Synthesis of lipid A derivatives and their interactions with polymyxin B and polymyxin B nonapeptide

Lipid A is the causative agent of Gram-negative sepsis, a leading cause of mortality among hospitalized patients. Compounds that bind lipid A can limit its detrimental effects. Polymyxin B, a cationic peptide antibiotic, is one of the simplest molecules capable of selectively binding lipid A and may serve as a model for further development of lipid A binding agents. However, association of polymyxin B with lipid A is not fully understood, primarily due to the low solubility of lipid A in water and inhomogeneity of lipid A preparations. To better understand lipid A-polymyxin B interaction, pure lipid A derivatives were prepared with incrementally varied lipid chain lengths. These compounds proved to be more soluble in water than lipid A, with higher aggregation concentrations. Isothermal titration calorimetric studies of these lipid A derivatives with polymyxin B and polymyxin B nonapeptide indicate that binding stoichiometries (peptide to lipid A derivative) are less than 1 and that affinities of these binding partners correlate with the aggregation states of the lipid A derivatives. These studies also suggest that cooperative ionic interactions dominate association of polymyxin B and polymyxin B nonapeptide with lipid A.     

One-step synthesis of amino-dextran-protected gold and silver nanoparticles and its application in biosensors

A sensitive method for the detection of the lectin protein concanavalin A (Con A) was developed using amino-dextran (AD)-protected gold (AD-Au) and silver nanoparticles (AD-Ag) as sensitive optical probes. The AD-Au and AD-Ag nanoparticles were synthesized by directly applying amino-dextran as a reductive and protective reagent. The size of the nanoparticles could be altered by changing the molar ratio of AD to the metal salt. The amino-dextran bound to Con A by forming a 4:1 Au-Con A complex at neutral pH, and the nanoparticles were induced to aggregate by Con A. The absorption intensity of the nanoparticles decreased linearly with as the Con A concentration was increased from 3.85×10^–8 to 6.15×10^–7 M. The Au-Con A complex was dissociated by the disaccharide isomaltose, which has a higher affinities for Con A than Au; this competitive strategy could also be used to detect similar types of saccharides.     

Synthesis of indole-based oxadiazoles and their interaction with bacterial peptidoglycan and SARS-CoV-2 main protease: In vitro,molecular docking and in silico ADME/Tox study

In the present study, Indole-based-oxadiazole (1A-17A) compounds were successfully synthesized. The structures of all synthesized compounds were fully characterized by different sophisticated spectroscopic techniques such 1H NMR, 13C NMR, and HREI-MS. Further, the synthesized compounds were explored to investigate their broad-spectrum antibacterial and antibiofilm potential against multidrug resistant Pseudomonas aeruginosa (MDR-PA) and methicillin resistant Staphylococcus aureus (MRSA). The compounds possessed a broad spectrum of antibacterial activity having MIC values of values 1–8 mg/ml against the tested microorganisms. Compound A6 and A7 shows maximum antibacterial activity against MDR-PA, whereas A6, A7 and A11 shows highest activity against MRSA. Furthermore, antibiofilm assay shows that A6, A7 and A11 showed maximum inhibition of biofilm formation and it was found that at 4 mg/ml; A6, A7 and A11 inhibit MRSA biofilm formation by 81.1, 77.5 and 75.9%, respectively; whereas in case of P. aeruginosa; A6 and A7 showed maximum biofilm inhibition and inhibit biofilm formation by 81.5 and 73.7%, respectively. Molecular docking study showed that compounds A6, A7, A8, A10, and A11 had high binding affinity to bacterial peptidoglycan, indicating their potential inhibitory activity against tested bacteria, whereas A6 and A11 were found to be the most effective inhibitors of SARS CoV-2 main protease (3CLpro), with a binding affinity of ? 7.78 kcal/mol. Furthermore, SwissADME and pkCSM-pharmacokinetics online tools was applied to calculate the ADME/Tox profile of the synthesized compounds and the toxicity of these chemicals was found to be low. The Lipinski, Veber, Ghose, and Consensus LogP criteria were also used to predict drug-likeness levels of the compounds. Our findings imply that the synthesized compounds could be a useful for the preventing and treating biofilm-related microbial infection as well as SARS-CoV2 infections.     

