Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties.

Purpose: Development of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions.

Methods: Semisynthetic glycopeptides 3-6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitory concentration (MIC) for the new derivatives was measured by the broth micro-dilution method on a panel of clinical isolates of Staphylococcus and Enterococcus.

Two approaches to the use of benzo[c][1,2]oxaboroles as active fragments for synthetic transformation of clarithromycin.

Clarithromycin (active against Gram positive infections) and 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole derivatives (effective for Gram negative microbes) are the ligands of bacterial RNA. The antimicrobial activities of these benzoxaboroles linked with clarithromycin at 9 or 4″ position were compared. Two synthetic pathways for these conjugates were elaborated.

Indole-3-carbinol (I3C) analogues are potent small molecule inhibitors of NEDD4-1 ubiquitin ligase activity that disrupt proliferation of human melanoma cells.

The HECT domain-containing E3 ubiquitin ligase NEDD4-1 (Neural precursor cell Expressed Developmentally Down regulated gene 4-1) is frequently overexpressed in human cancers and displays oncogenic-like properties through the ubiquitin-dependent regulation of multiple protein substrates. However, little is known about small molecule enzymatic inhibitors of HECT domain-containing ubiquitin ligases. We now demonstrate that indole-3-carbinol (I3C), a natural anti-cancer phytochemical derived from cruciferous vegetables such as cabbage and broccoli, represents a new chemical scaffold of small molecule enzymatic inhibitors of NEDD4-1.

Quantitative parameters of complexes of tris(1-alkylindol-3-yl)methylium salts with serum albumin: Relevance for the design of drug candidates.

Triarylmethane derivatives are extensively investigated as antitumor and antibacterial drug candidates alone and as photoactivatable compounds. In the series of tris(1-alkylindol-3-yl)methylium salts (TIMs) these two activities differed depending on the length of N-alkyl chain, with C4-5 derivatives being the most potent compared to the shorter or longer chain analogs and to the natural compound turbomycin A (no N-substituent). Given that the human serum albumin (HSA) is a major transporter protein with which TIMs can form stable complexes, and that the formation of these complexes might be advantageous for phototoxicity of TIMs we determined the quantitative parameters of TIMs-HSA binding using spectroscopic methods and molecular docking.

Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties.

Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a 'scaffold hopping' approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3-f]indole-5,10-dione 2 with an alternative anthra[2,3-b]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3-b]furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3-f]indole-5,10-dione 2.

Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD(+)/NADH Ratio and SIRT1.

A series of new 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives with different side chains were synthesized. Selected 2-unsubstituted derivatives 11-14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11-14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD(+)/NADH ratio through tNOX inhibition, suppression of a NAD(+)-dependent sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated apoptosis.

Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones.

A series of new 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones 6-13 bearing the cyclic diamine in the position 3 of the indole ring was synthesized. The majority of new compounds demonstrated a superior cytotoxicity than doxorubicin against a panel of mammalian tumor cells with determinants of altered drug response, that is, Pgp expression or p53 inactivation. For naphtho[2,3-f]indole-5,10-diones 6-9 bearing 3-aminopyrrolidine in the side chains, the ability to bind double-stranded DNA and inhibit topoisomerases 1 and 2 mediated relaxation of supercoiled DNA were demonstrated.

Thienoquinolines as novel disruptors of the PKCε/RACK2 protein-protein interaction.

Ten protein kinase C (PKC) isozymes play divergent roles in signal transduction. Because of sequence similarities, it is particularly difficult to generate isozyme-selective small molecule inhibitors. In order to identify such a selective binder, we derived a pharmacophore model from the peptide EAVSLKPT, a fragment of PKCε that inhibits the interaction of PKCε and receptor for activated C-kinase 2 (RACK2).

Study on retroaldol degradation products of antibiotic oligomycin A.

