selectivity. Among them, compound 12d has a Ki value of 2.6 nM for its binding affinity to the D3 receptor and has >2000- and 99-fold selectivity over the D1-like and D2-like receptors, respectively, representing a potent and selective D3 ligand.

Benzothiophenes containing a piperazine side chain as selective ligands for the estrogen receptor alpha and their bioactivities in vivo.

The synthesis of benzothiophenes containing a piperazine side chain and their binding affinities for estrogen receptors are described. These compounds bearing piperazine side chains were identified to be high-affinity ligands with high selectivity for ER alpha subtype. They were also potent agonists in bone tissue.

Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma.

Overexpression of Bcl-2/Bcl-X(L) protein has been observed in more than 80% of B-cell lymphomas. Diffuse large cell lymphoma (DLCL) is the most common subtype of non-Hodgkin's lymphoma. (-)-Gossypol, a natural product isolated from cottonseeds, was discovered as a potent small-molecule inhibitor of Bcl-2 and Bcl-X(L) proteins, with a Ki value in the nanomole per liter range for both. In vitro, (-)-gossypol showed significant growth inhibition effect against WSU-DLCL2 lymphoma cell line and fresh cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. As expected (-)-gossypol induced complete cytochrome c release from mitochondria, increased caspases-3 and -9 activity, and caused apoptotic death without affecting protein levels of Bcl-2, Bcl-X(L), Bax, and Bak. The addition of cyclophosphamide-Adriamycin-vincristine-prednisolone (CHOP) regimen to lymphoma cells preexposed to (-)-gossypol enhanced killing significantly. The maximum tolerated dose of (-)-gossypol in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg x 3 when given in combination with CHOP. Using WSU-DLCL2-SCID mouse xenograft model, the tumor growth inhibition, the tumor growth delay, and the log10 kill of mice treated with (-)-gossypol + CHOP were better than CHOP or (-)-gossypol alone. We conclude that adding Bcl-2/Bcl-X(L) small-molecule inhibitor to standard chemotherapy may prove an effective strategy in lymphoma therapy.

DNA topoisomerase I inhibitors from Rinorea anguifera.

An organic extract prepared from Rinorea anguifera was investigated in order to identify the natural principle(s) responsible for stabilization of a topoisomerase I-DNA covalent binary complex. Bioassay-guided fractionation resulted in the isolation of mauritianin and (+)-syringaresinol as new topoisomerase I inhibitors, and also of the known inhibitor camptothecin.

In vitro effects of the BH3 mimetic, (-)-gossypol, on head and neck squamous cell carcinoma cells.

PURPOSE: Bcl-xL overexpression is common in head and neck squamous cell carcinomas (HNSCC) and correlates with resistance to chemotherapy. Thus, a nonpeptidic, cell-permeable small molecule that mimics the BH3 domain of proapoptotic proteins may inhibit Bcl-xL function and have therapeutic potential for HNSCC by overcoming drug-resistance. (-)-Gossypol, the levorotatory isomer of a natural product isolated from cottonseeds and roots, was recently discovered to bind to the BH3 binding groove of Bcl-xL and Bcl-2. EXPERIMENTAL DESIGN: We investigated the in vitro effects of (-)-gossypol on HNSCC cell lines as well as on fibroblast and keratinocyte cultures by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell survival assays and assessed the results with respect to Bcl-2 family protein expression. RESULTS: We observed dose-dependent growth inhibition of 10 HNSCC cell lines at biologically achievable doses (2.5-10 micromol/L). (-)-Gossypol doses required to inhibit the growth of human fibroblast cell lines by 50% were 2- to 10-fold higher than for HNSCC cell lines. To inhibit human oral keratinocyte growth by 50%, (-)-gossypol concentrations were 2-to 3-fold higher than for HNSCC cell lines. CONCLUSIONS: There is a direct correlation between Bcl-xL-to-Bcl-xS ratios and sensitivity to (-)-gossypol. This agent induced apoptosis in a much higher proportion of cells with wild-type p53. Importantly, cell lines resistant to cisplatin were very sensitive to (-)-gossypol. These results demonstrate that (-)-gossypol has potent antitumor activity in HNSCC in vitro. This agent may be developed as a novel therapeutic agent for HNSCC, either alone or in combination with existing chemotherapeutic agents.

Design, synthesis, and evaluation of hexahydrobenz[f]isoquinolines as a novel class of dopamine 3 receptor ligands.

We previously identified hexahydrobenz[f]isoquinoline (4a) as a new class of dopamine 3 receptor (D(3)) ligand. Herein, we described the design, synthesis, and preliminary structure-activity relationships of new analogues of 4a as a novel class of D(3) ligands. Among these new analogues, compound 4 h is a potent D(3) ligand (K(i)=6.1 nM) and has a selectivity of 133-fold between D(3)- and D(2)-like receptors, and of 163-fold between D(3)- and D(1)-like receptors, respectively. Thus, compound 4 h represents a promising new lead compound for further design and optimization toward achieving highly potent and selective D(3) ligands.