Application of equation-of-motion coupled-cluster methods to low-lying singlet and triplet electronic states of HBO and BOH

The equilibrium structures and physical properties of the X (1)sigma(+) linear electronic states, linear excited singlet and triplet electronic states of hydroboron monoxide (HBO) (A (1)sigma(-), B (1)delta, a (3)sigma(+), and b (3)delta) and boron hydroxide (BOH) (A (1)sigma(+), B (1)Pi, and b (3)Pi), and their bent counterparts (HBO a (3)A('), b (3)A("), A (1)A("), B (1)A(') and BOH X (1)A('), b (3)A('), c (3)A("), A (1)A('), B (1)A('), C (1)A(")) are investigated using excited electronic state ab initio equation-of-motion coupled-cluster (EOM-CC) methods. A new implementation of open-shell EOM-CC including iterative partial triple excitations (EOM-CC3) was tested. Coupled-cluster wave functions with single and double excitations (CCSD), single, double, and iterative partial triple excitations (CC3), and single, double, and full triple excitations (CCSDT) are employed with the correlation-consistent quadruple and quintuple zeta basis sets. The linear HBO X (1)sigma(+) state is predicted to lie 48.3 kcal mol(-1) (2.09 eV) lower in energy than the BOH X (1)sigma(+) linear stationary point at the CCSDT level of theory. The CCSDT BOH barrier to linearity is predicted to lie 3.7 kcal mol(-1) (0.16 eV). With a harmonic zero-point vibrational energy correction, the HBO X (1)sigma(+)-BOH X (1)A(') energy difference is 45.2 kcal mol(-1) (1.96 eV). The lowest triplet excited electronic state of HBO, a (3)A('), has a predicted excitation energy (T(e)) of 115 kcal mol(-1) (4.97 eV) from the HBO ground state minimum, while the lowest-bound BOH excited electronic state, b (3)A('), has a T(e) of 70.2 kcal mol(-1) (3.04 eV) with respect to BOH X (1)A('). The T(e) values predicted for the lowest singlet excited states are A (1)A(")<--X (1)sigma(+)=139 kcal mol(-1) (6.01 eV) for HBO and A (1)A(')<--X (1)A(')=102 kcal mol(-1) (4.42 eV) for BOH. Also for BOH, the triplet vertical transition energies are b (3)A(')<--X (1)A(')=71.4 kcal mol(-1) (3.10 eV) and c (3)A(")<--X (1)A(')=87.2 kcal mol(-1) (3.78 eV).     

Synthesis, structure, and properties of supramolecular charge-transfer complexes between bis(18-crown-6)stilbene and ammonioalkyl derivatives of 4,4'-bipyridine and 2,7-diazapyrene

4,4'-Bipyridine and 2,7-diazapyrene derivatives (A) having two ammonioalkyl N-substituents were synthesized. The complex formation of these compounds with bis(18-crown-6)stilbene (D) was studied by spectrophotometry, cyclic voltammetry, (1)H NMR spectroscopy, and X-ray diffraction analysis. In MeCN, π-donor D and π-acceptors A form supramolecular 1:1 (D·A) and 2:1 (D·A·D) charge-transfer complexes. The D·A complexes have a pseudocyclic structure as a result of ditopic binding of the ammonium groups to the crown-ether fragments. The better the geometric matching between the components, the higher the stability of the D·A complexes (log K up to 9.39). A key driving force of the D·A·D complex formation is the excessive steric strain in the precursor D·A complexes. The pseudocyclic D·A complexes involving the ammoniopropyl derivative of 4,4'-bipyridine were obtained as single crystals. Crystallization of the related ammonioethyl derivative was accompanied by transition of the D·A complexes to a structure of the (D·A)(m) coordination polymer type.     

具有合成核酸活性的多肽 I: C-端去四肽和去六肽核糖核酸酶A及其水解和合成活性

为寻找一个比天然RNase A分子结构更简单, 但较之具有突出的合成活性的核酸酶模型, 首先由RNase A出发, 从C-端切去不同长度的肽段, 获得了比RNase A仅有微弱水解活性但有更强合成活性的C-端去四肽和去六肽核糖核酸酶A(RAl-120和RAl-118)两种降解产物. 研究了RAl-120和RAl-118的水解活性和合成活性, 得出结论认为RNase的His119对其水解活性是重要但并非必要角色, 对其合成活性既非重要又非必要.     

Salarins a and B and tulearin a: new cytotoxic sponge-derived macrolides

Three novel nitrogenous macrolides designated salarin A and B (1 and 2) and tulearin A (3) were isolated from the Madagascar Fascaplysinopsis sp. sponge. The structures of the compounds were elucidated by interpretation of MS and 1D and 2D NMR spectra. Both salarins carry an acetylcarbamate moiety, and in addition, 1 contains a triacylamine group and 2 a methoxymethylketone lactam. Tulearin A carries the naturally rare carbamate ester. The compounds were found to be toxic to brine shrimp larvae, and salarin A and tulearin A were also cytotoxic to leukemia cells.     