Studies of reactivity of antibiotic oligomycin A in various alkaline conditions showed that the compound easily undergoes retroaldol degradation in β-hydroxy ketone fragments positioned in the C7-C13 moiety of the antibiotic molecule. Depending on reaction conditions, the retroaldol fragmentation of the 8,9 or 12,13 bonds or formation of a product through double retroaldol degradation, when the fragment C9-C12 was detached, took place followed by further transformations of the intermediate aldehydes formed. The structures of the obtained non-cyclic derivatives of oligomycin A were supported by NMR and MS methods.

Glycopeptide antibiotic analogs efficient against vancomycin-resistant bacteria: a patent evaluation (WO2013022763).

The patent claims the preparation of vancomycin analogs equally active against bacterial strains that are primarily sensitive or resistant to this antibiotic. The pseudopeptide core of new compounds carries the amidine group that replaces the carboxamide linking group in the D ring-bearing amino acid residue of the glycopeptide. An elegant method of synthesis of amidine containing glycopeptides via thioamides was developed.

Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group.

A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10.

Role of the acyl groups in carbohydrate chains in cytotoxic properties of olivomycin A.

A series of olivomycin A derivatives containing different combinations of the acyl residues in the carbohydrate chains was obtained. The formation of complexes of Mg(2+)-coordinated dimers of these compounds with double-stranded DNA was studied using spectral methods such as absorption, fluorescence and circular dichroism (CD) spectral analyses. There was a good correlation of the values of binding constants of complexes (antibiotic)2Mg(2+)-DNA, the quantum yields of fluorescence and changes of the induced CD spectra with topoisomerase I inhibition and cytotoxicity.

Synthesis and cytotoxicity of oligomycin A derivatives modified in the side chain.

A novel way of chemical modification of the macrolide antibiotic oligomycin A (1) at the side chain was developed. Mesylation of 1 with methane sulfonyl chloride in the presence of 4-dimethylaminopyridine produced 33-O-mesyl oligomycin in 56% yield. Reactions of this intermediate with sodium azide produced the key derivative 33-azido-33-deoxy-oligomycin A in 60% yield.

A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A.

The antibiotic oligomycin A in the presence of K(2)CO(3) and n-Bu(4)NHSO(4) in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared.

Modification of olivomycin A at the side chain of the aglycon yields the derivative with perspective antitumor characteristics.

A novel way of chemical modification of the antibiotic olivomycin A (1) at the side chain of the aglycon moiety was developed. Interaction of olivomycin A with the sodium periodate produced the key acid derivative olivomycin SA (2) in 86% yield. This acid was used in the reactions with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate (PyBOP) or diphenylphosphoryl azide (DPPA) to give corresponding amides.

Target protein interactions of indole-3-carbinol and the highly potent derivative 1-benzyl-I3C with the C-terminal domain of human elastase uncouples cell cycle arrest from apoptotic signaling.

Elastase is the only currently identified target protein for indole-3-carbinol (I3C), a naturally occurring hydrolysis product of glucobrassicin in cruciferous vegetables such as broccoli, cabbage, and Brussels sprouts that induces a cell cycle arrest and apoptosis of human breast cancer cells. In vitro elastase enzymatic assays demonstrated that I3C and at lower concentrations its more potent derivative 1-benzyl-indole-3-carbinol (1-benzyl-I3C) act as non-competitive allosteric inhibitors of elastase activity. Consistent with these results, in silico computational simulations have revealed the first predicted interactions of I3C and 1-benzyl-I3C with the crystal structure of human neutrophil elastase, and identified a potential binding cluster on an external surface of the protease outside of the catalytic site that implicates elastase as a target protein for both indolecarbinol compounds.

Bacterial eukaryotic type serine-threonine protein kinases: from structural biology to targeted anti-infective drug design.

Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections.

Inhibition of hepatitis C virus replication by semi-synthetic derivatives of glycopeptide antibiotics.

Objectives: Some semi-synthetic derivatives of glycopeptide antibiotics have been shown to exert in vitro antiviral activity against HIV and coronaviruses. Here we report and characterize the in vitro anti-hepatitis C virus (HCV) activity of several semi-synthetic derivatives of teicoplanin aglycone.

