Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors.

KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adenocarcinoma (PDAC) cases, making it an attractive therapeutic target. Through structure-based drug design, a series of potent and selective KRAS G12D inhibitors were designed. The lead compound, ERAS-5024, inhibited ERK1/2 phosphorylation and cell proliferation in three-dimensional Cell-Titer Glo assays in AsPC-1 PDAC cells with single-digit nanomolar potency and caused tumor regression in the in vivo efficacy studies. We describe here the details of the design and synthesis program that led to the discovery of ERAS-5024.

Utilizing Electroplex Emission to Achieve External Quantum Efficiency up to 18.1% in Nondoped Blue OLED.

For the first time, electroplex emission is utilized to enhance the performance of nondoped blue organic light-emitting diodes (OLEDs). By decorating the twisted blue-emitting platform and adjusting the electronic structure, three molecules of 3Cz-Ph-CN, 3Cz-mPh-CN, and 3Ph-Cz-CN with a donor-acceptor structure are synthesized and investigated. When external voltage is applied, electroplex emission, which contributes to the emission performance of OLED, can be realized at the interface between the emitting layer and the electron-transporting layer. Accordingly, high external quantum efficiency of 18.1% can be achieved, while the emission wavelength of the device can be controlled in the blue region. Our results provide the possibility to enhance the performance of OLED through electroplex emission, in addition to the generally investigated thermally activated delayed fluorescence (TADF). Excitedly, when 3Ph-Cz-CN is used as host material in orange-emitting phosphorous OLEDs (PO-01 as the dopant), unprecedented high external quantum efficiency of 27.4% can also be achieved.

Tunable low-dimensional self-assembly of H-shaped bichromophoric perylenediimide Gemini in solution.

A material with diverse self-assembled morphologies is extremely important and highly desirable because such samples can provide tunable optical and electronic properties, which are critical in applications such as organic photovoltaics, microelectronics and bio-imaging. Moreover, the synthesis and controllable self-assembly of H-shaped bichromophoric perylenediimides (PDIs) are needed to advance these materials in organic photovoltaics, microelectronics and bio-imaging; however, this has remained a great challenge thus far. Here, we successfully synthesize a novel H-shaped bichromophoric PDI Gemini through the palladium-catalyzed coupling reaction. The as-prepared PDI Gemini exhibited unprecedented tunable self-assembly behavior in solution, yielding diverse low-dimensional superstructures, such as one-dimensional (1D) helices, two-dimensional (2D) rectangular nanocrystals, pyramid-shaped parallelograms, ultralarge micro-sheets, and uniform nanospheres, under different self-assembly conditions. Of particular interest, the 2D hierarchical superstructures along with their formation mechanisms represent the first finding in the self-assembly of PDI-based molecules. This study opens a new avenue for tunable self-assembly of conjugated molecules and affords opportunities for the fabrication of novel self-assembled optical and electronic materials based on PDI molecules.

Benzene-cored AIEgens for deep-blue OLEDs: high performance without hole-transporting layers, and unexpected excellent host for orange emission as a side-effect.

Great efforts have been devoted to explore efficient fluorescent materials, especially deep-blue luminogens, for organic light emitting diodes (OLEDs). In this paper, according to the design idea of creating luminogens with the characteristic of aggregation induced emission (AIE), four new benzene-cored luminogens with very simple structure have been intelligently designed, in which, without an additional hole-transporting layer (such as NPB), 3TPA-CN exhibited deep-blue emission and high performance in a simple nondoped LED device with a current efficiency (CE) of 5.21 cd A-1, external quantum efficiency (EQE) of 3.89%, and CIE coordinates of (0.15, 0.14). Excitingly, as a wonderful side-effect, 3TPA-CN can serve as an excellent host for orange emissive phosphorescent OLEDs (PhOLEDs), with a maximum current and power efficiency of 57.4 cd A-1 and 52.0 lm W-1, respectively, and a corresponding maximum EQE of 18.2%, higher than that of CBP (15.7%), one popular host for orange PhOLEDs, under the same conditions, thus broadening the utilization of AIEgens as host in PhOLEDs.

Enhanced Estrogenic Activity of Soybean Isoflavones by Coadministration of Liuwei Dihuang Pills in Ovariectomized Rats.

Soybean isoflavones are beneficial for treating hormone-related diseases. Simultaneous consumption of soybean isoflavones and Liuwei Dihuang pills (LWPs) is effective for treating perimenopausal period syndrome. However, why the combination of isoflavones and LWPs is more effective than ingestion of each component alone remains unknown. Here, we show that enhanced estrogenic activities would appear when the ovariectomized rats were fed with a soybean diet in combination of LWPs treatment. Our further studies explored enhancements of Lactobacillus (19-fold) and Bifidobacterium (12-fold) contents in the intestine of rat and 1.84-fold higher intestinal ß-glucosidase activity in LWPs treatment group compared with the control group. As a result, steady-state concentrations of genistein (1.20-fold), daidzein (1.36-fold), and equol (1.43-fold) in serum were significantly elevated in the combination group compared with the soybean alone group. The results present the first evidence of the mechanism of enhanced estrogenic activity of dietary soybean isoflavones in combination with LWPs. Our study indicates that alterations of gut bacteria after LWPs treatment play a key role in the enhanced estrogenic effect of dietary soybean, suggesting a direct relationship between dietary soybean, LWPs, and gut flora.

Pyrene fused perylene diimides: synthesis, characterization and applications in organic field-effect transistors and optical limiting with high performance.

