Natural Cyclopeptides as Anticancer Agents in the Last 20 Years

Cyclopeptides or cyclic peptides are polypeptides formed by ring closing of terminal amino acids. A large number of natural cyclopeptides have been reported to be highly effective against different cancer cells, some of which are renowned for their clinical uses. Compared to linear peptides, cyclopeptides have absolute advantages of structural rigidity, biochemical stability, binding affinity as well as membrane permeability, which contribute greatly to their anticancer potency. Therefore, the discovery and development of natural cyclopeptides as anticancer agents remains attractive to academic researchers and pharmaceutical companies. Herein, we provide an overview of anticancer cyclopeptides that were discovered in the past 20 years. The present review mainly focuses on the anticancer efficacies, mechanisms of action and chemical structures of cyclopeptides with natural origins. Additionally, studies of the structure–activity relationship, total synthetic strategies as well as bioactivities of natural cyclopeptides are also included in this article. In conclusion, due to their characteristic structural features, natural cyclopeptides have great potential to be developed as anticancer agents. Indeed, they can also serve as excellent scaffolds for the synthesis of novel derivatives for combating cancerous pathologies.     

Facile synthesis of phenolic-reinforced silica aerogel composites for thermal insulation under thermal-force coupling conditions

The objective of this research was to develop a reinforced silica aerogel composites with enhanced thermal insulation performance under thermal-force coupling conditions. Phenolic-reinforced silica aerogel composites (RAs) were synthesized via a sol-immersion-gel process based on the in-situ polymerization of resorcinol (R), formaldehyde (F), and triaminopropyltriethoxysilane (APTES). Ambient pressure drying (APD) was used to dry the gels. Samples with different carbon/silica ratios, RA12, RA13, and RA14, were synthesized by controlling the R/APTES molar ratio at 1/2, 1/3, and 1/4. The densities of the RA12, RA13 and RA14 samples were 0.32 ± 0.005, 0.34 ± 0.006, and 0.37 ± 0.003 g/cm³. The thermal conductivity of the RA12, RA13, and RA14 samples were 0.024, 0.026, and 0.027 W/(m·K). The existence of the phenolic network favored the mechanical strength of the RAs, RA14 showed compressive strength, tensile strength, and three-point bending strength of 4.3 MPa at 20% strain, 2.4 MPa, and 8.4 MPa at 1.45% strain. The RAs showed excellent thermal insulation performance on a customized apparatus, the back temperature was as low as 219.82 °C and 330.67 °C within 60 min in the environments of 600 °C −0.01 MPa and 600 °C −0.9 MPa. The excellent thermal-shock performance of RAs was also demonstrated under flame exposure from a butane torch, with a temperature difference of 878 °C within 30 min being reported. The excellent thermal insulation performance of RAs under thermal-force coupling conditions reveals a widespread application perspective in the field of new energy vehicles power battery thermal protection.     

环肽抗菌素的合成方法研究

环肽是较线状多肽更为稳定并具有多种生理功能和药用价值的环状多肽.综述了近年来一些抗菌环肽合成方法的新进展.     

不同强度混凝土制造的再生骨料对高性能混凝土力学性能的影响(英文)

研究了由强度为30～100 MPa混凝土制造的再生骨料对高性能混凝土力学性能的影响。结果表明:利用30 MPa和45 MPa低强度混凝土制造的再生骨料搅拌的高性能混凝土,其力学性能明显下降;而由80MPa和100MPa的高强度混凝土制造的再生骨料搅拌的高性能混凝土,其28d抗压强度略高于由天然骨料搅拌的高性能混凝土的;再生骨料降低高性能混凝土的弹性模量,但降低量随着制造再生骨料混凝土的强度的增加而减少;28 d后再生骨料高性能混凝土的劈裂强度高于天然骨料高性能混凝土;由80 MPa和100 MPa高强度混凝土制造的再生骨料可以搅拌高性能混凝土。     

脱砷-脱硫-脱氯净化剂在重整装置中的组合应用

本文介绍了ＲＡｓ-３脱砷剂、ＲＳ-１脱硫剂与ＫＴ-４０５脱氯剂在一定的反应压力、温度和氢油比的条件下,可将重整原料中的杂质降到Ａｓ＜１　ｐｐｂ,Ｓ＜０.５　ｐｐｍ,Ｃｌ＜０.５　ｐｐｍ,以符合重整进料质量指标,同时减少因设备腐蚀造成停工,保证装置长周期运转。     

