Design, Synthesis and Antitumor Activity of FAK/PLK1 Dual Inhibitors with Quinazolinone as the Skeleton.

Febrifugine is a kind of quinazolinone compound with high biological activity from a Chinese herb called Chang Shan (Dichroa febrifuga). Febrifugine and its derivatives possess extensive biological activities, some of which exhibited anti-tumor activities as FAK inhibitors. However, they are not very effective at inhibiting tumor metastasis, perhaps because tumors gain energy through compensatory activation of other signaling pathways that promote cell migration and invasion. Therefore, seventeen novel febrifugine derivatives with quinazolinone skeleton were designed, synthesized and acted as potential FAK/PLK1 dual inhibitors. These compounds were determined by 1 H-NMR, 13 C-NMR and MS. Most of the compounds exhibited good inhibitory activity against cancer cell lines by computer-assisted screening, antitumor activity test and FAK/PLK1 inhibitory activity test, wherein compound 3b was screened as a high-efficiency lead compound.

Design, Synthesis and Molecular Docking of Novel Quinazolinone Hydrazide Derivatives as EGFR Inhibitors.

A series of novel quinazolinone hydrazide derivatives were designed and synthesized as EGFR inhibitors. The results indicated that most of the aimed compounds had potential anti-tumor cell proliferation and EGFR inhibitory activities. In the comprehensive analysis of all the tested compounds, the target compound 9c showed the best anti-tumor cell proliferation activity, (IC50 =1.31 µM for MCF-7, IC50 =1.89 µM for HepG2, IC50 =2.10 µM for SGC), and IC50 =0.59 µM for the EGFR inhibitory activity. Docking results showed that compound 9c could ideally insert the active site and interact with the critical amino acid residues (Val702, Lys721, Met769, Asp831) in the active site.

Thiazolidinedione: A Privileged Scaffold for the Development of Anticancer Agents.

Thiazolidinedione, an important heterocyclic ring system, is a pharmacophore and a privileged scaffold in medicinal chemistry. Researchers have shown its potential application as a backbone for inhibitors, as it is involved in anticancer development strategies, cancer progression and metastasis. In this paper, the anticancer activities of thiazolidinedione derivatives were reviewed for the first time with respect to different substituents and their positions. This work may imitate a stirring wheel to guide further advanced development of new anticancer molecules with high efficacy.

Cloning and characterization of an oxiranedicarboxylate hydrolase from Labrys sp. WH-1.

OBJECTIVE: This study aimed to clone and characterize the oxiranedicarboxylate hydrolase (ORCH) from Labrys sp. WH-1. METHODS: Purification by column chromatography, characterization of enzymatic properties, gene cloning by protein terminal sequencing and polymerase chain reaction (PCR), and sequence analysis by secondary structure prediction and multiple sequence alignment were performed. RESULTS: The ORCH from Labrys sp. WH-1 was purified 26-fold with a yield of 12.7%. It is a monomer with an isoelectric point (pI) of 8.57 and molecular mass of 30.2 kDa. It was stable up to 55 °C with temperature at which the activity of the enzyme decreased by 50% in 15 min (T5015) of 61 °C and the half-life at 50 °C (t1/2, 50 °C) of 51 min and was also stable from pH 4 to 10, with maximum activity at 55 °C and pH 8.5. It is a metal-independent enzyme and strongly inhibited by Cu2+, Ag+, and anionic surfactants. Its kinetic parameters (Km, kcat, and kcat/Km) were 18.7 mmol/L, 222.3 s-1, and 11.9 mmol/(L·s), respectively. The ORCH gene, which contained an open reading frame (ORF) of 825 bp encoding 274 amino acid residues, was overexpressed in Escherichia coli and the enzyme activity was 33 times higher than that of the wild strain. CONCLUSIONS: The catalytic efficiency and thermal stability of the ORCH from Labrys sp. WH-1 were the best among the reported ORCHs, and it provides an alternative catalyst for preparation of L(+)-2,3-dihydrobutanedioic acid.

Modification, Antitumor Activity, and Targeted PPARγ Study of 18ß-Glycyrrhetinic Acid, an Important Active Ingredient of Licorice.

Licorice is a traditional Chinese medicine, which is often used as sweetener and cosmetic ingredients in food and pharmaceutical industries. Among them, glycyrrhetic acid is one of the most important agents. Studies have shown that glycyrrhetic acid exhibited antitumor activities as PPARγ agonist. However, the limited number of PPARγ glycyrrhetinic agonists and their high toxicity greatly limit the design based on the structure. Therefore, clarifying the binding mode between PPARγ and small molecules, we focused on the introduction of a natural active piperazine skeleton in the position of glycyrrhetinic acid C-3. According to the Combination Principle and the Structure-Based Drug Design, 19 glycyrrhetic acid derivatives were designed and synthesized as potential PPARγ agonists. Compounds 4c and 4q were screened as high-efficiency and low-toxicity lead compounds.