Three pyrene fused PDI derivatives have been obtained, in which totally different properties were observed when adopting different fusing types. For bilaterally benzannulated PDIs, through spin-coating, bottom-contact OFET devices exhibited a p-type mobility up to 1.13 cm(2) V(-1) s(-1), with an on/off ratio of 10(8) in air.

Antiangiogenesis therapy of endometriosis using PAMAM as a gene vector in a noninvasive animal model.

OBJECTIVE: To evaluate the characteristics and antiangiogenic effects of endostatin-loaded PAMAM on endometriosis in a noninvasive animal model. MATERIALS AND METHODS: A noninvasive animal model was established by injecting adenovirus-GFP transfected endometrial stromal and glandular epithelial cells subcutaneously into nude mice. Endostatin-loaded PAMAM was prepared and identified by transmission electron microscopy. For in vitro studies, the DNA protection and cytotoxicity of PAMAM were investigated and compared with Lipofectamine 2000. For in vivo study, endostatin-loaded PAMAM was injected into the noninvasive model and evaluated by continuously observing the fluorescent lesion, lesion weight, microvessel density and VEGF immunostaining. RESULTS: Compared with Lipofectamine 2000, PAMAM and HC PAMAM-ES group, MC PAMAM-ES group and LC PAMAM-ES group demonstrated a better stromal cells protective such that MC PAMAM-ES group of CCK8 was 0.617 ± 0.122 at 24 hr and 0.668 ± 0.143 at 48 hr and LC PAMAM-ES group of CCK8 was 0.499 ± 0.103 at 24 hr and 0.610 ± 0.080 at 48 hr in stromal cells (P < 0.05) but similar cytotoxicity in glandular epithelial cells in vitro. After 16 hrs of digestion, DNA decreased slightly under the protection of PAMAM. Endostatin-loaded PAMAM of HD PAMAM-ES group and LD PAMAM-ES group inhibited the growth of the endometriotic lesion in vivo at days 15, 20, 25 and 30 detected by noninvasive observation after injecting one dose endostatin of various medicines into the endometrial lesion in each mouse on day 10 (P < 0.05) and confirmed by lesion weight at day 30 with HD PAMAM-ES group being 0.0104 ± 0.0077 g and LD PAMAM-ES group being 0.0140 ± 0.0097 g (P < 0.05). Immunohistochemistry results showed that endostatin-loaded PAMAM reduced the microvessel density 3.8 ± 2.4 especially in HD PAMAM-ES group in the lesion (P < 0.05). CONCLUSION: Endostatin-loaded PAMAM inhibits the development of endometriosis through an antiangiogenic mechanism and can be observed through the noninvasive endometriosis model.

Alteration of gut bacteria and metabolomes after glucaro-1,4-lactone treatment contributes to the prevention of hypercholesterolemia.

D-Glucaro-1,4-lactone (1,4-GL) has been shown to have a hypocholesterolemic effect in rats and human subjects. However, little information is known concerning the alteration of metabolome associated with the effect. Here, we show that 1,4-GL delays the development of hypercholesterolemia with the coadministration of a high-fat, high-cholesterol diet (HFHC) in rats. Metabonomic results based on proton nuclear magnetic resonance indicate that urinary trimethylamine N-oxide, trimethylamine, lactate, acetate, formate, and creatinine are significantly altered after 1,4-GL and HFHC treatments. Colonic flora test results reveal that the quantity of Bifidobacterium and Lactobacillus in the intestines respectively increase by about 1.7- and 4.2-fold in rats treated with 1,4-GL compared with those in the control group. Rats that were coadministered with HFHC and 1,4-GL exhibit normal levels of lactate and acetate in serum and display urinary excretions of lactate and acetate that are 2 to 3 times higher compared with those treated with HFHC alone. The results imply that the increased probiotic quantities and urinary excretion of breakdown products of fat/cholesterol after 1,4-GL treatment contribute to the prevention of hypercholesterolemia. Our study offers insights into the model of action for 1,4-GL in preventing hypercholesterolemia.

[Preparation and immunological evaluation of oral solution of egg yolk-derived hepatitis B virus-specific transfer factor].

OBJECTIVE: To prepare the oral solution of egg yolk hepatitis B virus (HBV)-specific transfer factor (EYHBV-TF) and evaluate its immunological activity as an immune regulator against hepatitis B. METHODS: From hens immunized with the Hepatitis B vaccine the egg yolk was isolated to extract the specific transfer factor EYHBV-TF, and its physicochemical properties were examined. Leukocyte adhesion inhibition test (LAI) was performed to detect the immunogenic activity of EYHBV-TF. The solution of EYHBV-TF was then administered orally in normal mice, and the specific cellular immune activity induced was assayed with delayed type skin hypersensitivity test (DTH), with the non-specific immune activity assessed with immune organ index. The immune responses induced by oral EYHBV-STF solution were compared with those by EYHBV-STF injection and by different dosages (injection and oral) of porcine spleen HBV-specific transfer factor (PSHBV-STF), porcine spleen nonspecific transfer factor, and egg yolk extracts from non-immunized hens. RESULTS: The prepared EYHBV-STF oral solution, which met the standards for biological products, could inhibit leukocyte adhesion in vitro and significantly enhance mouse foot pad swelling, demonstrating its capability of transferring antigen-specific delayed type hypersensitivity reactions to naive recipient. EYHBV-STF oral solution also significantly improved the immune organ index in mice (P<0 01) with similar effects to those caused by EYHBV-STF injections and by PSHBV-STF injection and oral solution. CONCLUSION: Orally administered EYHBV-STF and EYHBV-STF injection both possess hepatitis B antigen-specific cellular immune activity and can significantly enhance specific cellular immune responses.