N-(末端三甲基硅脯氨酸肽链)邻苯二甲酰亚胺的光诱导单电子转移成环反应

分子内单电子转移成环反应是有效地合成环化物的方法.以L-脯氨酸为起始原料合成了两个光反应底物N-(末端三甲基硅脯氨酸肽链)邻苯二甲酰亚胺,在其分子结构中,邻苯二甲酰亚胺基团为受电子体部分,末端三甲基硅脯氨酸肽链为给电子体部分,构成了分子内给受电子体系.N-(末端三甲基硅脯氨酸肽链)邻苯二甲酰亚胺在甲醇溶剂中进行了光反应...     

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.     

Novel Therapeutical Approaches to Managing Atherosclerotic Risk

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem.     

Old and Novel Therapeutic Approaches in the Management of Hyperglycemia,an Important Risk Factor for Atherosclerosis

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD).     

Frost resistance of recycled aggregate concrete

The research presented in this paper deals with concrete containing building waste recycled as aggregates. The frost resistance is used as a durability indicator. The characteristics of recycled aggregates (RAs) and their impact on the characteristics of RA concrete are presented. Some basic factors concerning the frost resistance of RA concrete as RA content and degree of water saturation are considered. The RA concrete is compared with a control concrete made with natural aggregates. The pertinence of different criteria for the assessment of the frost resistance is also discussed.     

Organoarsen-Verbindungen. XXV. Synthese und Reaktionen von 1.3-Azarsolidin-2-thionen

Synthesis and Reactions of 1, 3-Azarsolidine-2-thiones Secondary 2-aminoethylarsines of the type RAs(H) CH₂CH₂ NHR′ react with CS₂ yielding 1,3-azarsolidine-2-thiones. Under suitable conditions the corresponding ammonium salts of the 2-arsinoethyl-dithiocarbamates are isolable as primary reaction products. 1,3-Azarsolidine-2-thiones are attacked by electrophilic agents on the sulfur atom yielding 2-alkylthio- and 2-organostannylthio-azarsolines, respectively, as well as 1,3-azarsolidine-2-ones.     

X-ray reflectivity study of cyclic peptide monolayers at the air-water interface

The dynamic and living characteristics of monolayers at the air-water interface of a cyclohexapeptide ( C6G ) and a cyclooctapeptide ( C8G ), both composed of glutamic acid and 3-aminobenzoic acid subunits in an alternating sequence, were investigated using the Langmuir balance technique, Brewster angle microscopy (BAM), and X-ray reflectivity (XR). An alanine-containing cyclohexapeptide ( C6A ) was included in this study for comparison. All three cyclopeptides preferentially adopt an orientation parallel to the subphase at low surface pressure. Continuous compression then causes the molecules to flip to a perpendicular state, thus minimizing their molecular area. In contrast to C8G and C6A , a pronounced hysteresis observed during the compression-expansion cycle of C6G indicates that strong intermolecular interactions between the cyclopeptide rings occur in the monolayers of this peptide. This result is supported by BAM measurements that show the formation of crystallite structures for C6G at high surface pressures, whereas no structures were observed for C8G and C6A . These results indicate that C6G is able to self-assemble upon surface compression, an ability that is obviously critically dependent on the correct ring size and composition of the peptide. The presence of hydrogen bond acceptors in the side chains of C6G suggests that the structural stabilization of the monolayer is due to H-bonding, possibly between ring NH groups and side chain CO groups. Our in situ study thus provides a detailed understanding of the molecular dynamics and uninterrupted interfacial behavior of the three peptides in a real-time frame.     

Organoarsen-Verbindungen. XXVI. Zur Synthese der 1.3-Azarsoline

Organo-arsenic Compounds. XXVI. Synthesis of 1.3-Azarsolines 2-Aminoalkylarsines of the type RAs(H)CH₂CH₂NH₂ react with formic acid or carbonic acid chlorides to give the corresponding amides 1–3 , whereas reaction with iminoester hydrochlorides yields 1,3-azarsolines 4–6 . I. R.- and n.m.r.-data are reported.     

