Construction and synthesis of lactoferricin derivatives with enhanced antibacterial activity

A series of peptides derived from sequences from human, bovine, murine and caprine lactoferrin has been prepared and investigated for antibacterial effect. Among the four species investigated peptides based on the bovine sequence displayed significant activity. The bovine sequence, bovine lactoferricin, showed a MIC value of 30 μg/mL on E. coli and S. aureus, whereas the three other lactoferricins possessed MIC values above 200 μg/mL. Based on these findings, novel peptides with enhanced antibacterial activities, were prepared with sequences designed by molecular modelling and structure‐activity studies. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.     

Quaternization of N-aryl chitosan derivatives: synthesis, characterization, and antibacterial activity

Chemical modification of chitosan by introducing quaternary ammonium moieties into the polymer backbone renders excellent antimicrobial activity to the adducts. In the present study, we have synthesized 17 derivatives of chitosan consisting of a variety of N-aryl substituents bearing either electron-donating or electron-withdrawing groups. Selective N-arylation of chitosan was performed via Schiff bases formed by the reaction between the 2-amino groups of the glucosamine residue of chitosan with aromatic aldehydes under acidic conditions, followed by reduction of the Schiff base intermediates with sodium cyanoborohydride. Each of the derivatives was further quaternized using N-(3-chloro-2-hydroxypropyl)trimethylammonium chloride (Quat-188) as the quaternizing agent that reacted with either the primary amino or hydroxyl groups of the glucosamine residue of chitosan. The resulting quaternized materials were water soluble at neutral pH. Minimum inhibitory concentration (MIC) antimicrobial studies of these materials were carried out on Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) bacteria in order to explore the impact of the extent of N-substitution (ES) on their biological activities. At ES less than 10%, the presence of the hydrophobic substituent, such as benzyl and thiophenylmethyl, yielded derivatives with lower MIC values than chitosan Quat-188. Derivatives with higher ES exhibited reduced antibacterial activity due to low quaternary ammonium moiety content. At the same degree of quaternization, all quaternized N-aryl chitosan derivatives bearing either electron-donating or electron-withdrawing substituents did not contribute antibacterial activity relative to chitosan Quat-188. Neither the functional group nor its orientation impacted the MIC values significantly.     

Synthesis and biological activity of pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one derivatives: in silico approach

Xanthine oxidase (XO) is responsible for the pathological condition called gout. Inhibition of XO activity by various pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidine-4-one derivatives was assessed and compared with the standard inhibitor allopurinol. Out of 10 synthesized compounds, two compounds, viz. 3-amino-6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3b) and 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3g) were found to have promising XO inhibitory activity of the same order as allopurinol. Both compounds and allopurinol inhibited competitively with comparable Ki (3b: 3.56?µg, 3g: 2.337?µg, allopurinol: 1.816?µg) and IC₅₀ (3b: 4.228?µg, 3g: 3.1?µg, allopurinol: 2.9?µg) values. The enzyme–ligand interaction was studied by molecular docking using Autodock in BioMed Cache V. 6.1 software. The results revealed a significant dock score for 3b (?84.976?kcal/mol) and 3g (?90.921?kcal/mol) compared with allopurinol (?55.01?kcal/mol). The physiochemical properties and toxicity of the compounds were determined in silico using online computational tools. Overall, in vitro and in silico study revealed 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2–a]pyrimidin-4-one (3g) as a potential lead compound for the design and development of XO inhibitors.     