Methods: Anti-HCV activity was analysed in: (i) three different subgenomic HCV replicon systems using a luciferase or quantitative RT-PCR (qRT-PCR) assay; and (ii) an infectious HCV cell culture system by means of qRT-PCR and immunofluorescence assays.

The first series of 4,11-bis[(2-aminoethyl)amino]anthra[2,3-b]furan-5,10-diones: Synthesis and anti-proliferative characteristics.

We developed the synthesis of a series of furan-fused tetracyclic analogues of the antitumor agent ametantrone. The reactions included nucleophilic substitution of propoxy groups in 4,11-dipropoxyanthra[2,3-b]furan-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]furan-5,10-dione in good yields. Studies of anti-proliferative activity on a panel of mammalian tumor cell lines demonstrated that anthra[2,3-b]furan-5,10-diones were the most potent derivatives among heteroarene-fused ametantrone analogues with one heteroatom.

Synthesis and cytotoxic potency of novel tris(1-alkylindol-3-yl)methylium salts: role of N-alkyl substituents.

Novel derivatives of tris(indol-3-yl)methane and tris(indol-3-yl)methylium salts with the alkyl substituents at the N-atoms of the indole rings were synthesized. An easy substitution of indole rings in trisindolylmethanes for other indoles under the action of acids is demonstrated, and the mechanism of substitution is discussed. To obtain trisindolylmethylium salts, the environmentally safe method of oxidation of trisindolylmethanes with air oxygen in acidic conditions was developed.

1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells.

Indole-3-carbinol (I3C), a natural autolysis product of a gluccosinolate present in Brassica vegetables such as broccoli and cabbage, has anti-proliferative and anti-estrogenic activities in human breast cancer cells. A new and significantly more potent I3C analogue, 1-benzyl-I3C was synthesized, and in comparison to I3C, this novel derivative displayed an approximate 1000-fold enhanced potency in suppressing the growth of both estrogen responsive (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells (I3C IC(50) of 52 microM, and 1-benzyl-I3C IC(50) of 0.05 microM).

Synthesis and study of the antifungal activity of new mono- and disubstituted derivatives of a genetically engineered polyene antibiotic 28,29-didehydronystatin A1 (S44HP).

Mono- and disubstituted novel derivatives of the heptaene nystatin analog 28,29-didehydronystatin A(1) (S44HP, 1) were obtained by chemical modification of the exocyclic C-16 carboxyl and/or an amino group of mycosamine moiety. The strategy of preparation of mono- and double-modified polyene macrolides was based on the use of intermediate hydrophobic N-Fmoc (9-fluorenylmethoxycarbonyl) derivatives that facilitated the procedures of isolation and purification of new compounds. The antifungal activity of the new derivatives was first tested in vitro against yeasts and filamentous fungi, allowing the selection of the most active compounds that were subsequently tested for acute toxicity in mice.

The first examples of chemical modification of oligomycin A.

The first examples of chemical modification of antibiotic oligomycin A are described. The interaction of oligomycin A with hydroxylamine yielded six-membered nitrone annelated with the antibiotic at the positions 3,4,5,6,7. The reaction with 1-aminopyridinium iodide in pyridine led to pyrazolo[1,5-a]pyridine conjugated with the antibiotic at the positions 2 and 3 (product of addition to the C(2)-C(3) double bond followed by spontaneous oxidation).

Reaction of the antitumor antibiotic olivomycin I with aryl diazonium salts. Synthesis, cytotoxic and antiretroviral potency of 5-aryldiazenyl-6-O-deglycosyl derivatives of olivomycin I.

The azo coupling of the antibiotic olivomycin I (1) with aryl diazonium tetrafluoroborates produced 5-aryldiazenyl-6-O-deglycosyl derivatives of 1. The structures of new compounds were confirmed by (1)H NMR and mass spectrometry analysis. A quantum-chemical study was performed to analyze the possible directions of electrophilic substitution of 1 and the easiness of 6-O-disaccharide hydrolysis in the course of azo coupling.