Effect of quaternization degree on physiochemical and biological activities of chitosan from squid pens.

Chitosan was prepared by alkaline N-deacetylation of ß-chitin from squid pens, and N-(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride (HTCC) derivatives, with different degrees of quaternization (DQ) ranging from 0.77 to 1.06, were synthesized. It was identified by FT-IR, 1H NMR and XRD analysis. All of the HTCC showed good water solubility in a wide pH range. The moisture absorption and retention abilities of all the HTCC were much better than that of the chitosan. The moisture absorption and retention values of all the HTCC at 43% RH for 24 h were above 49% and 92%, respectively. The scavenging ability of HTCC against hydroxyl and ABTS radicals improved with increasing concentration. The effectiveness of HTCC against hydroxyl radicals was lower than that of chitosan. These results indicated that HTCC, which has a much better moisture absorption and retention capacity, may act as a potential moisturizer in vitro.

[Characteristic wavelengths analysis for remote sensing reflectance on water surface in Taihu Lake].

The research on characteristic wavelengths analysis of reflectance spectrum is a very important and basic task for remote sensing of inland-water color. The present paper analyzed remote sensing reflectances of 312 samples measured in Taihu Lake between 2006 and 2009, and these reflectances were separated into three classes by chlorophyll-a concentrations. The reflectance spectra smoothed by Savitzky-Golay algorithm were calculated by first- and second-order derivatives. Then, zero values were located in the derivatives and counted at all wavelengths. Thus the frequency distribution of zeros at each wavelength was got. At which wavelength a local maximum of the frequencies appears a characteristic wavelength will most likely be there. These characteristic wavelengths are corresponding to maximum, minimum, from-concave-to-convex inflection point and from-convex-to-concave inflection point of a spectrum curve. At last the paper provided the characteristic wavelengths for Taihu Lake water at the spectral coverage from 350 to 900 nm, which are 359, 440, 464, 472, 552, 566, 583, 628, 636, 645, 660, 676, 689, 706, 728, 791, 806, and 825 nm. In addition, these wavelengths we found were explained by absorption of phytoplankton pigments and components of water in Taihu Lake. Being able to distinguish overlaps between peaks and vales at the same wavelength in different measurements, the method to analyze characteristic wavelengths is universally applicable to various spectrum curves. The characteristic wavelengths chosen by the paper are helpful to improving some algorithms of retrieval of water quality parameters.

beta-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism.

AIM: The role of CYP1A in the protection of aristolochic acid (AA)I-induced nephrotoxicity has been suggested. In the present study we investigated the effects of beta-naphthoflavone (BNF), a non-carcinogen CYP1A inducer, on AAI-induced kidney injury. METHODS: Mice were pretreated with 80 mg/kg BNF by daily intraperitoneal injection (ip) for 3 days followed by a single ip of 10 mg/kg AAI. AAI and its major metabolites in blood, liver and kidney, the expression of CYP1A1 and CYP1A2 in microsomes of liver and kidney, as well as the nephrotoxicity were evaluated. RESULTS: BNF pretreatment prevented AAI-induced renal damage by facilitating the disposal of AAI in liver. BNF pretreatment induced the expression of CYP1A1 in both liver and kidney; but the induction of CYP1A2 was only observed in liver. CONCLUSION: BNF prevents AAI-induced kidney toxicity primarily through CYP1A induction.

The relationship between diphenylamine structure and NSAIDs-induced hepatocytes injury.

OBJECTIVE: Many nonsteroidal anti-inflammatory drugs (NSAIDs) with diphenylamine structure induce severe hepatotoxicities. We evaluated the role of diphenylamine structure in liver injuries induced by these NSAIDs. METHODS: Effects of diphenylamine, diclofenac and tolfenamic acid on mitochondrial permeability transition (MPT) and efflux of calcium in isolated liver mitochondria as well as on cellular ATP content and mitochondrial membrane depolarization in rat primary hepatocyte cultures were examined. RESULTS: Diclofenac and tolfenamic acid induced cyclosporine A (CsA)-sensitive mitochondrial swelling and membrane depolarization in isolated liver mitochondria. Only diclofenac caused the release of calcium in isolated liver mitochondria. Diphenylamine had no effects on isolated liver mitochondria. All three compounds decreased ATP content and induced mitochondrial membrane depolarization. CsA attenuated these effects, suggesting MPT might be involved in the hepatotoxicities caused by diphenylamine, diclofenac and tolfenamic acid. SKF-525A, a general inhibitor of CYP450, markedly inhibited the injury induced by diphenylamine, but not diclofenac or tolfenamic acid. CONCLUSION: The hepatotoxicities caused by diclofenac and tolfenamic acid may be attributed to the mitochondrial dysfunction induced by these drugs instead of the diphenylamine structure per se.