铰链结构对抗菌肽生物活性的影响及在分子设计中的应用研究进展

铰链结构,又称铰链区或转角,是部分抗菌肽序列中存在的一种特殊结构。但目前抗菌肽结构的研究多集中于标准的α-螺旋和β-折叠二级结构,对于铰链结构及其作用总结较少。铰链结构对抗菌肽生物活性有重要影响,主要原因是铰链结构能够提高抗菌肽的结构灵活性,促进其对细菌细胞膜的破坏作用或与胞内作用靶点的结合效率,进而提高抗菌肽的抗菌活性。同时,降低的抗菌肽结构刚性,消减了抗菌肽对真核细胞的毒性。文中结合了笔者课题组相关工作,就铰链结构特点、对抗菌肽生物活性的影响以及在抗菌肽分子设计方面的应用进行了综述,以期为新型抗菌肽的设计和开发提供参考。     

Copper(II) complexes of the beta-blocker pindolol: properties, structure, biological activity

The complex formation between copper(II) and the antihypertensive drug pindolol (HPin) was studied both in aqueous and methanolic media. Two complexes are formed at different metal-to-ligand molar ratios. The mononuclear complex Cu(Pin)₂(HPin)₂ contains two ligands in an anionic bidentate form and two - in a neutral form bound monodentately. The second complex Cu₂Pin₂Cl₂ is dinuclear and its structure was determined by X-ray diffraction. The compound crystallizes in the monoclinic group C2/c with cell components a = 14.4998(13)Å, b = 18.511(2)Å, c = 14.2982(13)Å, =90 °, =109.556(2)°, =90 ° and Z = 12 at 293K. A pharmacological study on the influence of pindolol and its mononuclear complex on the heart rate of rats was performed. The complex is more active and has a longer effect in comparison with the pure non-coordinated pindolol in equitoxic doses.     

Folding propensity and biological activity of peptides: New insights from conformational properties of a novel peptide derived from Vitreoscilla haemoglobin

The synthetic peptide Vitr-p-13 (YPIVGQELLGAIK-NH(2)), derived from the bacterial dimeric Vitreoscilla haemoglobin (VHb) in the position 95-107, is characterized by a pre-eminent "statistical coil" conformation in water as demonstrated by CD experiments and long time-scale MD simulations. In particular, Vitr-p-13 does not spontaneously adopt an alpha-helix folding in water, but it is rather preferentially found in beta-hairpin-like conformations. Long time-scale MD simulations have also shown that Vitr-p-13 displays a "topological-trigger" which initiates alpha-helix folding within residues 7-10, exactly like seen in the temporins, a group of linear, membrane-active antimicrobial peptides of similar length. At variance with temporins, in Vitr-p-13 such a process is energetically very demanding (+10 kJ/mol) in water at 300 K, and the peptide was found to be unable to bind model membranes in vitro and was devoid of antimicrobial activity. The present results, compared with previous studies on similar systems, strengthen the hypothesis of the requirement of a partial folding when still in aqueous environment to allow a peptide to interact with cell-membranes and eventually exert membrane perturbation-related antibiotic effects on target microbial cells.     

DNA‐binding activity and cytotoxic and cell‐cycle arrest properties of some new coumarin derivatives: a multispectral and computational investigation

Coumarins are the most important class of natural compounds found widely in various plants. Many coumarin derivatives with different biological and pharmacological activities have been synthesized. In this study, the antiapoptotic and cytotoxic effects and DNA‐binding properties of some synthetic coumarin derivatives (4b, 4d, 4f, 4 g (DBP‐g), 4 h and 4j) against K562 cell lines were investigated using different techniques. MTT assay indicated that the DBP‐g compound was more active than other derivatives, with a IC₅₀ value of 55 μM, and therefore this compound was chosen for further investigation. Apoptosis induction was assessed using acridine orange/ethidium bromide double‐staining and cell‐cycle analysis. In addition, in vitro DNA‐binding studies were carried out using ultraviolet–visible light absorption and fluorescence spectroscopy, as well as viscosity measurement and molecular modelling studies. In vitro results indicated that DBP‐g interacted with DNA through a groove‐binding mode with a binding constant (K_b) of 1.17 × 10⁴ M^?1. In agreement with other experimental data, molecular docking studies showed that DBP‐g is a minor groove binder. Overall, it can be concluded that DBP‐g could be used as an effective and novel chemotherapeutic agent.     

Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design,synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives

The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I–III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III)?>?3-alkenyl-5-(phenylamino) indolone (Series I)?>?3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC₅₀ value of 1.8?±?0.8?µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.