Synthesis and bioactivity studies of 1-adamantanamine derivatives of peptides

Small enkephalin-related peptides containing a 1-adamantanamine moiety coupled through an amide linkage at the C-terminus were synthesized. Several of the compounds showed high μ opioid activity and μ receptor selectivity. The new adamantanamine derivatives were also examined for antiviral activity against HIV-1 in a cell culture system. Some of them inhibited syncytia formation even when the antigen assay gave evidence for viral replication.     

Novel 4-azasteroidal N-glycoside analogues bearing sugar-like D ring: synthesis and anticancer activities

A series of novel N-glycoside analogues with 4-azasteroid moiety bearing sugar-like D ring were conveniently synthesized by constructing the core dihydropyran ring embedded in 4-azasteroidal skeleton which was prepared from 4-aza-5α-androst-3,17-dione 1 in four steps. The structure of 6b were unambiguously proved by the appropriate X-ray structural analysis. Anticancer activity was found for all of the analogues with purinyl moiety against breast cancer (MCF-7), human neuroblastoma (SK-N-SH), cervical cancer cell (HeLa) and prostatic cancer (PC-3), while the analogue 7 containing 1,2,4-triazole heterocycle as the nucleobase was inactive against all of the tested cancer cell lines. The biology results showed the purinyl moiety attached to the pyran ring of 6a-d, substituent at 6'-position of purine base and introduction of a halogen atom at 2'-position of 6'-chloropurine had obviously effect on the evaluated anticancer activity.     

Synthesis and cytotoxic activity of novel acyclic nucleoside analogues with functionality in click chemistry

We describe synthesis of novel acyclic nucleoside analogues which are building blocks for CuAAC reaction and their activity against two types of human cancer cell lines (HeLa, KB). Three of chosen compounds show promising cytotoxic activity. Synthesis pathway starting from simple and easily accessible substrates employing DMT or TBDPS protective groups is described. Adenosine and thymidine analogues containing alkyne moiety and adenosine analogue containing azido group were synthesized. The obtained units showed ability of forming triazole motif under the CuAAC reaction conditions.     

A novel mixed-ligand antimycobacterial dimeric copper complex of ciprofloxacin and phenanthroline

A novel mixed-ligand Cu(II) complex of ciprofloxacin (cfH) and phenanthroline, is found to crystallize as a dimeric moiety containing monocationic and dicationic species. Two such dimeric moieties are found in the same unit cell leading to a dicationic cluster. The higher negative redox potential for this cluster dampens its antimycobacterial activity against M. smegmatis.     

Induction of Glutathione Peroxidase by Linoleic Acid Hydroperoxide in Hansenula mrakii

The yeast Hansenula mrakii IFO 0895 could grow in a minimal medium containing 4 mm linoleic acid hydroperoxide, and the hydroperoxide moiety of linoleic acid hydroperoxide was reduced to the alcohol moiety. The activity of glutathione peroxidase was detected from the insoluble fractions of the cell homogenates of H. mrakii IFO 0895 only when the cells were grown in a linoleic acid hydroperoxide-containing medium.     

Synthesis, characterization, electrochemical studies and antitumor activity of some new chalcone analogues containing ferrocenyl pyrazole moiety

A series of new α,β-unsaturated conjugated ketones containing ferrocenyl pyrazole unit were synthesized and fully characterized by IR and NMR spectroscopy. Electrochemical characterization of subject compounds was performed by means of cyclic voltametry. The in vitro cytotoxic activity of all the synthesized compounds was studied against cervix adenocarcinoma HeLa, melanoma Fem-x and myelogenous leukemia K562 cell lines by the MTT method. Derivative 1l containing 3-pyridyl moiety exhibited a better cytotoxic activity in the cell growth inhibition of K562 cell lines in comparison with cisplatin as a reference compound.     

In vitro apoptotic activity of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones in L5178Y cells

Compounds containing B-N bonds have shown interesting biological activity. One class of such molecules is the 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones (3a-j), which contain a B-N bond, have an alpha-amino acid moiety in the heterocycle, and have an exocyclic moiety related to an amino acid. The purpose of this work was to determine the inhibitory effects of 3a-j on the proliferation of murine L5178Y lymphoma cells. A new five-membered heterocyclic nucleus with apoptotic activity was found. The target products showed potent cytotoxicity in the L5178Y cell line. Among them, 3a exhibited the highest antineoplastic activity in L5178Y cells with an IC(50) value of 22.5+/-0.2 microM.     