Cyclization of Peptides through a Urea Bond: Application to the Arg‐Gly‐Asp Tripeptide

Various synthetic cyclopeptides bind different cellular proteins with high affinity and specificity. In this study, we designed a new series of cyclic tetrapeptides containing the RGD sequence, a ligand for the α_vβ₃ integrin receptor, in which the ring closure was performed through a urea bond between the α‐amino group of the peptide and either the α‐ or the ε‐amino group of an additional lysine. Interestingly, we showed that the urea‐closed peptide had a higher affinity for α_vβ₃ receptors than a reference pentacyclopeptide. Moreover, the synthetic strategy allows coupling of the resulting cyclic tetrapeptide through the carboxylic acid moiety of its lysine residue to fluorescent molecules or drugs. In addition, this strategy could be easily adapted for the cyclization of any other peptides.     

Oral Semaglutide,the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.     

Synthesis and Structure–Activity Correlation of a Brunsvicamide‐Inspired Cyclopeptide Collection

Cyanobacterial cyclopeptides : A series of analogues of the cyanobacterial cyclopeptide brunsvicamide A was prepared by effective solid‐support‐based total synthesis. Variations in stereochemistry revealed the importance of the D ‐lysine and the L ‐isoleucine residues for the substrate‐competitive inhibitory activity of brunsvicamide A against carboxypeptidase A.

     

抗人类共激活蛋白单克隆抗体的制备

目的制备抗人类共激活蛋白(CLP)单克隆抗体,并进行纯化。方法配制2×DMEM培养基,与等量的2.2%甲基纤维素溶液混合,加入HAT、胎牛血清等,配成半固体HAT选择性细胞培养基。用基因重组人CLP抗原免疫BALB/c小鼠,取免疫小鼠脾细胞,与小鼠骨髓瘤NS-2细胞融合后,直接在半固体培养基上克隆化培养,筛选可持续、稳定、高效分泌抗CLP单克隆抗体的杂交瘤细胞株。对分泌的单抗进行鉴定后,制备小鼠腹水,经DEAE离子交换柱纯化,半饱和硫酸铵沉淀,G25凝胶过滤除盐。结果共筛选出14株分泌抗CLP单抗的杂交瘤细胞,其培养上清可与相对分子质量约16000的CLP抗原结合,抗体类型为鼠IgGa1型。多数克隆分泌的抗体相对亲和力大于1∶20000,14株克隆分泌的单抗分别对应3个抗原结合位点。纯化后的单抗纯度接近95%。结论已成功制备并纯化了抗人CLP单克隆抗体,为建立CLP免疫学检测方法奠定了基础。     

IgGs-Abzymes from the Sera of Patients with Multiple Sclerosis Recognize and Hydrolyze miRNAs

Autoantibodies-abzymes hydrolyzing DNA, myelin basic protein, and oligosaccharides have been revealed in the sera of patients with multiple sclerosis (MS). In MS, specific microRNAs are found in blood and cerebrospinal fluid, which are characterized by increased expression. Autoantibodies, specifically hydrolyzing four different miRNAs, were first detected in the blood of schizophrenia patients. Here, we present the first evidence that 23 IgG antibodies of MS patients effectively recognize and hydrolyze four neuroregulatory miRNAs (miR-137, miR-9-5p, miR-219-2-3p, and miR-219-5p) and four immunoregulatory miRNAs (miR-21-3p, miR-146a-3p, miR-155-5p, and miR-326). Several known criteria were checked to show that the recognition and hydrolysis of miRNAs is an intrinsic property of MS IgGs. The hydrolysis of all miRNAs is mostly site-specific. The major and moderate sites of the hydrolysis of each miRNA for most of the IgG preparations coincided; however, some of them showed other specific sites of splitting. Several individual IgGs hydrolyzed some miRNAs almost nonspecifically at nearly all internucleoside bonds or demonstrated a combination of site-specific and nonspecific splitting. Maximum average relative activity (RA) was observed in the hydrolysis of miR-155-5p for IgGs of patients of two types of MS—clinically isolated syndrome and relapsing-remitting MS—but was also high for patients with primary progressive and secondary progressive MS. Differences between RAs of IgGs of four groups of MS patients and healthy donors were statistically significant (p < 0.015). There was a tendency of decreasing efficiency of hydrolysis of all eight miRNAs during remission compared with the exacerbation of the disease.     

Acetylcholinesterase Reactivators (HI-6, Obidoxime,Trimedoxime, K027, K075, K127, K203, K282): Structural Evaluation of Human Serum Albumin Binding and Absorption Kinetics

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively.