Design and Synthesis of Thiourea-Conjugating Organic Arsenic D-Glucose with Anticancer Activities.

Organic arsenic compounds such as p-aminophenylarsine oxide (p-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic properties, therapeutic efficacy, and target selectivity. In order to strengthen the selectivity of 4-(1,3,2-dithiarsinan-2-yl) aniline 7 to tumor cell, a thiourea moiety was used to strengthen the anticancer activity. To avoid forming a mixture of α/ß anomers, the strategy of 2-acetyl's neighboring group participation was used to lock the configuration of 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate from 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide. 1-(4-(1,3,2-dithiarsinan-2-yl) aniline)-2-N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranos-1-yl)-thiourea 2 can increase the selectivity of human colon cancer cells HCT-116 (0.82 ± 0.06 µM vs. 1.82 ± 0.07 µM) to human embryonic kidney 293T cells (1.38 ± 0.01 µM vs. 1.22 ± 0.06 µM) from 0.67 to 1.68, suggesting a feasible approach to improve the therapeutic index of arsenic-containing compounds as chemotherapeutic agents.

A Novel Imidazolinone Derivative with 5-Arylidene and 2-Substituted Mercapto Group as Potent Anti-Hepatitis C Virus Compound.

Here six novel imidazolinone derivatives have been synthesized and the compound 4b containing 5-para-methoxy-phenylidene and 2-thioalkylation terminal substitution with 3'-cyano-2',6'-dimethylphenyl showed the best anti-HCV activity and the lowest cytotoxicity. Selectivity index (SI=CC50 /IC50 ) for the 4b was determined as 36, indicating that compound 4b was highly selective towards HCV.

Nd(III)-induced rice mitochondrial dysfunction investigated by spectroscopic and microscopic methods.

The production capacity and yield of neodymium (Nd) in China have ranked the first in the world. Because of its unique biophysical and biochemical properties, Nd compounds have entered into the agricultural environment greatly to promote plant growth. Mitochondria play a crucial role in respiration and metabolism during the growth of plants. However, little is known about the mechanism by which Nd act at the mitochondrial level in plant cells. In this study, rice mitochondrial swelling, collapsed transmembrane potential and decreased membrane fluidity were examined to be important factors for mitochondria permeability transition pore (mPTP) opening induced by Nd(III). The protection of cyclosporin A (CsA) and dithiothreitol (DTT) could confirm that Nd(III) could trigger mPTP opening. Additionally, mitochondrial membrane breakdown observed by TEM and the release of cytochrome c (Cyt c) could also elucidate the mPTP opening from another point of view. At last, the study showed that Nd(III) could restrain the mitochondrial membrane lipid peroxide, so it might interact with anionic lipid too. This detection will be conductive to the safe application of Nd compounds in agriculture and food industry.

Method for the extraction of circulating nucleic acids based on MOF reveals cell-free RNA signatures in liver cancer.

Cell-free RNA (cfRNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cfRNA isolation technologies due to the low abundance and instability of cfRNA. Here, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids (containing cfRNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework (MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cfRNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cfRNA in serum from patients with liver cancer was described and a cfRNA signature with six cfRNAs was identified to diagnose liver cancer with high diagnostic efficiency (area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer.

A novel and photostable pH probe for selectively staining nuclei in living cells.

A novel pH probe based on hemi-cyanine was synthesized, which displays extremely large Stokes shift (122 nm) and good photostability. The probe responds to basic pH (pKa 8.32) with a colorimetric and fluorescence turn-on signal. Interestingly, the probe has good cell membrane permeability and could selectively stain nuclei in living cells.

Total synthesis of landomycin A, a potent antitumor angucycline antibiotic.

The first total synthesis of landomycin A, the longest and most potent antitumor angucycline antibiotic, has been achieved in 63 steps and 0.34% overall yield starting from 2,5-dihydroxybenzoic acid, 3,5-dimethylphenol, triacetyl d-glucal, and d-xylose, with a convergent linear sequence of 21 steps.

