Natural aromatic compounds as scaffolds to develop selective G-quadruplex ligands. From previously reported berberine derivatives to new palmatine analogues

In this paper, the selective interactions of synthetic derivatives of two natural compounds, berberine and palmatine,with DNA G-quadruplex structureswere reported. In particular, the previous works on this subject concerning berberine were further presented and discussed, whereas the results concerning palmatine are presented here for the first time. In detail, these palmatine derivatives were developed by inserting seven different small peptide basic chains, giving several new compounds that have never been reported before. The preliminary studies of the interactions of these compounds with various G-quadruplex-forming sequences were carried out by means of various structural and biochemical techniques, which showed that the presence of suitable side chains is very useful for improving the interaction of the ligands with G-quadruplex structures. Thus, these new palmatine derivatives might act as potential anticancer drugs

Mitotic Illegitimate Recombination Is a Mechanism for Novel Changes in High-Molecular-Weight Glutenin Subunits in Wheat-Rye Hybrids

Wide hybrids can have novel traits or changed expression of a quantitative trait that their parents do not have. These phenomena have long been noticed, yet the mechanisms are poorly understood. High-molecular-weight glutenin subunits (HMW-GS) are seed storage proteins encoded by Glu-1 genes that only express in endosperm in wheat and its related species. Novel HMW-GS compositions have been observed in their hybrids. This research elucidated the molecular mechanisms by investigating the causative factors of novel HMW-GS changes in wheat-rye hybrids. HMW-GS compositions in the endosperm and their coding sequences in the leaves of F1 and F2 hybrids between wheat landrace Shinchunaga and rye landrace Qinling were investigated. Missing and/or additional novel HMW-GSs were observed in the endosperm of 0.5% of the 2078 F1 and 22% of 36 F2 hybrid seeds. The wildtype Glu-1Ax null allele was found to have 42 types of short repeat sequences of 3-60 bp long that appeared 2 to 100 times. It also has an in-frame stop codon in the central repetitive region. Analyzing cloned allele sequences of HMW-GS coding gene Glu-1 revealed that deletions involving the in-frame stop codon had happened, resulting in novel ∼1.8-kb Glu-1Ax alleles in some F1 and F2 plants. The cloned mutant Glu-1Ax alleles were expressed in Escherichia coli, and the HMW-GSs produced matched the novel HMW-GSs found in the hybrids. The differential changes between the endosperm and the plant of the same hybrids and the data of E. coli expression of the cloned deletion alleles both suggested that mitotic illegitimate recombination between two copies of a short repeat sequence had resulted in the deletions and thus the changed HMW-GS compositions. Our experiments have provided the first direct evidence to show that mitotic illegitimate recombination is a mechanism that produces novel phenotypes in wide hybrids

Selecting Diversified Compounds to Build a Tangible Library for Biological and Biochemical Assays

The quality of diverse compound selection mainly depends on cluster algorithms, descriptors, the combinations of the descriptors, and similarity metrics. The Jarvis-Patrick algorithm, MDL search keys, and Daylight fingerprints are a well accepted algorithm and structure descriptors for compound library diversity analysis. Based upon our 288 experiments on selecting compounds from various descriptor combinations, we have found (1) hybrid Daylight and MDL structural descriptors for diversity analyses can produce worse results; (2) selections based purely on 2,048-bit Daylight fingerprints yield better results than the ones based purely on MDL 166-bit search keys; (3) when Daylight fingerprints and MDL search keys are combined, it is better to compute the similarities independently, then to take the smaller value for the outcome. This will yield better average separation of clusters; (4) regarding the consistency of different clustering approaches, the Daylight fingerprints based clustering is more consistent with the SCA approach than it does with the MDL search keys based approach; (5) The MDL search keys based selection approach tends to select a greater number of compounds from larger clusters. As the Daylight fingerprint is folded two and three times, respectively, information is lost, and this approach tends to select a greater number of compounds from larger clusters as well. These results have not been reported before to our knowledge

Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity

Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models. Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC50 of SA for inhibition of AR activity was 213.17 μg/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3. Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC

3,5-Diarylpyrazole Derivatives Obtained by Ammonolysis of the Total Flavonoids from <i>Chrysanthemum indicum</i> Extract Show Potential for the Treatment of Alzheimer’s Disease

Four new 3,5-diarylpyrazole analogues (<b>1</b>–<b>4</b>) were isolated from an extract of the flowers of <i>Chrysanthemun indicum</i> using a combination of ammonolysis of the total flavonoid extract and an Aβ aggregation inhibitory activity guided purification procedure. All four compounds (<b>1</b>–<b>4</b>) showed moderate to potent activity against Aβ aggregation with EC₅₀ values of 4.3, 15.8, 1.3, and 2.9 μM, respectively. Moreover, compound <b>3</b> showed low cytotoxicity and significant neuroprotective activity against Aβ<i>-</i>induced cytotoxicity in the SH-SY5Y cell line. This report is the first to show that 3,5-diarylpyrazole analogues can inhibit Aβ aggregation and exhibit neuroprotective activity with potential for the treatment of Alzheimer’s disease. Taken together, the method presented here offers an alternative approach to yield bioactive compounds