Discovery of Quinic Acid Derivatives as Oral Anti-inflammatory Agents

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-κB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative 3 being the most potent. Compound 3 was named as KZ-41. The NF-kB inhibitory potency (IC50) of our most active analog KZ-41 was determined to be 2.83±1.76 mM. Further examination of the structure and activity relationship (SAR) demonstrated that acetylation of the hydroxyl groups reduced NF-κB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 mM. The dehydroxyl QA amides 18 and 20 were synthesized to retain anti-inflammatory activity while having enhanced resistance to microbial degradation. They showed NF-kB inhibition at concentration 1 mM. The extent of NF-kB inhibition was close to positive control drug dexamethasone. The dehydroxyl QA amide with a double bond 38 was also synthesized. The QA amide esters 24, 25, 29 and 33 were designed and synthesized to retain anti-inflammatory activity with additional antioxidant properties. As expected, compound 25 showed strong anti-oxidant activity. Furthermore, they were hydrolyzed by the microflora, for an example, 25 was hydrolyzed into sinapic acid (SA) and 3. Both SA and 3 will not be consumed by gut bacteria, and are easily absorbed in animal digestive tract. This was done by other researchers, and not reported here. To facilitate pre-clinical biopharmaceutic and pharmacokinetic (B/PK) studies of our lead QA amide analog KZ-41, we developed and validated a novel hydrophilic interaction liquid chromatography–tandem mass spectrometry (HILIC-MS/MS) analytical assay. An analog of KZ-41 was used as internal standard (IS). KZ-41 and the IS were obtained by protein precipitation and separated by HILIC chromatography using acetonitrile and water. A triple quadrupole mass spectrometer operating in the negative electrospray ionization mode with multiple reaction monitoring was used to detect KZ-41 and IS transitions of m/z 232 → 178 and 272 → 218 respectively. The lower limit of quantification (LLOQ) was 0.5 ng/mL in plasma. The method was validated for selectivity, linearity, accuracy and precision in rat plasma. The ion suppression, recovery and stability of the analyte in the biological matrix were also tested. The assay developed is rapid, sensitive and robust enough to support preclinical B/PK studies of KZ-41. The study was also conducted to characterize the biopharmaceutics and pre-clinical pharmacokinetics of the lead QA amide analog, KZ-41. Rats (n=6/group) received a dose of either an i.v. or p.o. dose (10 mg/kg) of KZ-41. Pharmacokinetic parameters were determined from concentration - time profiles by non-compartmental analysis. Bacterial stability study was conducted in cultured bacterial gluconobacter oxydans. Plasma protein binding and metabolic stability were determined using equilibrium dialysis and rat liver microsomes respectively. Following i.v. administration, KZ-41 demonstrated a medium clearance (15.1±4.8 mL/min/kg), medium volume of distribution (3.3±1.1 L/kg), and a terminal half-life of 2.6±0.4 hrs. KZ-41 was rapidly absorbed with complete oral bioavailability (F≈1), which was consistent with the fact that KZ-41 was not susceptible to degradation in bacterial and liver microsomal studies. KZ-41 binding to plasma proteins was about 30%. These studies demonstrate that KZ-41 is a potential new orally active anti-inflammatory agent. In summary, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-κB. The NF-kB inhibitory potency (IC50) of our most active analog KZ-41 was determined as 2.83±1.76 mM. It was rapidly absorbed with complete oral bioavailability (F≈1). It could be a potential new orally active anti-inflammatory agent. Mechanistic studies and pre-clinical efficacy studies of these newly designed compounds in various in vitro and in vivo models are on-going by other researchers, and are not reported in this dissertation

Corrosion Types of Magnesium Alloys

Magnesium (Mg) alloys are susceptible to corrosion in aggressive environments. Corrosion of Mg alloys depends greatly on their composition and microstructure (grain size, the size, shape and distribution of second phases), post-processing and media. In most cases, localized corrosion, such as pitting corrosion and filiform corrosion, generally occurs due to microgalvanic corrosion between the intermetallic compounds and their neighboring α-Mg matrix. However, open literature reported that several corrosion morphologies, that is, intergranular corrosion (IGC) and exfoliation corrosion (EFC), cannot appear on Mg alloys. In this chapter, all typical corrosion modes of Mg alloys and influencing factors are introduced, including general corrosion, galvanic corrosion, pitting corrosion, filiform corrosion, IGC, EFC, stress corrosion cracking (SCC), corrosion fatigue (CF) and so on. The focus is laid on pitting corrosion and EFC. Corrosion mechanisms of Mg alloys are also discussed

