Discovery, synthesis and biological evaluation of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) as novel sphingomyelin synthase 1 inhibitors.

Sphingomyelin synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 µM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 µM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.

Folding-induced folding: the assembly of aromatic amide and 1,2,3-triazole hybrid helices.

Folding-induced folding for the construction of artificial hybrid helices from two different kinds of aromatic sequences is described. Linear compounds 1 a, 1 b, and 2, containing one aromatic amide trimer or pentamer and one or two aromatic 1,2,3-triazole tetramers, have been designed and synthesized. The trimeric and pentameric amide segments are driven by intramolecluar N-H⋅⋅⋅F hydrogen bonding to adopt a folded or helical conformation, whereas the triazole segment is intrinsically disordered. In organic solvents of low polarity, the amide foldamer segment induces the attached triazole segment(s) to fold through intramolecular stacking, leading to the formation of hybrid helices. The helical conformation of these hybrid sequences has been confirmed by (1)H and (19)F NMR spectroscopy, UV/Vis spectroscopy, circular dichroism (CD) experiments, and theoretical calculations. It was found that the amide pentamer exhibits a stronger ability to induce the folding of the attached triazole segment(s) compared with that of the shorter trimer. Enantiomers (R)-3 and (S)-3, which contain an R- or S-(1-naphthyl)ethylamino group at the end of a tetraamide segment, have also been synthesized. CD experiments showed that introduction of a chiral group caused the whole framework to produce a strong helicity bias. Density-functional-theory calculations on (S)-3 suggested that this compound exists as a right-handed (P) helix.

The Role of Chronic Inflammation in Various Diseases and Anti-inflammatory Therapies Containing Natural Products.

Chronic inflammation represents a long-term reaction of the body's immune system to noxious stimuli. Such a sustained inflammatory response sometimes results in lasting damage to healthy tissues and organs. In fact, chronic inflammation is implicated in the development and progression of various diseases, including cardiovascular diseases, respiratory diseases, metabolic diseases, neurodegenerative diseases, and even cancers. Targeting nonresolving inflammation thus provides new opportunities for treating relevant diseases. In this review, we will go over several chronic inflammation-associated diseases first with emphasis on the role of inflammation in their pathogenesis. Then, we will summarize a number of natural products that exhibit therapeutic effects against those diseases by acting on different markers in the inflammatory response. We envision that natural products will remain a rich resource for the discovery of new drugs treating diseases associated with chronic inflammation.

Foldamer organogels: a circular dichroism study of glucose-mediated dynamic helicity induction and amplification.

This paper reports a systematic study of the dynamic process for the self-assembly of chiral organogels from achiral hydrogen bonded hydrazide foldamers by induction of chiral glucose. Six foldamers incorporated with six decyl chains and two benzene, naphthalene, anthracene, or pyrene units at the ends are revealed to strongly gelate apolar and polar solvents, including alkanes, arenes, esters, alcohols, and 1,4-dioxane. The gels are characterized by UV-vis, fluorescent, XRD, SEM, and AFM methods, based on which a dislocated "tail-to-tail" stacking pattern is proposed. Addition of octylated glucose considerably enhances the capacity of the foldamers to gelate apolar solvents due to strong complexation. The complexation also causes unique dynamic helicity induction in the gels, which is studied systematically by circular dichroism. The results are treated with the Avrami theory according to a reported method (J. Am. Chem. Soc. 2005, 127, 4336), which suggests that the gelation involves a nucleation-elongation mechanism. In addition, the "Sergeants and Soldiers" effect in the gel phase is also revealed.

Diastereomeric recognition of chiral foldamer receptors for chiral glucoses.

[reaction: see text] Three chiral aromatic hydrazide foldamers have been designed and synthesized, in which two R- or S-proline units were incorporated at the terminals of their backbones. The 1H NMR, circular dichroism (CD), and fluorescent experiments and molecular dynamics simulations revealed that the foldamers adopted a chiral helical conformation and complexed alkylated glucoses in chloroform with a good diastereomeric selectivity.

Temperature-Responsive Chiral (A)6B Supramolecular Cages Based on Conformational Preferences.

Two chiral (A)6B-typed supramolecular cages were constructed from hydrogen-bonded C6 -symmetric zinc porphyrin hexamers and chiral C3-symmetric pyridyl hexadentates with a core of 1,3,5-triphenylbenzene. Circular dichroism and molecular simulations revealed that the symmetry of the supramolecular cages switched from pseudo-C3v to C3 with the rotational confinement of the biphenyl backbones at low temperatures, which generated conformationally chiral transfer and amplification. This unique phenomenon suggests a new strategy to develop smart materials with high sensitivity and excellent reversibility.

[Fine localization of rice EUI1 gene controlling elongation of the uppermost internode].

The height of rice is one of the important agricultural traits, which affects on the rice architecture and production directly. The investigation of the length of the uppermost internode showed that the elongation mutation of the first internode is controlled by a recessive nuclear locus. The gene is localized between the STS marker of E30531 and the CAPS marker of C903 on the long arm of chromosome 5, apart from 6.7 cM and 2.8 cM respectively. The fine localization maps the gene between 0.3 cM flanks, which will help clone this gene and study the mechanism of the gene function.