Synthesis of N′-substituted Ddz-protected hydrazines and their application in solid phase synthesis of aza-peptides

Hydrazine derivatives are of considerable scientific and industrial value. Substituted hydrazines are precursors for many compounds of great interest and importance, among them aza-peptides. (Aza-peptides are peptide analogues in which one or more of the α-carbons, bearing the side chain residues, has been replaced by a nitrogen atom.) Aza-amino acid residues conserve the pharmacophores necessary for biological activity while inducing conformational changes and increased resistance to proteolytic degradation. These properties make aza-peptides attractive tools for structure-activity relationship studies and drug design. We describe the synthesis of N′-substituted 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) protected hydrazines. A general approach for solid phase synthesis of aza-peptides has been developed based on the in-situ activation of the N-Ddz,N′-substituted hydrazines with phosgene, followed by introduction to the N-terminus of a resin-bound peptide. The Ddz-aza-amino building units include aliphatic, aromatic and functionalized side chains, protected for synthesis by the Fmoc strategy. Solid phase aza-peptide synthesis is demonstrated including selective mild deprotection of Ddz with Mg(ClO₄)₂ and coupling of the next amino acid with triphosgene. Ddz deprotection is orthogonal with the Fmoc and Boc protecting groups, making the solid phase Ddz-aza-peptide synthesis compatible with both the Fmoc and the Boc strategies. The Ddz-protected hydrazines have wide applications in the synthesis of substituted hydrazines and in the synthesis of aza containing peptidomimetics.     

Design and total synthesis of unnatural analogues of the sub-nanomolar SERCA inhibitor thapsigargin

Thapsigargin is a densely oxygenated guaianolide which displays potent sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) binding affinities. The total syntheses of designed unnatural analogues of this important natural product are described. This article constitutes the chemical synthesis behind an ongoing project. Rational modifications have been made to the lactone region of thapsigargin in order to obtain derivatives for future structure-activity relationship studies.     

Multiple on-resin olefin metathesis to form ring-expanded analogues of the lantibiotic peptide, lacticin 3147 A2

Chemical synthesis of lantibiotic analogues wherein monosulfide bridges are replaced with other groups can shed light on structure-activity relationships and generate variants that are resistant to aerobic oxidation and have better metabolic stability. This work describes the first complete synthesis of a carbocyclic lantibiotic analogue 2, using sequential on-resin ring-closing olefin metathesis and solution-phase peptide synthesis. The methodology described should find wide application for the preparation of rigidified peptidomimetics containing multiple carbocyclic rings. [structure: see text].     

Solid-phase synthesis of sulfamate peptidomimetics

A synthetic method for the preparation of sulfamate peptidomimetics is described. The methodology allows sulfamoylation in the solid phase using sulfamoyl chloride in DMA, followed by the acylation of the corresponding sulfamoylated product. Following this approach, several derivatives have been prepared starting from distinct alcohol sources, including alpha-, beta-, and gamma-hydroxyacids and phenols. The presence of protected amino functions on the building blocks opens the possibility of the addition of more diversity. This approach, which is compatible with Fmoc/Boc/Alloc protection, provides a useful and efficient tool for the preparation of new sulfamate peptidomimetics.     

Structure-Activity relationship of MDSA and its derivatives against Staphylococcus aureus Ser/Thr phosphatase Stp1

Ser/thr phosphatase Stp1 is an important virulence factor for Staphylococcus aureus (S. aureus) and plays a key role in its infectivity, suggesting that it could serve as a potential target for treatment of S. aureus infection. Previous studies found that the activity of Stp1 was inhibited by MDSA and its derivatives. In this paper, we used molecular docking, molecular modeling, molecular dynamics simulations, binding free energy decomposition calculations, and hydrogen bond analyses to explore the structure-activity relationship. Energy decomposition indicated that MDSA, hydroxymethyl MDSA, carboxymethyl MDSA and methyl MDSA can bind to the catalytic pocket of Stp1. Furthermore, Met39, Ile163, Ile164, Val167, Gly195 and Asp233 were key residues in the Stp1-inhibitor complexes. Due to the lack of a double salicylate structure, salicylic acid cannot bind to the active site of Stpl, leading to loss of inhibitory activity. Based on these results, the structure-activity relationship at the atomic level was determined, which can promote the development of new and more effective anti-drug resistance inhibitors.     

