Discovery of a Chiral DNA-Targeted Platinum–Acridine Agent with Potent Enantioselective Anticancer Activity

A structure–activity relationship study was performed for a set of rigidified platinum–acridine anticancer agents containing linkers derived from chiral pyrrolidine and piperidine scaffolds. Screening a library of microscale reactions and selected resynthesized compounds in non-small-cell lung cancer (NSCLC) cells showed that cytotoxicities varied by more than three orders of magnitude. A potent hit compound was discovered containing a (R)-N-(piperidin-3-yl) linker ( P2-6R ), which killed NCI-H460 and A549 lung cancer cells 100 times more effectively than the S enantiomer ( P2-6S ). P2-6R accumulated in A549 cells significantly faster and produced 50-fold higher DNA adduct levels than P2-6S . Ligand similarity analysis suggests that only module 6R may be compatible with strainless monofunctional intercalative binding. NCI-60 screening and COMPARE analysis highlights the spectrum of activity and potential utility of P2-6R for treating NSCLC and other solid tumors.     

Inclusion Behavior of Dimer β-CyclodextrinBridged with Aspartic Acid Derivative

The capped cyclodextrins (CDs) are very useful macromolecular hosts in supramolecular chemistry. Previously, we demonstrated that the dimer cyclodextrin bridged with 1,2-diaminoethane causes significant enhancement of affinity to a small organic guest molecule1. A variety of interesting peptides have been developed as artificial enzymes. Here our designed peptide, Adm-Trp-Arg-Arg-NH2, named ATA was synthesized by the usual solid-phase Fmoc strategy2 with trityl resin in Shimadzu-PSSM8 p…     

Synthesis and α-Glucosidase Inhibitory Activity of Ursolic Acid,Lupeol, and Betulinic Acid Derivatives

Chemistry of Natural Compounds - Seven synthetic derivatives of ursolic acid, lupeol, and betulinic acid (1a–1b, 2a–2b, and 3a–3c) were synthesized to study their...     

Structure–Activity Relationship Study of a Potent α-Thrombin Binding Aptamer Incorporating Hexitol Nucleotides

The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the hexitol backbone. Importantly, the NU172- T ^H9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.     

Application of Fragment Screening and Merging to the Discovery of Inhibitors of the Mycobacterium tuberculosis Cytochrome P450 CYP121

Pieces of the puzzle: The first fragment-based approach was used to target cytochrome?P450 enzymes (CYPs) for drug development. The experiments provide new insights into the binding site of the essential Mycobacterium tuberculosis CYP121 enzyme, and resulted in a promising novel lead compound based on fragment merging.     

Synthesis of Cu@Ag Nanoparticles with a Core–Shell Structure Stabilized with Oxyethylated Carboxylic Acid

Russian Journal of General Chemistry - Bimetallic Cu@Ag nanoparticles with a core–shell structure were synthesized by reduction of copper 2-[2-(2-methoxyethoxy)ethoxy]acetate with hydrazine...     

Discovery of Potent, Selective and Reversible Caspase-3 Inhibitors

Recent studies towards understanding the molecular mechanisms of apoptosis have revealed the importance of a group of cysteinyl aspartate specific proteases, the caspases, in the programmed cell death process (Hengartner, M.O. Nature 2000, 407, 770). Caspase-3, in particular, has been characterized as the dominant effector caspase involved in the proteolytic cleavage of a variety of protein substrates including cytoskeletal proteins, kinases and DNA repair enzymes during apoptosis (Nicholson…     

Persicamidines—Unprecedented Sesquarterpenoids with Potent Antiviral Bioactivity against Coronaviruses

A new family of highly unusual sesquarterpenoids (persicamidines A–E) exhibiting significant antiviral activity was isolated from a newly discovered actinobacterial strain, Kibdelosporangium persicum sp. nov., collected from a hot desert in Iran. Extensive NMR analysis unraveled a hexacyclic terpenoid molecule with a modified sugar moiety on one side and a highly unusual isourea moiety fused to the terpenoid structure. The structures of the five analogues differed only in the aminoalkyl side chain attached to the isourea moiety. Persicamidines A–E showed potent activity against hCoV-229E and SARS-CoV-2 viruses in the nanomolar range together with very good selectivity indices, making persicamidines promising as starting points for drug development.     

Mechanism of the Antioxidant Activity and Structure–Activity Relationship of N-Monosubstituted Amino Acid Derivatives of Fullerene С60

Kinetics and Catalysis - The kinetic characteristics, mechanisms of activity, and relationship between the antioxidant activity and the molecular and supramolecular structure of fullerene C60 and...     

Thermodynamic Functions in the Binary System of a C60 Fullerene Derivative with Methionine Amino Acid–Н2О

Russian Journal of Physical Chemistry A - The temperature of the onset of ice crystallization (∆Т) is determined for binary aqueous solutions of a water-soluble tris-adduct of light...     

Glucose-lowering Activity of Amino Acid-N-phosphonic Acid Oxovanadium Complexes and Its Interaction with DNA

Vanadium has well-documented lowering glucose properties both in vitro and in vivo.The design of newoxovanadium(IV) coordination compounds,intended for use as insulin-enhancing agents in the treatment of diabe-tes mellitus,can potentially benefit from a synergistic approach,in which the whole complex has more than an ad-ditive effect from its component parts.Biological testing with oxovanadium(IV) organic phosphonic acid,for insu-lin-enhancing potential included acute administration,by oral garage in streptozotocin (STZ) diabetic rats.Thecomplexes of oxovanadium(IV) amino acid-N-phosphonic acid exhibit higher lowering glucose activity in vivo.Theinteraction of the complexes of oxovanadium(IV) amino acid-N-phosphonic acid with DNA was investigated byagarose gel electrophoresis.The results indicated that these complexes have strong interaction with DNA.     