Low compressible noble metal carbides with rock-salt structure: ab initio total energy calculations of the elastic stability

We have systematically studied the mechanical stability of all noble metal carbides with the rock-salt structure by calculating their elastic constants within the density function theory scheme. It was found that only four carbides (RuC, PdC, AgC and PtC) are mechanically stable. In particular, we have shown that RuC, PdC, and PtC have very high bulk modulus, which has been remarkably observed by the most recent experiment for the case of PtC. From the calculated density of states, we can conclude that these compounds are metallic, like the conventional group IV and group V transition metal carbides.Comment: Appl. Phys. Lett. 89, 071913 (2006

Recent progress on cellulose‐based ionic compounds for biomaterials

Glycans play important roles in all major kingdoms of organisms, such as archea, bacteria, fungi, plants, and animals. Cellulose, the most abundant polysaccharide on the Earth, plays a predominant role for mechanical stability in plants, and finds a plethora of applications by humans. Beyond traditional use, biomedical application of cellulose becomes feasible with advances of soluble cellulose derivatives with diverse functional moieties along the backbone and modified nanocellulose with versatile functional groups on the surface due to the native features of cellulose as both cellulose chains and supramolecular ordered domains as extractable nanocellulose. With the focus on ionic cellulose‐based compounds involving both these groups primarily for biomedical applications, a brief introduction about glycoscience and especially native biologically active glycosaminoglycans with specific biomedical application areas on humans is given, which inspires further development of bioactive compounds from glycans. Then, both polymeric cellulose derivatives and nanocellulose‐based compounds synthesized as versatile biomaterials for a large variety of biomedical applications, such as for wound dressings, controlled release, encapsulation of cells and enzymes, and tissue engineering, are separately described, regarding the diverse routes of synthesis and the established and suggested applications for these highly interesting materials.Ionic cellulose‐based compounds as either polymeric cellulose derivatives or ionic nanocellulose have gained tremendous attention within the last years due to their remarkable properties, especially their biological properties. Recent advances about various ionic cellulose‐based compounds with diverse functional moieties either along the cellulose chains or on the surface of nanocellulose for biomedical applications are systematically summarized. imag

Potential super-hard Osmium di-nitride with fluorite structure: First-principles calculations

We have performed systematic first-principles calculations on di-carbide, -nitride, -oxide and -boride of platinum and osmium with the fluorite structure. It is found that only PtN$_{2}$, OsN$_{2}$ and OsO$_{2}$ are mechanically stable. In particular OsN$_{2}$ has the highest bulk modulus of 360.7 GPa. Both the band structure and density of states show that the new phase of OsN$_{2}$ is metallic. The high bulk modulus is owing to the strong covalent bonding between Os 5\textit{d} and N 2\textit{p} states and the dense packed fluorite structure.Comment: Phys. Rev. B 74,125118 (2006

The Empirical Research on the College Students’ Belief in Marxism——a Case Study of Chongqing, China

Abstract:Applying the empirical research method, this research investigated the current status of 575 Chongqing college students’ belief in Marxism. The results suggested that college students’ beliefve in Marxism had significant differences in gender, grade, academic performance and political status, college students’ cognition of Marxism affect their attitude. college students’ belief in Marxism is basically satisfactory, and universities need to strengthen belief education for different types of students

Polysaccharide-based nanomedicines for cancer immunotherapy: a review

Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics. However, direct administration of “naked” immunotherapeutic agents (such as nucleic acids, cytokines, adjuvants or antigens without delivery vehicles) often results in: (1) an unsatisfactory efficacy due to suboptimal pharmacokinetics; (2) strong toxic and side effects due to low targeting (or off-target) efficiency. To overcome these shortcomings, a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, as they could interact with immune system to stimulate an enhanced immune response. Their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.info:eu-repo/semantics/publishedVersio