Interaction of peptidomimetics with bilayer membranes: biophysical characterization and cellular uptake

Enzymatically stable cell-penetrating α-peptide/β-peptoid peptidomimetics constitute promising drug delivery vehicles for the transport of therapeutic biomacromolecules across membrane barriers. The aim of the present study was to elucidate the mechanism of peptidomimetic-lipid bilayer interactions. A series of peptidomimetics consisting of alternating cationic and hydrophobic residues displaying variation in length and N-terminal end group were applied to fluid-phase, anionic lipid bilayers, and their interaction was investigated using isothermal titration calorimetry (ITC) and ellipsometry. Titration of lipid vesicles into solutions of peptidomimetics resulted in exothermic adsorption processes, and the interaction of all studied peptidomimetics with anionic lipid membranes was found to be enthalpy-driven. The enthalpy and Gibbs free energy (ΔG) proved more favorable with increasing chain length. However, not all charges contribute equally to the interaction, as evidenced by the charge-normalized ΔG being inversely correlated to the sequence length. Ellipsometry data suggested that the hydrophobic residues also played an important role in the interaction process. Furthermore, ΔG extracted from ellipsometry data showed good agreement with that obtained with ITC. To further elucidate their interaction with biological membranes, quantitative uptake and cellular distribution were studied in proliferating HeLa cells by flow cytometry and confocal microscopy. The cellular uptake of carboxyfluorescein-labeled peptidomimetics showed a similar ranking as that obtained from the adsorbed amount, and binding energy to model membranes demonstrated that the initial interaction with the membrane is of key importance for the cellular uptake.     

11,16 Oxetane lactones. Spectroscopic evidences and conformational analysis

Sesquiterpene lactones constitute a wide group of compounds with several biological activities, including allelopathic. The naturally occurring sesquiterpene lactones dehydrocostuslactone and cynaropicrin have been modified in three different ways: preparation of 11,13-oxetane lactones, addition of a second Michael acceptor and reduction of the α-methylene-γ-lactone in order to future structure-activity relationship (SAR) studies. We have obtained all oxetane lactones stereoisomers at C-11 and C-16 positions. This fact has allowed us to establish some correlations between experimental data, derived by NMR and X-ray analysis, and the configuration at C-11 and C-16, which could be a useful tool to establish the stereochemistry as well as to confirm the presence of an oxetane ring on similar compounds. Comparative conformational analyses as a key aspect in the biological behaviour of those compounds in future structure-activity relationship (SAR) studies are presented.     

Computer-assisted studies of molecular structure-biological activity relationships

Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conformational analysis and display, quantum mechanical methods, and methods relying on discriminant development and pattern-recognition techniques. Application areas for this technology include drug design, agricultural chemical design, and studies of chemical toxicity and genetic toxicity (mutagenic or carcinogenic potential). These structure-activity methods are introduced, and citations are given. Several current structure-activity relationship (SAR) studies using pattern recognition are presented as examples of typical projects that are feasible with this approach. These include the investigation of a set of 122 antiinflammatory steroids, a study of 153 retinoids for cancer prevention, and a study of chemicals that have been tested in a sister chromatid exchange mutagen screen.     

Docking of noncompetitive inhibitors into dengue virus type 2 protease: understanding the interactions with allosteric binding sites

A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.     

抗癌性吲哚喹唑啉衍生物3D-QSAR研究及其分子设计

吲哚喹唑啉衍生物是近年来发现的一类具有良好抗癌活性的化合物. 作者在最近报道的二维定量构效关系(2D-QSAR)的基础上, 采用比较分子力场方法(CoMFA)进一步对该系列化合物进行三维定量构效关系(3D-QSAR)研究, 建立了3D-QSAR的CoMFA模型, 其非交叉验证相关系数r2=0.986, 标准偏差SD=0.084, 统计方差比F=114.6, 交叉验证相关系数q2=0.695, 表明该模型合理、可信, 并具有良好的预测能力. 研究结果表明: (1) 取代基R1的部位上静电效应起主要作用, 并且确保取代基R1的第一个原子具有较大的净正电荷, 对提高化合物的抗癌活性十分重要. 这与2D-QSAR研究结果相一致. (2) 取代基R2的部位上立体效应起主要作用, R2的体积大小要适中. 应用这些规律进行了分子设计, 在理论上获得了一些具有较高抗癌活性的新的吲哚喹唑啉衍生物, 并期待实验证实. 该QSAR的研究结果可为实验工作者合成新药提供理论参考.     

Influence of Open Chain and Cyclic Structure of Peptidomimetics on Antibacterial Activity in E. coli Strains

An efficient method for the synthesis of functionalized peptidomimetics via multicomponent Ugi reaction has been developed. The application of trifluoroethanol (TFE) as a reaction medium provided desired products with good yields. Further, using the developed cyclisation reaction, the obtained peptidomimetics were transformed into the cyclic analogues (diketopiperazines, DKPs). The goal of the performed studies was to revised and compare whether the structure of the obtained structurally flexible acyclic peptidomimetics and their rigid cycling analogue DKPs affect antimicrobial activity. We studied the potential of synthesized peptidomimetics, both cyclic and acyclic, as antimicrobial drugs on model E. coli bacteria strains (k12, R2–R4). The biological assays reveal that DKPs hold more potential as antimicrobial drugs compared to open chain Ugi peptidomimetics. We believe that it can be due to the rigid cyclic structure of DKPs which promotes the membrane penetration in the cell of studied pathogens. The obtained data clearly indicate the high antibiotic potential of synthesized diketopiperazine derivatives over tested antibiotics.     

