Design, synthesis and bioactivity evaluation of selenium-containing PI3Kδ inhibitors.

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 µM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.

The dual luciferase reporter system and RT-qPCR strategies for screening of MicroRNA-21 small-molecule inhibitors.

The therapeutic potential of microRNA-21 (miR-21) small-molecule inhibitors has been of particular interest to medicinal chemists. Moreover, the development of more facile screening methods is lacking. In the present study, two potential screening strategies for miR-21 small-molecule inhibitor including the stem-loop reverse transcription-quantitative PCR and dual luciferase reporter assay system were demonstrated and discussed in detail. A pmirGLO-miR21cswt plasmid and its two different mutants were constructed for dual luciferase reporter assay system. In addition, the sensitivity and specificity of these two methods were validated. Our results demonstrated that both strategies are decent choices for the screening of small-molecule inhibitors for miR-21 and possibly other miRNAs. Eventually, we applied our optimized strategy to discover and characterize several promising compounds such as azobenzene derivate A, enoxacin, and norfloxacin for their potential impact on intracellular miR-21 concentration.

Discovery of novel 2-benzylisoquinolin-1(2H)-ones as potent vasodilative agents.

2-Benzylisoquinolin-1(2H)-ones has been proposed as vasodilative agents on the basis of scaffold hopping. In the present study, a series of 2-benzylisoquinolin-1(2H)-ones were synthesized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The structure-activity relationships of target compounds were discussed. Among these compounds, C7 and C8 displayed potent vasodilative effects and significantly inhibited the contraction of rat mesenteric arterial rings induced by phenylephrine. The antihypertensive effects of compounds C7 and C8 on SHR were further evaluated. The results indicated that oral administrational C7 and C8 can significantly reduce both diastolic and systolic blood pressure in a dose-dependent manner. Moreover, C7 maintained the effects for 4h at a dosage of 4.0mg/kg. These findings suggest that the title compounds can serve as novel vasodilative agents and promising antihypertensive agents.

Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents.

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6h at a dosage of 4.0mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.

Discovery of 2-aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-ones as novel EGFR inhibitor by scaffold hopping.

2-Aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one has been proposed as a novel scaffold of EGFR inhibitor based on scaffold hoping. In the present study, a series of 2-aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one derivatives were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against two human cancer cell lines, including A431 and A549. The SAR of the title compounds was preliminarily discussed. The compounds with ideal inhibition were evaluated through ELISA-based EGFR-TK assay. Compound 6c showed the best activity against A431 and EGFR tyrosine kinase. These findings suggest that title compounds are EGFR inhibitors with novel structures.

[Synthesis of 2-hydroxyl-5-butyramidobenzoic acid and its effect on acetic acid-induced colitis in rats].

OBJECTIVE: To study the method for synthesis of 2-hydroxyl-5- butyramidobenzoic acid and test its effect on acetic acid-induced colitis in rats. METHODS: 2-hydroxyl-5-butyramidobenzoic acid was synthesized from 5-aminosalicylic acid and butyric acid by amidation, esterification and hydrolization. The effect of 2-hydroxyl-5-butyramidobenzoic acid on acetic acid enema-induced colitis in rats was investigated. RESULTS: The structure of 2-hydroxyl-5-butyramidobenzoic acid was identified by IR and 1H-NMR. After treatment with acetic acid, the colon mucosal damage index (CMDI), fecal occult blood (OB) test, and activity of myelperoxidase (MPO) increased significantly in the rats as compared to the control levels. 2-hydroxyl-5- butyramidobenzoic acid obviously reduced the CMDI and OB, and reduced the level of MPO in the rats with colitis. CONCLUSION: The synthesis of 2-hydroxyl-5-butyramidobenzoic acid requires only mild conditions with simple procedures, and the synthesized 2-hydroxyl-5-butyramidobenzoic acid shows obvious therapeutic effects on mucosal damage of in rats with acetic acid-induced colitis.

[Application of macroporous resin in purification for effective part from Polygonum cuspidatum].

OBJECTIVE: To study the technological parameters of the purification process for effective part from Polygonum cuspidatum. METHOD: Using adsorption capacities and desorption rates of polydatin, resveratrol,emodin,physcion and total anthraquinone as the primary screening indexes, six resins were surveyed,and the optimized conditions of adsorption and desorption of the effective ingredients were studied. RESULT: Resin D101 gave good separation performance and was selected to purify the effective part in Polygonum cuspidatum. The optimum parameters were established as the following: 1 BV (bed volume) sample extract was passed through the column with a flow rate of 2.4 BV x h(-1), 30 min later,the column was washed with 2 BV water, 2 BV 20% ethanol, 5 BV 50% ethanol, 2 BV 70% ethanol and 5 BV 95% ethanol, respectively. The combined 50% and 95% ethanolic elutes were concentrated to yield the purified effctive part. CONCLUSION: The purity of the total effective ingredients in the product was up to 36. 87%. Macroporous resin D101 could be well used in separating and purifying the effective part from Polygonum cuspidatum.

Asterosaponins from the starfish Culcita novaeguineae and their bioactivities.

Bioassay-guided fractionation of the n-BuOH extract of the starfish Culcita novaeguineae resulted in the isolation of one new sulfated steroidal glycoside (asterosaponin) (1), along with three known asterosaponins, thornasteroside A (2), marthasteroside A(1) (3) and regularoside A (4), as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Their structures were elucidated by extensive spectral studies and chemical evidences. All the saponins showed moderate cytotoxicity against cancer cell lines K-562 and BEL-7402.

Three new asterosaponins from the starfish Culcita novaeguineae and their bioactivity.

Bioassay-guided fractionation of the active n-BuOH extract of the starfish Culcita novaeguineae resulted in the isolation of three new sulfated steroidal glycosides (asterosaponins) 1, 2 and 3, as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Compounds 1-3 possess the same pentasaccharide moiety, beta-D-fucopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->4)-[beta-D-quinovopyranosyl-(1-->2)]-beta-D-xylopyranosyl-(1-->3)-beta-D-quinovopyranosyl, linked to C-6 of 3beta-sulfated steroidal aglycones and differ from each other in the side chains. Their structures were elucidated by extensive spectral studies and chemical evidences. Saponins 1 and 3 showed significant cytotoxicity against two cancer cell lines (IC50 values for 1:3.57 microg/mL [K-562], 2.55 microg/mL [BEL-7402]; for 3:3.75 microg/mL [K-562], 1.89 microg/mL [BEL-7402]), as well as hemolytic activity to rabbit erythrocytes (ED50 values: 16 and 31 microg/mL, respectively), while 2 was inactive in these bioassays.

Study on the characteristics of pectin-ketoprofen for colon targeting in rats.

Pectin-ketoprofen (PT-KP) prodrug with the potential for colon targeted delivery has been evaluated. A sensitive HPLC method was established for the determination of concentration of ketoprofen (KP) in rats. This method was also used to evaluate the colon targeting property of PT-KP. KP or PT-KP was given to rats by oral administration at a dosage of 10mg/kg. Plasma and the different parts of gastrointestinal (GI) tract were taken after 2, 4, 6, 8, 10 and 12h of oral administration of KP or PT-KP to rats and the concentration of KP was measured by HPLC. Preliminary experiments show KP distributes mainly in stomach, proximal small intestine and distal small intestine. However, KP released from PT-KP mainly distributes in cecum and colon. Therefore, this approach suggests that PT-KP prodrug has a good colon targeting property.