Gibberellins and related substances

Chemistry of Natural Compounds - 1. A study of the gibberellin-like substances of the leaves of tobaccoN. tabacum has shown that the latter contains gibberellin A3 and possibly A6 in the free...     

Total synthesis of marinomycins A-C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A

Marinomycins A-C (1-3), and their monomeric analogues monomarinomycin A (m-1) and iso-monomarinomycin A (m-2), were synthesized by a convergent strategy from key building blocks ketophosphonate 5, aldehyde 6, and dienyl bromide carboxylic acid 7. The first attempt to construct marinomycin A [1, convertible to marinomycins B (2) and C (3) by light] by direct Suzuki-type dimerization/cyclization of boronic acid dienyl bromide 4 led to premature ring closure to afford, after global desilylation, monomarinomycin A (m-1) and iso-monomarinomycin A (m-2) in good yield and only small amounts (< or =2%) of the desired product. A subsequent stepwise approach based on Suzuki-type couplings improved considerably the overall yield of marinomycin A (1), and hence of marinomycins B (2) and C (3). Alternative direct dimerization approaches based on the Stille and Heck coupling reactions also led to monomarinomycins A (m-1 and m-2), but failed to deliver useful amounts of marinomycin A (1).     

Syntheses and Anti-cancer Activities of Derivatives of Tetrandrine and Fangchinoline

A series of derivatives of tetrandrine and fangchinoline was designed and synthesized to find more active anti-cancer compounds. Their anti-cancer activities were tested against human hcpatocellular carcinoma BEL-7402 and PLC/PRF/5 cells, human lung adenocarcinoma A549 cells as well as human leukaemia K562 cells, and the structure-activity relationship（SAR） was also studied. All the compounds except BI exhibited superior inhibitory ac- tivities against PLC/PRF/5 cells with half maximal inhibitory conccntration（ICs0） values of less than 15 μmol/L, and compounds A2, A4, B2 and B4 showed IC50 values of less than 9 pmol/L. Compounds A2, A6, B2 and B4 showed potent anti-cancer activities against all the tested cells with 1C5o values of less than 10 pmol/L. The results show that terandrine and fangchinoline derivatives are potential suppressors to human cancer.     

Structure and ethanol complexation of cyclic tetrasaccharide in aqueous solution studied by NMR and molecular mechanics

The structure and ethanol complexation of a cyclic tetrasaccharide (CTS) in aqueous solution were investigated by proton NMR spectroscopy and molecular mechanics calculations. Two glucose units, A and B, of CTS are alternatively bonded by alpha-1,3 and alpha-1,6 linkages. The overlapped signals of protons A5, A6S, A6R, B3, B6S and B6R were resolved by spectral simulations to determine their chemical shifts and vicinal coupling constants. All vicinal coupling constants except for the A5-A6 spin system are consistent with the dihedral angles in the X-ray crystal structure. Each of protons A5, A6S, and A6R in the two units of A is equivalent with respect to the chemical shift. The vicinal coupling constants of (3)J(5-6S) and (3)J(5-6R) for unit A are close to the average of two rotamers that are present in crystals. The intensities of cross-peaks in the rotating frame nuclear Overhauser effect spectroscopy (ROESY) spectrum were rather well correlated with the effective distances calculated for the X-ray structure and molecular mechanics structures calculated in vacuo and water, although they are slightly better correlated with molecular mechanics structure in vacuo than with the other structures. From the changes of the chemical shifts of several CTS protons with increasing ethanol concentration, it was suggested that adsorption sites of ethanol on the plate structure of CTS are protons B2 and B4 (site B) in the concave face side and protons A1 and A2 (site A) in the convex back side. The binding constants for sites A and B are 0.0061 and 0.0176 M(-1), respectively. These binding constants are much smaller than a value of 4.1 M(-1) for the ethanol-alpha-cyclodextrin complex.     

Characterisation and antiproliferative activity of irinotecan and sulphonatocalixarene inclusion complex

The interaction between water-soluble sulphonatocalix[4]arene (SC4A) and irinotecan (CPT-11) was investigated by using UV spectrophotometry. Inclusion complex of SC4A with CPT-11 was confirmed by ¹H NMR and DSC analysis. Water solubility study showed that SC4A has remarkable solubilisation on CPT-11 and the complex has good water solubility. The antiproliferative activity of the complex was evaluated. The results showed that the complexation of CPT-11 with SC4A increases the antiproliferative activity of CPT-11.     