Characterization of Molecular Structures Using Topological Indices

Abstract

The characterization of molecular structure using structural invariants has increased greatly over the last ten years. Specifically, topological indices have become more widely used in the quantification of molecular structure for use in quantitative structure-activity relationship studies, chemical documentation, and molecular similarity studies. The basis, calculation, and utility of topological indices has been examined, with an eye to the specific advantages and problems in their use. In addition, variable clustering and principal component analysis are examinee as two potential solutions to the problem of index intercorrelation.     

Generate: a program for 3-D structure generation and conformational analysis of peptides and peptidomimetics

The program Generate, aimed at generating 3-D structures for peptides and peptidomimetics, is presented. The algorithm is based on a build-up procedure, using a library of conformations of amino acid residues. This library is built from conformational analysis of amino acids placed in a di- or tripeptide environment to mimic the surroundings of the amino acid in a true peptide, considering different positions of the residue in the peptide chain (peptidyl fragment, NH(+)(3)-terminus or COO(-)-terminus). Cis-trans isomerism in the amide bonds is taken into account by construction of rotamer libraries for different isomers. Water solvation is included through the GB/SA model. New amino acid residues can easily be added to the libraries, making it possible to generate conformations of peptidomimetics.     

Design and synthesis of antitumor compounds based on the cytotoxic diterpenoids from the genus Rabdosia

Two active sites responsible for antitumor activity, an oxirane ring and an alpha-methylene-cyclopentanone moiety, have been extracted from studies on the structure-activity relationship of the cytotoxic diterpenoids isolated from Rabdosia shikokiana. Series of the simplified cyclopentanone derivatives containing both of the two active sites in the molecule have been synthesized and evaluated for cytotoxicity against P 388 cells. The compounds possessing both of two active sites displayed cytotoxicity at a concentration of 1 microgram/ml, while those possessing a single active site showed no activity.     

The chemistry of cyclotides

Cyclotides are head-to-tail cyclic peptides that contain a cystine knot motif built from six conserved cysteine residues. They occur in plants of the Rubiaceae, Violaceae, Cucurbitaceae, and Fabaceae families and, aside from their natural role in host defense, have a range of interesting pharmaceutical activities, including anti-HIV activity. The variation seen in sequences of their six backbone loops has resulted in cyclotides being described as a natural combinatorial template. Their exceptional stability and resistance to enzymatic degradation has led to their use as scaffolds for peptide-based drug design. To underpin such applications, methods for the chemical synthesis of cyclotides have been developed and are described here. Cyclization using thioester chemistry has been instrumental in the synthesis of cyclotides for structure-activity studies. This approach involves a native chemical ligation reaction between an N-terminal Cys and a C-terminal thioester in the linear cyclotide precursor. Since cyclotides contain six Cys residues their syntheses can be designed around any of six linear precursors, thus providing flexibility in synthesis. The ease with which cyclotides fold, despite their topologically complex knot motif, as well as the ability to introduce combinatorial variation in the loops, makes cyclotides a promising drug-design scaffold.     

Study on Quantitative Structure Property Relationship by Gray Model

One of the challenges in quantitative structure-property relationship (QSPR) investigations is to predict the properties of a substance when the structure is known. P_oct,partition coefficient between octanol and water, is of great importance in quantitative structure-activity relationship (QSAR) studies. The logarithm of the capacity factor (logk') obtained from RPLC has been used as an alternative method of the conventional shaking-flask method for predicting the logarithm of P_oct (logP). This approach has received much attention, but some problems have been reported. In this study, a type of new gray model has been used to model and predict logP as function of different structure parameters.     

Establishing the structure-activity relationship of teixobactin

The updated studies have been summarized to provide structure-activity relationship of teixobactin.     

Cyclic Peptidomimetics Derived from the Apical Membrane Antigen I of Plasmodium falciparum and Their Use in Malaria Vaccine Design

A library of 35 cyclic peptidomimetics has been prepared, by a combination of solid‐ and solution‐phase methods, which, together, scan amino acid residues 444–489 in a protruding loop in the subdomain‐III of the apical membrane antigen‐I (AMA‐I), an integral membrane protein found on the surface of Plasmodium falciparum merozoites. The mimetics each contain twelve residues from AMA‐I linked through the N‐ and C‐termini to a β‐hairpin‐inducing template, comprising the dipeptide D ‐proline‐L ‐Apro (Apro=cis‐4‐amino‐L ‐proline). These peptidomimetics were each coupled via the 4‐amino group to a phospholipid, which allows their incorporation into reconstituted influenza virus‐like particles (virosomes) for immunization of mice, as well as their use in ELISA to characterize epitopes recognized by anti‐AMA‐I growth‐inhibitory monoclonal antibodies.