Quantitative,Real-time Analysis of Base Excision Repair Activity in Cell Lysates Utilizing Lesion-specific Molecular Beacons

We describe a method for the quantitative, real-time measurement of DNA glycosylase and AP endonuclease activities in cell nuclear lysates using base excision repair (BER) molecular beacons. The substrate (beacon) is comprised of a deoxyoligonucleotide containing a single base lesion with a 6-Carboxyfluorescein (6-FAM) moiety conjugated to the 5''end and a Dabcyl moiety conjugated to the 3'' end of the oligonucleotide. The BER molecular beacon is 43 bases in length and the sequence is designed to promote the formation of a stem-loop structure with 13 nucleotides in the loop and 15 base pairs in the stem^1,2. When folded in this configuration the 6-FAM moiety is quenched by Dabcyl in a non-fluorescent manner via Förster Resonance Energy Transfer (FRET)^3,4. The lesion is positioned such that following base lesion removal and strand scission the remaining 5 base oligonucleotide containing the 6-FAM moiety is released from the stem. Release and detachment from the quencher (Dabcyl) results in an increase of fluorescence that is proportionate to the level of DNA repair. By collecting multiple reads of the fluorescence values, real-time assessment of BER activity is possible. The use of standard quantitative real-time PCR instruments allows the simultaneous analysis of numerous samples. The design of these BER molecular beacons, with a single base lesion, is amenable to kinetic analyses, BER quantification and inhibitor validation and is adaptable for quantification of DNA Repair activity in tissue and tumor cell lysates or with purified proteins. The analysis of BER activity in tumor lysates or tissue aspirates using these molecular beacons may be applicable to functional biomarker measurements. Further, the analysis of BER activity with purified proteins using this quantitative assay provides a rapid, high-throughput method for the discovery and validation of BER inhibitors.     

New lipophilic phthalimido- and 3-phenoxybenzyl sulfonates: inhibition of antigen 85C mycolyltransferase activity and cytotoxicity

Four new sulfonates were prepared as potential inhibitors of antigen 85C, a mycolyl transferase involved in the biosynthesis of the mycobacterial cell wall being designed on the basis of the proposed catalytic mechanism and antigen 85C crystal structure. The inhibitors contained a sulfonate moiety, 3-phenoxybenzyl alcohol or N-(hydroxyethyl)phthalimide as trehalose mimetics, and an alkyl chain of different length mimicking either the mycolate (alpha-chain or the mycolic acid (beta-branch. One compound displayed promising activity in a mycolyltransferase inhibition assay (compound 2b, IC50 = 4.3 microM). The two compounds containing a phthalimide moiety (compounds 3a and 3b) showed significant and selective cytotoxicity against the breast cancer cell line MDA-MB231.     

Isoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: Effects on HDAC biology and antiproliferative activity

A series of hydroxamic acid based histone deacetylase inhibitors 6–15, containing an isoxazole moiety adjacent to the Zn-chelating hydroxamic acid, is reported herein. Some of these compounds showed nanomolar activity in the HDAC isoform inhibitory assay and exhibited micro molar inhibitory activity against five pancreatic cancer cell lines.     

Synthetic Sialyl Compounds as Well as Natural Gangliosides Induce Neuritogenesis in a Mouse Neuroblastoma Cell Line (Neuro2a)

Amphipathic compounds containing N-acetylneuraminic acid (sialic acid) [for example, D-N-acetylneuraminyl-(alpha 2-1)-2S,3R,4E-2-N-tetracosanoyl sphingenine, sialyl alkyl glycerol ethers, and sialyl cholesterols] induced neuritogenesis in a neuroblastoma cell line (Neuro2a). The sialic acid in the hydrophilic moiety of the compounds is specifically required for neuritogenesis. The requirement for molecular specificity of the hydrophobic moiety, however, is rather low. Regarding the hydrophobic moiety, no preference for cholesterol, alkyl glycerol ether, or ceramide residues was observed as to their neuritogenic activity. Sialyl compounds with alpha-ketosidic sialyl linkages were more active than the corresponding beta-anomers. These sialyl compounds induced the growth of only one neurite, but a long one, from the cell body. This type of neuritogenes is completely different from that induced by compounds capable of elevating the concentration of intracellular cyclic AMP, which induced the appearance of many neurites from a single cell body. Besides this morphological change, the active sialyl compounds also caused a change in the carbohydrate composition of the cell surface. Sialyl compound treatment drastically increased the concentration of peanut agglutinin binding sites.     