A Study on Anti-oxidative Activity of Soybean Peptides with Linoleic Acid Peroxidation Systems

Introduction Freeradicalsproducedbyperoxidationcancause cellulardamageandforfeitureofavarietyofphysiologi calfunctions[1,2].Inrecentyears,ithasbeenreported thatsomenon enzymicsmallmolecularcompounds,suchasVitaminC(VC)andVitaminE(VE),glutathi one(GSH),SODm…     

Photovoltaic Characteristics of a Naphthylamine Derivative

Organic photovoltaic （OPV） cells were fabricated via vacuum vapor deposition with {4-[2-（3-di-cyanomethylidene-5,5-dimethylcyclohexenyl）vinyl]phenyl}di（1-naphthyl）amine （DNP-2CN） as the electron donor, and fullerene （C60） as the electron acceptor. A thin film （10 nm） of tris（8-quinolinolato）aluminum （Alq3） was adopted as the buffer layer. A device based on this DNP-2CN exhibited an open circuit voltage （Voc） of 370 mV, a short-circuit current density （Jsc） of 0.61 mAocm 2, and a white-light power conversion efficiency （ η） of 0.09% （AM1.5, 75 mW.cm^- 2）.     

Synthesis of Cholesterol Derivative with Amino Acid as Hydrophilic Group and the Vesicles Prepared Therefrom

Cholesterolisoneofthemainconstituentsofmembranelipidsandhasbeenconsideredtogovernthemembranefluidityandpermeabilityofsolutes'.Inthecourseofstudyonliposomesconstructedbyphospholipidsasmodelbiomembraneordrugdeliverysystem,itwasalsofoundthatthestabilityofliposomeswasenhancedbyincorporationofcholesterolintothelipidbilayerZ".Allthesepropertiesofcholesterolinmembranechemistryarecausedbyitsuniquesmicture,inwhichtherigidandflatsteroidalringshowsgoodcompatibilitywithlipid.DuetotheeXtraordinaryfijnctio…     

Extensive Structure–Activity Relationship Study of Albicidin's C-Terminal Dipeptidic p-Aminobenzoic Acid Moiety

Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram-negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure–activity relationship studies are key for the in-depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27 newly synthesized albicidins give profound insights into possibilities for variations of the C-terminus. Furthermore, in the present study, a novel derivative has been identified as overcoming resistance posed by the Klebsiella-protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere between building blocks D and E.     

Synthesis and Kinetics of a Novel Mimic with Glutathione Peroxidase Activity——Tellurium-containing Hyaluronic Acid （TeHA）

Many diseases are associated with the overproduction of the reactive oxygen species (ROS) which inflict cell damage in vivo. Examples of ROS-related diseases include reperfusion injury, brain ischemia, tumor, physiological aging and various types of infla…     

Superoxide Dismutase Mimetic Activity of the Metal (II) Complexes of a Dithiocarbamate Derivative of β-Cyclodextrin1

Abstract

The synthesis of a new β-cyclodextrin derivative containing a dithiocarbamate group (3) by condensation of mono-2-methylamino-2-deoxy-β-CD (2) with CS₂ in the presence of NEt₃ is reported. SOD-mimetic activity was found for the Mn(II) and Cu(II) complexes of 2 and 3 (IC₅₀ = 0.76-7.4 μ). To study the influence of the cyclodextrin residue on the catalytic activity of these complexes, a comparison was made with diethylamine and diethyldithiocarbamate complexes. Complexes of 2 and 3 resulted in 1.3 to 11 fold higher activities. An explanation for this observation, in terms of a possible cooperation of the cyclodextrin residue with the catalytic center of the complex, is given.     

One-Pot Synthesis of Tri-Acetalated Aldohexoses with 1,1-Dialkoxycyclohexane–p-Toluenesulfonic Acid

Abstract

2-Deoxy-d-arabino-hexose (1), 2-acetamido-2-deoxy-d-glucose (2), and 2-deoxy-2-trifluoroacetamido-d-glucose (3) were each treated with 1,1-dimethoxycyclohexane or 1,1-dibenzyloxycyclohexane in 1,4-dioxane in the presence of p-toluenesulfonic acid. The major products were the 1,1-dimethyl or 1,1-dibenzyl acetals (4-9) of 3,4:5,6-di-O-cyclohexylidene-2-deoxy-aldehydo-d-arabino-hexose, and of 2- (acylamino)-3,4:5,6-di-O-cyclohexylidene-2-deoxy-aldehydo-D-glucose. The dibenzyl acetal derivatives were converted, by hydro-genolysis, into the corresponding, acyclic aldehydes (10-12) in good yields.     

Effect of the Acid–Base Properties of the Support on the Activity of Pd–Zeolite Catalysts for CO Oxidation

The effect of the acid–base properties of zeolite Y on the activity of palladium–zeolite catalysts for CO oxidation was studied. The modification of the support with basic additives was found to improve the catalyst activity. A linear correlation between the ratio between the amounts of O₂and CO adsorbed on the surface of palladium and the catalyst activity was established.     

Discovery of a small-molecule inhibitor of Dvl–CXXC5 interaction by computational approaches

The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl–CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide–ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl–CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl–CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl–CXXC5 interaction. Overall, CXXC5–Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl–CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl–CXXC5 interaction disruptors.