Total synthesis and stereochemical revision of acortatarins A and B

A first total synthesis of acortatarins A, B, and an enantiomer of the proposed structure of acortatarin B is described by using readily available d-sugars. This convergent total synthesis revealed the revision of the absolute configuration of acortatarin A and structural revision of acortatarin B. The key steps involved are regioselective epoxide opening with deprotonated 2,5-disubstituted pyrrole and spiroketalization.     

Synthesis and characterization of zirconogermanates

Six new zirconogermanates have been prepared under hydrothermal conditions using amines as bases. There are four new structure types (ASU-n) with a common motif of ZrGe(5). ASU-23 is a layered structure: ZrGe(3)O(8)(OH)F.[C(10)H(26)N(4)].H(2)O, space group P2(1)/n, a = 6.7957(8) A, b = 12.700(1) A, c = 24.293(3) A, beta = 97.936(2) degrees, V = 2076.4(4) A(3). ASU-24 is a pillared layered structure: Zr(3)Ge(6)O(18)(OH(2),F)(4)F(2).[C(6)H(18)N(2)].[C(6)H(17)N(2)](2).2H(2)O, space group P2(1)/n, a = 7.4249(3) A, b = 25.198(1) A, c = 11.3483(5) A, beta = 90.995(1) degrees, V = 2122.9(2) A(3). This material has the lowest framework density (FD) of any oxide material that we are aware of (FD = 8.48 metal atoms/nm(3)). Two other materials form three-dimensional open-frameworks, ASU-25: ZrGe(3)O(9).[C(3)H(12)N(2)], space group P112(1)/a, a = 13.1994(4) A, b = 7.6828(2) A, c = 11.2373(3) A, gamma = 91.233(3) degrees, V = 1139.29(5) A(3). The other is ASU-26: ZrGe(3)O(9).[C(2)H(10)N(2)], space group Pn, a = 13.7611(3) A, b = 7.7294(2) A, c = 11.2331(3) A, beta = 104.793(1) degrees, V = 1155.21(4) A(3). ASU-25 is related to the mineral umbite K(2)ZrSi(3)O(9).H(2)O. The germanium equivalent has been prepared through the inorganic route: K(2)ZrGe(3)O(9).H(2)O, space group P2(1)2(1)2(1), a = 13.6432(6) A, b = 7.4256(3) A, c = 10.3973(4) A, V = 1053.33(8) A(3). The structural relationships between ASU-25 and its inorganic counterpart are described. The thermal decomposition of the germanium umbite generated the cyclic trigermanate K(2)ZrGe(3)O(9), analogue of the mineral wadeite, crystallizing in the orthorhombic system, a = 7.076 A, b = 12.123 A, c = 10.451 A, V = 904.5 A(3).     

Coordination chemistry of trivalent lanthanide and actinide ions in dilute and concentrated chloride solutions

We have used EXAFS spectroscopy to investigate the inner sphere coordination of trivalent lanthanide (Ln) and actinide (An) ions in aqueous solutions as a function of increasing chloride concentration. At low chloride concentration, the hydration numbers and corresponding Ln,An-O bond lengths are as follows: La3+, N = 9.2, R = 2.54 A; Ce3+, N = 9.3, R = 2.52 A; Nd3+, N = 9.5, R = 2.49 A; Eu3+, N = 9.3, R = 2.43 A; Yb3+, N = 8.7, R = 2.32 A; Y3+, N = 9.7, R = 2.36 A; Am3+, N = 10.3, R = 2.48 A; Cm3+, N = 10.2, R = 2.45 A. In ca. 14 M LiCl, the early Ln3+ ions (La, Ce, Nd, and Eu) show inner sphere Cl- complexation along with a loss of H2O. The average chloride coordination numbers and Ln-Cl bond lengths are as follows: La3+, N = 2.1, R = 2.92 A; Ce3+, N = 1.8, R = 2.89 A; Nd3+, N = 1.9, R = 2.85 A; Eu3+, N = 1.1, R = 2.81 A. The extent of Cl- ion complexation decreases going across the Ln3+ series to the point where Yb3+ shows no Cl- complexation and no loss of coordinated water molecules. The actinide ions, Am3+ and Cm3+, show the same structural effects as the early Ln3+ ions, i.e., Cl- ion replacement of the H2O at high chloride thermodynamic activities. The Clion coordination numbers and An-Cl bond lengths are: Am3+, N = 1.8, R = 2.81 A; Cm3+, N = 2.4, R = 2.76 A. When combined with results reported previously for Pu3+ which showed no significant chloride complexation in 12 M LiCl, these results suggest that the extent of chloride complexation is increasing across the An3+ series. The origin of the differences in chloride complex formation between the Ln3+ and An3+ ions and the relevance to earlier work is discussed.     