Synthesis and pharmacological characterization of glucopyranosyl-conjugated benzyl derivatives as novel selective cytotoxic agents against colon cancer.

Glucopyranosyl-conjugated benzyl derivatives containing a [1,2,3]-triazole linker were synthesized. Benzyl served as an important pharmacophore in anti-cancer compounds. Compound 8d inhibited the proliferation of colorectal cancer cells with the potency comparable to 5-fluorouracil (5-FU) with improved selectivity towards cancer cells. The antiproliferative activity of 8d is achieved through triggering apoptotic cell death.

Chitosan quaternary ammonium salt induced mitochondrial membrane permeability transition pore opening study in a spectroscopic perspective.

Chitosan is non-toxic, biodegradable and biocompatible. However, it is insoluble in water, which limits its applications in biomedical areas. Hydroxypropyltrimethyl ammonium chloride chitosan (HACC), a chitosan derivative, can be dissolved in physiological condition and has been widely used in the field of biomedicine and bioengineering. The biological effect of HACC has been extensively studied. However, it is rarely investigated at the subcellular level. To study the biological effect of HACC, mitochondria, energy-producing organelles in eukaryotes, were chosen as a model. The investigation mainly focused on the changes of mitochondrial membrane property in the presence of HACC. Results showed that HACC can induce the collapse of mitochondrial transmembrane potential (∆Ψm), the increase in mitochondrial membrane swelling and the decrease of mitochondrial membrane fluidity, demonstrating that mitochondrial membrane permeability transition pore (mPTP) opening happened. Possible mechanism of mPTP opening investigation indicated that it was occurred in a typical model. In addition, HACC can induce the release of cytochrome C (Cyt c) and affect the respiratory activity of mitochondria. The study will provide a lot of important information on biosafety evaluation of HACC.

Cationic porphyrins and analogues as new DNA topoisomerase I and II inhibitors.

A series of cationic porphyrins, and analogues such as cationic corroles and phthalocyanines were found to have biological activities towards topoisomerases I and II in vitro. Cationic porphyrins and phthalocyanines do not induce Topo I-DNA covalent complexes but inhibit topoisomerase I by direct binding to DNA, which limits topoisomerase I access to the DNA substrate. The lowest concentration where an inhibition effect is clearly visible of some derivatives is between 0.1 and 0.6 microM. Furthermore, some complexes were found to inhibit the activity of the topoisomerase II.

Microcalorimetric and microscopic studies of the effect of chitosan quaternary ammonium salt on mitochondria.

Chitosan quaternary ammonium salt (HACC) has been regarded as an effective biomedical carrier with good application because of its good water-solubility, high cationic potential and strong cell adhesion. Mitochondria are important organelle involved in ATP production and are the center of energy metabolism. In this work, we firstly investigated the effect of HACC on the thermogenic curve of isolated mitochondrial metabolism by microcalorimetry. The results showed that different concentration of HACC had great influence on the mitochondrial energy metabolism. Specifically, low level of HACC stimulated the metabolic activity of mitochondria and the inhibition was found with high concentration of HACC. Then, the effect of HACC on mitochondrial respiratory chain was studied, which was consistent with the results of microcalorimetry. Finally, the alteration of mitochondrial structure induced by HACC was observed and it showed that the membrane of mitochondria was dramatically damaged. These new findings can help us deeply understand the influence and action mechanism of HACC in the metabolic process and provide theoretical and practical foundation for the biosafety of HACC as a medical carrier.

Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators.

Introduction and Objective: Org27569 is a prototypical allosteric modulator of the cannabinoid receptor 1 (CB1). It belongs to the indole-2-carboxamide scaffold and has been intensively investigated in pharmacology and in structure-activity relationship (SAR) studies. Although azaindoles are rare in natural products and differ only by the presence of an extra ring nitrogen, they were demonstrated as valuable bioisosteres in many pharmacologically important molecules. To extend the SAR investigation of the indole-2-carboxamide class of CB1 allosteric modulators, azaindole (pyrrolopyridine) rings were used to replace the indole ring of Org27569 analogs to explore the potential of azaindole-2-carboxamides as CB1 allosteric modulators. Using 6- and 7-azaindole in lieu of the indole moiety within this class of CB1 allosteric modulators indeed improved the aqueous solubility. Materials and Methods: We synthesized 6- and 7-azaindole-2-carboxamides and their indole-2-carboxamide counterparts. The molecules were evaluated by [3H]CP55,940 binding and [35S]GTPγS binding assays for their allosteric modulation of the CB1 receptor. Results: The 7-azaindole-2-carboxamides lost the ability to bind to the CB1 receptor. The 6-azaindole-2-carboxamides (e.g., 3c and 3d) showed markedly reduced binding affinities to the CB1 receptor in comparison with their indole-2-carboxamide counterparts. However, they behaved similarly as indole-2-carboxamides in potentiating the orthosteric agonist binding and inhibiting the orthosteric agonist-induced G-protein coupling. The results indicated that some azaindole scaffolds (e.g., 6-azaindole) are worth further exploration, whereas the 7-azaindole ring is not a viable bioisostere of the indole ring in the Org27569 class of CB1 allosteric modulators.

Physical, antibacterial and antioxidant properties of chitosan films containing hardleaf oatchestnut starch and Litsea cubeba oil.

More and more attention was attached to food safety, it is necessary to endow food packaging films with good antibacterial and antioxidant properties Edible films based on chitosan (CH), hardleaf oatchestnut starch (HOS) and Litsea cubeba oil (LEO) were prepared by solution casting. The properties and structures of the blend film with different proportion (xCH/yHOS) were evaluated. The CH-HOS films were firstly prepared by blending CH solution with HOS paste. The tensile strength (TS) and DPPH radical scavenging ability of CH-HOS films increased from 27.33 MPa to 33.54 MPa and 20.67% to 52.34%, respectively, and water vapor permeability (WVP) decreased from 1.531 × 10-11 g m-1 pa-1 s-1 to 1.491 × 10-11 g m-1 pa-1 s-1, with the HOS content increased from the ratio of 1:0 to 1:1. Then, the LEO was added to 1CH-1HOS films. Tensile strength (TS), water vapor permeability, moisture absorption and total soluble matter (TSM) of the 1CH-1HOS film were remarkably decreased with 16%LEO. Meanwhile, the static contact angle and antimicrobial activity of 1CH-1HOS-16LEO film increased significantly. Hence, this blend film system has great potential for food packaging in the future.

Carbohydrate-conjugated 4-(1,3,2-dithiarsolan-2-yl)aniline as a cytotoxic agent against colorectal cancer.

Arsenic trioxide (As2O3) has been approved for the treatment of acute promyelocytic leukemia (APL); however, its use in the treatment of solid tumors is limited due to its pharmacokinetic properties. Organic arsenic compounds provide better options for pharmaceutical optimization. p-Aminophenyl arsenoxide (p-APAO), an organic arsenic compound, was found to interact with the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion protein in a similar manner to arsenic trioxide. Analogs of p-APAO such as 4-(1,3,2-dithiarsolan-2-yl)aniline (p-APDTAs) were recently found to show improved cytotoxicity toward several solid tumor cell lines with lower toxicity to normal cells. Here, we synthesized a carbohydrate-conjugated 4-(1,3,2-dithiarsolan-2-yl)aniline (p-APDTAs) and showed that it exhibited reduced cytotoxicity to normal cells, suggesting a feasible approach to improve the therapeutic index of arsenic-containing compounds as chemotherapeutic agents.

Chitosan combined with swimming promotes health in rats.

PURPOSE: Chitosan is an easily accessible and biocompatible natural molecule which facilitate the immune system. In recent studies, chitosan is being applied to the drug nanosphere to deliver drugs. However, whether chitosan could promote health under exercising condition remains yet to be elucidated. Hence, we designed to investigate the effect of chitosan on swimming rats. METHODS: Sprague-Dawley (SD) rats were divided into four groups, exercise with chitosan, exercise with water, sedentary with chitosan, and sedentary with water. After four weeks of exercise and chitosan/water gavage, the blood was collected, and its biochemical index, complete blood count, and related parameters, and cytokines were detected and analyzed. RESULTS: The level of blood urea nitrogen (p = 0.0380), total cholesterol (p = 0.048), and low-density lipoprotein (p = 0.0338) were decreased, while the number of red blood cells (p = 0.001), hematocrit (p = 0.01), and mean corpuscular volume (p = 0.039) were increased in chitosan group. Furthermore, the combination of chitosan and swimming decreased the red blood cells distribution width. CONCLUSIONS: Our study support that chitosan could facilitate the health during exercise.

Cationic corrole derivatives: a new family of G-quadruplex inducing and stabilizing ligands.

Water-soluble cationic corrole derivatives were designed and synthesized, and the first observation of their interactions with the telomeric G-quadruplex was made.

Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB1.

The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB1 antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB1 ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring. These positively modulate the binding of the CB1 orthosteric agonist CP55,940 while exhibiting an antagonism of G-protein coupling activity. Interestingly, compounds 7d and 8d demonstrated ERK1/2 phosphorylation mediated via ß-arrestin unlike the orthosteric CP55,940 that does so in a G protein-dependent manner. These can serve as new lead compounds for the future development of CB1 allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.

Operationally simple hydrotrifluoromethylation of alkenes with sodium triflinate enabled by Ir photoredox catalysis.

We report herein a single component Ir photoredox catalyst which is capable of catalyzing the hydrotrifluoromethylation of terminal alkenes and Michael acceptors with sodium triflinate (Langlois reagent) in methanol under irradiation at room temperature. Various synthetically useful functional groups, including ester, amide, ether, aldehyde, sulfone, ketone and aryl boronate, are well tolerated in this reaction.

A twisted intramolecular charge transfer probe for rapid and specific detection of trace biological SO2 derivatives and bio-imaging applications.

We reported a reactive probe for HSO3(-), which showed a colorimetric and ratiometric fluorescence response to HSO3(-) with fast response (t1/2 = 20 s), good specificity and low detection limit (3.0 nM). The probe was cell membrane permeable and successfully used for visualizing trace SO2 derivatives in living cells.

Effect of orally administered hydroxypropyl chitosan on the levels of iron, copper, zinc and calcium in mice.

Two hydroxypropyl chitosan HPCS samples (HPCS1 Mw 1.6 × 10(5), HPCS2 Mw 3.5 × 10(4)) were prepared by the reaction of chitosan with propylene oxide under alkali conditions. The median lethal dose of the hydroxypropyl chitosan was greater than 10 g/kg for the laboratory mice. HPCS1 at the 0.1%, 1.0%, 1.5% and HPCS2 at the 1.0% level in diets were used to feed the mice for 90 days respectively. No pathological symptoms, clinical signs or deaths were observed for all mice. The weights of the mice in HPCS groups and control group had no significant difference. The levels of Fe, Cu, Zn and Ca in the mice were measured by atomic absorption spectrophotometry. HPCS had no significant effect on the levels of Fe, Cu, Zn and Ca in the tested mice's livers and hearts. However, hydroxypropyl chitosan at high dose exhibited inhibitory effects on the levels of Fe, Zn and Ca in some organizations.

Cationic metal-corrole complexes: design, synthesis, and properties of guanine-quadruplex stabilizers.

A series of pyridinium and quaternary ammonium copper corroles has been designed and synthesized. All new compounds have been fully characterized by NMR spectroscopy, high-resolution mass spectrometry, UV/Vis spectrscopy, and elemental analysis. Biochemical studies have indicated that all of these corrole derivatives can stabilize G-quadruplex structures, with corrole 4 being the most effective according to the results of circular dichroism (CD) melting experiments, polymerase chain reaction (PCR) stop assays, and surface plasmon resonance (SPR) experiments. Moreover, both corroles 3 and 4 tend to induce the human telomeric sequence to form hybrid G-quadruplex structures, whereas corroles 8 and 9 are more inclined to induce the human telomeric sequence to form antiparallel G-quadruplex structures.