Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC₅₀ of 0.88?µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH₃O group or CF₃O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.     

Studies on interactions of carbazole derivatives with DNA,cell image,and cytotoxicity

DNA-binding agents have been considered as an established opportunity for the development of anticancer drugs and DNA fluorescence probes. This work reported the synthesis of two novel carbazole derivatives (1 and 2) and investigated their DNA binding properties, living cell image, and cytotoxicity. The results demonstrated that both compounds presented the higher binding affinity to G-quadruplex than to duplex DNA by means of UV–Vis absorption titration and fluorescent intercalator displacement. Continuous variation analysis indicated that their binding stoichiometries of the compound/G-quadruplex were near 2 except the compound/bcl-2. Circular dichroism spectra showed that both compounds had no influence on the conformation of G-quadruplexes. Fluorescence titrations indicated that 2 had the potential to be a G-quadruplex selective fluorescent probe, while 1 could be used as a fluorescent probe for duplex DNA. Confocal fluorescence images indicated that both compounds could enter the living HepG2 cells, and 1 mainly located in nucleus whereas 2 mainly distributed in cytoplasm. DNase and RNase digest tests indicated that both compounds could enter into the nucleus and interact with duplex DNA, especially, 2 could interact with RNA and/or G-quadruplex DNA. They also exhibited an obvious antiproliferative activity to HepG2 by using MTT assays, with IC₅₀ values of 2.7 and 9.5?μM for 1 and 2, respectively.     

Isolation and Biological Activity of a Peptidal Antibiotic P168

The structure of the xyloglucan synthesised in vitro by the particulate fraction of suspension-cultured soybean (Glycine max) cells from UDP-glucose and UDP-xylose is mainly composed of two kinds of oligosaccharide-building blocks, a heptasaccharide unit and a pentassaccharide unit [T. Hayashi and K. Matsuda, J. Biol Chem., 256, 11117 (1981)]. The synthesis of the pentasaccharide unit is probably the first step in the construction of oligosaccharide building blocks to elongate the ²-1,4-glucan backbone. This enzymatically synthesized xyloglucan was shown to have the same molecular size (M_w, 180,000) as the xyloglucan prepared from soybean cell walls by gel filtration on a Sepharose CL-6B column, and the same building blocks distributed among each fraction. A pulse-chase experiment indicated that the pentasaccharide unit was converted into the heptasaccharide unit. The conversion was regulated by the concentration of UDP-xylose.     

Neue phloroglucin-derivate aus Leontonyx-arten sowie weitere verbindungen aus vertretern der tribus inuleae

The investigation of several South African species of the tribe Inuleae afforded in addition to known compounds 16 new constituents. From Leontonyx a group of 9 new phloroglucinol derivatives, from Stoebe species two new p-hydroxyacetophenone, two thymol and two coumaric acid derivatives and from Relhania a new euparine-derivative were isolated. The structures are elucidated mainly by spectroscopic methods. The chemotaxonomic aspects are discussed briefly. The phloroglucinol derivatives, which in part are derived from geraniol, seem to be especially characteristic.     

Modification of the B-ring during flavonoid synthesis in Petunia hybrida: Effect of the hydroxylation gene Hf1 on dihydroflavonol intermediates

The white flowering mutant W48 of Petunia hybrida is dominant for the hydroxylation gene Hf1 and homozygous recessive for the hydroxylation gene Ht1 and the anthocyanin gene An1. Flower buds of this mutant accumulate dihydrokaempferol-glucosides. Thus the effect of Hf1 being dominant is not the hydroxylation of the C15 skeleton, as is the case in mutants that are able to synthesize anthocyanins. This can be explained either by a feed-back inhibition of the hydroxylation by small amounts of dihydromyricetin (glucosides), or by a controlling effect of the gene An1 on the expression of Hf1. However, the white flowering mutant W58, which is homozygous recessive for the gene An6 and dominant for Hf1, accumulates dihydromyricetin (glucosides). This excludes a possible feed-back inhibition by dihydromyricetin and we conclude that An1 controls the expression of Hf1. Feeding of radioactive malonic acid to isolated flower limbs of mutants able to synthesize anthocyanins, leads to the incorporation of radioactivity into dihydrokaempferol (glucosides) and dihydroquercetin (glucosides). These results show that glucosylation of dihydroflavonols is a normal event in anthocyanin biosynthesis and is not induced by an inhibition of anthocyanin synthesis.     

