Coculture-Based Screening Revealed Selective Cytostatic Effects of Pyrazol-Azepinoindoles.

This work focuses on the search for new small molecules for anticancer therapy using the fluorescent cells cocultivation test (FCCT). This method allows the control of the specificity of the action of compounds from the earliest stages of drug development. For the FCCT, labeled MCF7' breast cancer cells and noncancerous breast MCF10A cells are cocultured.

3,4-Diarylisoxazoles-Analogues of Combretastatin A-4: Design, Synthesis, and Biological Evaluation and .

Focusing on the molecular docking results, a series of 3,4-diarylisoxazoles, analogues of Combretastatin A4, bearing various substituents at the fifth position of the isoxazole ring and pharmacophore groups bioisosteric to methoxy substituent at ring B, were synthesized in good yields and high regioselectivity. Depending on the substituent at C5, three approaches were chosen for the construction of isoxazole ring, including nitrosation of gem-dihalocyclopropanes, nitrile oxide synthesis, and difluoromethoxylation of isoxazolone to afford 5-haloisoxazoles, 5-unsubstituted isoxazoles, and 5-difluoromethoxyisoxazoles, respectively. Isoxazoles and showed selective cytotoxicity and antitubulin inhibition properties , with pharmacodynamic profiles closely related to that of CA-4.

Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca or Mg Cross-Linked Alginate.

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated.

The Synthesis and Biological Evaluation of 2-(1-Indol-3-yl)quinazolin-4(3)-One Derivatives.

The treatment of many bacterial diseases remains a significant problem due to the increasing antibiotic resistance of their infectious agents. Among others, this is related to , especially methicillin-resistant (MRSA) and . In the present article, we report on antibacterial compounds with activity against both and MRSA.

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates.

Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. studies of the affinity of the synthesized compounds to the protein target have been carried out.

[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones.

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels-Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids.

Synthesis and Biological Evaluation of Novel -Indolinones with Anticancer Activity.

Novel variously substituted thiohydantoin-based -indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCT, and HCT. Several compounds demonstrated a relatively high cytotoxic activity vs.

Conjugates of Chloramphenicol Amine and Berberine as Antimicrobial Agents.

In order to obtain antimicrobial compounds with improved properties, new conjugates comprising two different biologically active agents within a single chimeric molecule based on chloramphenicol (CHL) and a hydrophobic cation were synthesized and studied. Chloramphenicol amine (CAM), derived from the ribosome-targeting antibiotic CHL, and the plant isoquinoline alkaloid berberine (BER) are connected by alkyl linkers of different lengths in structures of these conjugates. Using competition binding, double reporter system, and toeprinting assays, we showed that synthesized CAM-Cn-BER compounds bound to the bacterial ribosome and inhibited protein synthesis like the parent CHL.

Electrochemical Detection of a Novel Pt(IV) Prodrug with the Metronidazole Axial Ligand in the Hypoxic Area.

We report herein a Pt(IV) prodrug with metronidazole in axial positions -. The nitroaromatic axial ligand was conjugated with a cisplatin scaffold to irreversibly reduce under hypoxic conditions, thereby retaining the Pt(IV) prodrug in the area of hypoxia. X-ray near-edge adsorption spectroscopy (XANES) on dried drug-preincubated tumor cell samples revealed a gradual release of cisplatin from the prodrug instead of rapid intracellular degradation.

Anticancer activity of G4-targeting phenoxazine derivatives in vitro.

G4-stabilizing ligands are now being considered as anticancer, antiviral and antibacterial agents. Phenoxazine is a promising scaffold for the development of G4 ligands. Here, we profiled two known phenoxazine-based nucleoside analogs and five new nucleoside and non-nucleoside derivatives against G4 targets from telomere repeats and the KIT promoter region.

Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation.

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against strain LPTD.

Synthesis and initial in vitro evaluation of PSMA-targeting ligands with a modified aromatic moiety at the lysine ε-nitrogen atom.

We report an improved series of ligands targeting prostate specific membrane antigen (PSMA). The new compounds were designed by the introduction of changes in the structure of the aromatic fragment at ε-nitrogen atom of lysine that resulted in improved biological parameters. Some of them demonstrated high selectivity and nanomolar IC values.

Copper coordination compounds with (5,5')-2,2'-(alkane-α,ω-diyldiselenyl)-bis-5-(2-pyridylmethylene)-3,5-dihydro-4-imidazol-4-ones. Comparison with sulfur analogue.