Synthesis,antibacterial and anticancer activity,and docking study of aminoguanidines containing an alkynyl moiety

Abstract

Two series of aminoguanidines containing an alkynyl moiety were designed, synthesised, and screened for antibacterial and anticancer activities. Generally, the series 3a–3j with a 1,2-diphenylethyne exhibited better antibacterial activity than the other series (6a–6k) holding 1,4-diphenylbuta-1,3-diyne moiety antibacterial activity. Most compounds in series 3a–3j showed potent growth inhibition against the tested bacterial strains, with minimum inhibitory concentration (MIC) values in the range 0.25–8?µg/mL. Compound 3g demonstrated rapid and persistent bactericidal activity at 2?×?MIC. The resistance study revealed that resistance of the tested bacteria towards 3g is not easily developed. Molecular docking studies revealed that compounds 3g and 6e bind strongly to the LpxC and FabH enzymes. Moreover, excellent activity of selected compounds against the growth of cancer cell lines A549 and SGC7901 was also observed, with IC₅₀ values in the range 0.30–4.57?µg/mL. These findings indicate that compounds containing the aminoguanidine moiety are promising candidates for the development of new antibacterial and anticancer agents.     

Antibacterial Activity and Structure−Activity Relationship of a Series of Newly Synthesized Pleuromutilin Derivatives

A series of novel thioether or sulfoxide‐type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram‐positive pathogens. In this work, a five‐membered heterocyclic moiety, a pyrimidine‐heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether‐containing pleuromutilin derivatives exert a more potency activity than the sulfoxide‐type derivatives against Gram‐positive pathogens. The structure?activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.     

New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines

The design of profen hybrids containing a NO donor moiety connected to an aliphatic spacer led to compounds with a similar cyclooxygenase inhibition compared to their parent profen and with significant antiproliferative activities on PC3 cells. However, inhibition of COX-2 pathway alone did not seem sufficient to inhibit cancer cell proliferation, and NO-release in a time-dependent manner strongly contributes to this activity.     

Synthesis and biological evaluation of a novel phenyl substituted sydnone series as potential antitumor agents

A series of compounds containing an N-(4'-substituted-3'-nitrophenyl)sydnone moiety with potential antitumor activity was prepared based on active analogues. The rationale behind the design of these compounds is presented along with the 4-step synthetic route to the derivatives in the 4'-position of the phenyl sydnone framework. Out of the six novel compounds, the 4'-fluoro derivative has an improved activity against all three cell lines as compared to the earlier leads.     

Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers

(R)- and (S)-Epichlorohydrins were used to prepare the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazoles that function as hypoxic cell radiosensitizers. The synthetic design allowed for introduction of a side chain of varying bulk that permitted an examination of the steric effects on enantio-discrimination in biological assay systems. The single stereocenter also connected the two pharmacophores--a 2-nitroimidazole moiety critical to hypoxic cell radiosensitization, and a haloacetylcarbamoyl group to function as an anti-angiogenesis pharmacophore. In the chick embryo chorioallantoic membrane (CAM) assay, the R-enantiomers possessing the bulky p-tert-butylphenyl group showed higher anti-angiogenic activity than the corresponding S-enantiomers, while there were no differences in the activity between the enantiomers containing the less bulky methyl and tert-butyl groups. Among the compounds we report, R-p-tert-butylphenyl-bromoacetylcarbamoyl-2-nitroimidazole, TX-1898, was found to be the most promising candidate for further development of as anti-angiogenic hypoxic cell radiosensitizer.     

Sialic acids, but not their linkage to galactose residues, are required for full expression of the biological activity of human chorionic gonadotropin

One of the characteristic features of the asparagine-linked sugar chains of human chorionic gonadotropin (hCG) is that their sialic acid residues occur exclusively as the Neu5Ac alpha 2----3Gal group. In order to determine whether this sialic acid linkage is important for the functional role played by the sugar moiety of hCG or not, isomeric hCG containing the Neu5Ac alpha 2----6Gal group was prepared and its hormonal activity in vitro was investigated. On addition of the isomeric hCG to the culture medium of a murine Leydig tumor cell line, it was found that it shows the same hormonal activity as natural hCG.     

Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.