Synthesis and evaluation of 4-hydroxyl aurone derivatives as multifunctional agents for the treatment of Alzheimer’s disease

A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu²⁺-induced Aβ_1–42 aggregation with 99.2% and 84.0% at 25 μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC₅₀ values of 0.271 μM and 0.393 μM, respectively. However the 6-methoxyl aurones 15a–c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood–brain barrier (BBB) permeabilities in vitro.     

Synthesis and carbonic anhydrase inhibitory properties of amino acid – coumarin/quinolinone conjugates incorporating glycine,alanine and phenylalanine moieties

N-Protected amino acids (Gly, Ala and Phe) were reacted with amino substituted coumarin and quinolinone derivatives, leading to the corresponding N-protected amino acid–coumarin/quinolinone conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against various human (h) isoforms, such as hCA I, hCA II, hCA IV and hCA XII. The quinolinone conjugates were inactive as enzyme inhibitors, whereas the coumarins were ineffective hCA I/II inhibitors (K_Is?>?50?μM) but were submicromolar hCA IV and XII inhibitors, with inhibition constants ranging between 92?nM and 1.19?μM for hCA IV, and between 0.11 and 0.79?μM for hCA XII. These coumarin derivatives, as many others reported earlier, thus show an interesting selective inhibitory profile for the membrane-bound over the cytosolic CA isoforms.     

Discovery and SAR of a novel series of Natriuretic Peptide Receptor-A (NPR-A) agonists

Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC₅₀ value of 0.073 μM, indicating 350-fold potency compared to the hit compound 3.     

Effects of lanthanum on rumen fermentation, urinary excretion of purine derivatives and digestibility in steers

The objective of this study was to evaluate the effects of LaCl₃ supplementation on rumen fermentation, urinary excretion of purine derivatives and feed digestibility in the total tract of steers. Eight ruminally cannulated Simmental steers (420 ± 20 kg) were used in a replicated 4 × 4 Latin square experiment. The treatments were control (without LaCl₃); La-low; La-medium and La-high with 450, 900 and 1800 mg LaCl₃ per steer per day, respectively. Diet consisted of 600 g/kg corn stover and 400 g/kg concentrate (dry matter [DM] basis). Dry matter intake (averaged 9 kg/day) was restricted to a maximum of 90% of ad libitum intake. Ruminal pH (range of 6.59–6.42) was quadratically (P<0.04) changed, whereas total volatile fatty acids (VFA) concentration (range of 74.16–88.61 mM) was linearly (P<0.01) and quadratically (P<0.01) increased with increasing La supplementation. Ratio of acetate to propionate decreased linearly (P<0.01) from 3.28 to 1.79 as La supplementation increased due to the increased in propionate production. In situ ruminal neutral detergent fibre (aNDF) degradation of corn stover was improved but the crude protein (CP) degradability of soybean meal was decreased with increasing La supplementation. Urinary excretion of purine derivatives was quadratically (P<0.01) changed with altering La supplementation (75.5, 81.0, 82.4 and 70.6 mmol/day for control, low-, medium- and high-LaCl₃ supplementation, respectively). Similarly, digestibilities of organic matter, aNDF and CP in the total tract were also linearly and quadratically increased with increasing La supplementation. The present results indicate that supplementation of diet with LaCl₃ improved rumen fermentation and feed digestion in beef cattle. It was suggested that the La stimulated the digestive microorganisms or enzymes in a dose-dependent manner. In the experimental conditions of this trial, the optimum La dose was about 900 mg LaCl₃ per steer per day.     

Two new flavonoids from Derris laxiflora Benth

Two new compounds, derriscoumaronochromone (1) and cis-3,4′-dihydroxy- 5,7-dimethoxyflavan (2), as well as trans-4'-O-methylcatechin (3) were isolated from Derris laxiflora, The structures of these compounds were determined by analysis of their spectroscopic data.