A series of new organic ligands (5,5')-2,2'-(alkane-α,ω-diyldiselenyl)-bis-5-(2-pyridylmethylene)-3,5-dihydro-4-imidazol-4-ones (L) consisting of two 5-(2-pyridylmethylene)-3,5-dihydro-4-imidazol-4-one units linked with polymethylene chains of various lengths ( = 2-10, where is the number of CH units) have been synthesized. The reactions of these ligands with CuCl·2HO and CuClO·6HO gave Cu or Cu containing mono- and binuclear complexes with CuLCl ( = 2-4) or CuL(ClO) ( = 1, 2) composition. It was shown that the agents reducing Cu to Cu in the course of complex formation can be both a ligand and an organic solvent in which the reaction is carried out.

Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.

Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells.

PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation.

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates.

Biological evaluation and spectral characterization of a novel tetracenomycin X congener.

The aromatic polyketide tetracenomycin X (TcmX) was recently found to be a potent inhibitor of protein synthesis; its binding site is located in a unique locus within the tunnel of the large ribosomal subunit. The distinct mode of action makes this relatively narrow class of aromatic polyketides promising for drug development in the quest to prevent the spread of drug-resistant pathogens. Here we report the isolation and structure elucidation of a novel natural tetracenomycin X congener - 6-hydroxytetraceonomycin X (6-OH-TcmX).

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents.

In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL.

Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them.

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition.

Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability.

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system-namely, 2-selenoxodispiro[imidazolidine-4,3'-pyrrolidine-2',3″-indoline]-2″,5-diones () and 2-senenoxodispiro[imidazolidine-4,3'-pyrrolidine-4',3″-indoline]-2″,5-diones ()-were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds , , and demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC) 7.

Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma.

Herein, we describe the design, synthesis, and biological evaluation of novel betulin and -acetyl-d-galactosamine (GalNAc) glycoconjugates and suggest them as targeted agents against hepatocellular carcinoma. We prepared six conjugates derived via the C-3 and C-28 positions of betulin with one or two saccharide ligands. These molecules demonstrate high affinity to the asialoglycoprotein receptor (ASGPR) of hepatocytes assessed by in silico modeling and surface plasmon resonance tests.

Cyanine mitochondrial dye with slightly selective cytotoxicity against A549 cancerous cells.

Delocalized lipophilic cations (DLCs) are known as mitochondria-addressed molecules. Mitochondria targeting may provide opportunities for tumor detection. DLCs may have antioxidant or anticancer properties.

Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones.

A series of 73 ligands and 73 of their Cu and Cu copper complexes with different geometries, oxidation states of the metal, and redox activities were synthesized and characterized. The aim of the study was to establish the structure-activity relationship within a series of analogues with different substituents at the N(3) position, which govern the redox potentials of the Cu/Cu redox couples, ROS generation ability, and intracellular accumulation. Possible cytotoxicity mechanisms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have been investigated.

Panel of potential lncRNA biomarkers can distinguish various types of liver malignant and benign tumors.

Purpose: Liver cancers are among the deadliest malignancies due to a limited efficacy of early diagnostics, the lack of appropriate biomarkers and insufficient discrimination of different types of tumors by classic and molecular methods. In this study, we searched for novel long non-coding RNA (lncRNA) as well as validated several known candidates suitable as probable biomarkers for primary liver tumors of various etiology.

Methods: We described a novel lncRNA HELIS (aka "HEalthy LIver Specific") and estimated its expression by RT-qPCR in 82 paired tissue samples from patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), combined HCC-CCA, pediatric hepatoblastoma (HBL) and non-malignant hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH).

Tetracenomycin X inhibits translation by binding within the ribosomal exit tunnel.

The increase in multi-drug resistant pathogenic bacteria is making our current arsenal of clinically used antibiotics obsolete, highlighting the urgent need for new lead compounds with distinct target binding sites to avoid cross-resistance. Here we report that the aromatic polyketide antibiotic tetracenomycin (TcmX) is a potent inhibitor of protein synthesis, and does not induce DNA damage as previously thought. Despite the structural similarity to the well-known translation inhibitor tetracycline, we show that TcmX does not interact with the small ribosomal subunit, but rather binds to the large subunit, within the polypeptide exit tunnel.

Synthesis and biological activity of 5-aryliden-2-thiohydantoin S-aryl derivatives.

Three new and complementary approaches to S-arylation of 2-thiohydantoins have been developed: copper-catalyzed cross coupling with either arylboronic acids or aryl iodides under mild conditions, or direct nucleophilic substitution in activated aryl halides. For 38 diverse compounds, reaction yields for all three methods have been determined. Selected by molecular docking, they have been tested on androgen receptor activation, and p53-Mdm2 regulation, and A549, MCF7, VA13, HEK293T, PC3, LnCAP cell lines for cytotoxicity, Two of them turned out to be promising as androgen receptor activators (likely by allosteric regulation), and another one is shown to activate the p53 cascade.