Synthesis and Biological Evaluation of Bromo‐ and Fluorodanicalipin A

We disclose the syntheses of (+)‐bromodanicalipin A as well as (±)‐fluorodanicalipin A. The relative configuration and ground‐state conformation in solution of both molecules was secured by J‐based configuration analysis which revealed that these are identical to natural danicalipin A. Furthermore, preliminary toxicological investigations suggest that the adverse effect of danicalipin A may be due to the lipophilicity of the halogens.     

细菌视紫红质多重突变体结构变化及其中间态的寿命

采用基因定点突变的方法, 构建了细菌视紫红质(Bacteriorhodopsin, BR)的3种突变体蛋白, 即单突变体BRE194Q、三突变体BRI119T/T121S/A126T和四突变体BRI119T/T121S/A126T/E194Q. 测定了突变体和野生型BR在水溶液和聚乙烯醇(PVA)膜中的紫外-可见吸收光谱和拉曼光谱, 采用显微视频录像技术记录了PVA膜中野生型和3个突变体样品的M态寿命. 与野生型BR相比较, 在水溶液中, 单突变体的可见吸收光谱的最大吸收峰发生了轻微红移, 三突变体和四突变体的最大吸收峰则分别发生了11.0和12.0 nm的明显蓝移. 在PVA膜中, 3个突变体BR的可见吸收光谱的最大吸收峰均发生蓝移, 四突变体BR的最大吸收峰为557 nm, 蓝移达15.0 nm. 四突变体BR在水溶液中的共振拉曼光谱不仅表现有与M态特征相关的1567和1573 cm-1谱带, 还有L态特征带1334 cm-1及N态特征带1200, 1328, 1530和1549 cm-1. 在PVA膜中的样品与在水溶液中的比较, 四突变体共振拉曼光谱的1334和1549 cm-1带消失, 同时1187 cm-1带的强度下降. 显微视频录像技术记录的PVA膜中样品的M态寿命表明, 野生型BR的M态寿命最短, 单突变体的M态寿命小于1.0 s, 三突变体的寿命为3.0 s, 四突变体的寿命为2.0 s.     

Theoretical and Experimental Studies of Subnanoscale Molecules and Clusters

Russian Journal of Physical Chemistry A - A brief review is given of theoretical and experimental studies of a series of subnanoscale molecules and clusters performed by the authors with the staff...     

1H-NMR and LC-MS Based Metabolomics Analysis of Wild and Cultivated Amaranthus spp.

Amaranthus crops are important for their use as food and nutritional sources, as well as for their medicinal properties. They are mostly harvested from the wild, and cultivation of Amaranthus species is still rare, and therefore, attempts are being made to commercialize and market this important crop. This research investigated the effect of cultivation and environment on the chemical profile of both cultivated and wild A. cruentus and A. hybridus by multivariate statistical analysis of spectral data deduced by Nuclear Magnetic Resonance (NMR). Furthermore, wild samples of A. cruentus and A. hybridus were subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) for further analysis. Through NMR analysis, it was found that maltose and sucrose increased in both cultivated A. cruentus and A. hybridus. Moreover, the amino acid, proline was present in cultivated A. cruentus in high quantity whereas, proline and leucine were prominent in A. hybridus. Other compounds that were found in both wild and cultivated A. cruentus and A. hybridus are trehalose, trigonelline, lactulose, betaine, valine, alanine, fumarate, formate and kynurenine. LC-MS analysis revealed the presence of rutin, 2-phenylethenamine and amaranthussaponin I in both wild A. cruentus and A. hybridus, while chlorogenic acid was identified only in cultivated A. hybridus. On the contrary, L-tryptophan, kaempferol, phenylalanine and quercetin were detected only in wild A. cruentus. Amaranth is not only rich in macro and micronutrients, but the leaves also contain phytochemicals that vary between species and cultivated plants, and might, therefore, affect the medicinal properties of the material.     

五脂酮A, B和Butyryl Binankadsurin A的分离与结构

从采自广西柳州地区融水县的一种南五味子(Kadsurasp.)种子中分得三个已知化合物---binankadsurinA(1),acetylbinankadsurinA(2),angeloylbinankadsurinA(3)及三个新化合物---五脂酮(schisanlignone)A(4),B(5),butyrylbinankadsurinA(6)。它们的结构由光谱分析和化学转化而阐明。1系首次从自然界分得。在抗癌药理筛选中,4与5在体外都对白血病P-388细胞有抑制作用。其IC~5~0分别为10和40μg/mL。