Synthesis, cytotoxicity and antioxidant activity of new conjugates of N-acetyl-d-glucosamine with α-aminophosphonates.

A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M - HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33-80 µM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 µM), demonstrated good activity (IC50 = 17 µM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 µM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.

Laser-Induced Chirality of Plasmonic Nanoparticles Embedded in Porous Matrix.

Chiral plasmonic nanostructures have emerged as promising objects for numerous applications in nanophotonics, optoelectronics, biosensing, chemistry, and pharmacy. Here, we propose a novel method to induce strong chirality in achiral ensembles of gold nanoparticles via irradiation with circularly-polarized light of a picosecond Nd:YAG laser. Embedding of gold nanoparticles into a nanoporous silicate matrix leads to the formation of a racemic mixture of metal nanoparticles of different chirality that is enhanced by highly asymmetric dielectric environment of the nanoporous matrix. Then, illumination with intense circularly-polarized light selectively modifies the particles with the chirality defined by the handedness of the laser light, while their "enantiomers" survive the laser action almost unaffected. This novel modification of the spectral hole burning technique leads to the formation of an ensemble of plasmonic metal nanoparticles that demonstrates circular dichroism up to 100 mdeg. An unforeseen peculiarity of the chiral nanostructures obtained in this way is that 2D and 3D nanostructures contribute almost equally to the observed circular dichroism signals. Thus, the circular dichroism is neither even nor odd under reversal of direction of light propagation. These findings will help guide the development of a passive optical modulator and nanoplatform for enhanced chiral sensing and catalysis.

The First 5'-Phosphorylated 1,2,3-Triazolyl Nucleoside Analogues with Uracil and Quinazoline-2,4-Dione Moieties: A Synthesis and Antiviral Evaluation.

A series of 5'-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, H-phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the 1,2,3-triazole-4-yl-ß-D-ribofuranose fragment is attached via a methylene group or a butylene chain to the N-1 atom of the heterocycle moiety (uracil or quinazoline-2,4-dione) was synthesized. All compounds were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1). Antiviral assays revealed three compounds, 13b, 14b, and 17a, which showed moderate activity against influenza virus A (H1N1) with IC50 values of 17.9 µM, 51 µM, and 25 µM, respectively. In the first two compounds, the quinazoline-2,4-dione moiety is attached via a methylene or a butylene linker, respectively, to the 1,2,3-triazole-4-yl-ß-D-ribofuranosyl fragment possessing a 5'-diphenyl phosphate substituent. In compound 17a, the uracil moiety is attached via the methylene unit to the 1,2,3-triazole-4-yl-ß-D-ribofuranosyl fragment possessing a 5'-(phenyl methoxy-L-alaninyl)phosphate substituent. The remaining compounds appeared to be inactive against influenza virus A/PR/8/34/(H1N1). The results of molecular docking simulations indirectly confirmed the literature data that the inhibition of viral replication is carried out not by nucleoside analogues themselves, but by their 5'-triphosphate derivatives.

Synthesis, antimicrobial activity and cytotoxicity of triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues.

Four new triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues were synthesized by coupling with 8-bromoctyl- or 10- bromdecyltriphenylphosphonium bromide and evaluated for the in vitro antibacterial activity against S. aureus, B. cereus, E. faecalis, two MRSA strains isolated from patients and resistant to fluoroquinolone antibiotic ciprofloxacin and ß-lactam antibiotic amoxicillin, E. coli, antifungal activity against T. mentagrophytes C. albicans and cytotoxicity against human cancer cell lines M-HeLa, MCF-7, A549, HuTu-80, PC3, PANC-1 and normal cell line Wi-38. In these compounds a TPP cation was attached via an octyl or a decyl linker to the N 3 atom of the heterocycle moiety (thymine, 6-methyluracil, quinazoline-2,4-dione) which was bonded with 2',3',5'-tri- O - acetyl-greek beta-d-ribofuranose residue by the (1,2,3-triazol-4-il)methyl bridge. All synthesized compounds showed high antibacterial activity against S. aureus within the range of MIC values 1.2-4.3 greek muM, and three of them appeared to be bactericidal with respect to tis bacterium at MBC values 4.1-4.3 greek muM. Two lead compounds showed both high antibacterial activity against the MRSA strains resistant to Ciprofloxacin and Amoxicillin within the range of MIC values 1.0-4.3 greek muM and high cytotoxicity against human cancer cell lines HuTu-80 and MCF-7 within the range of IC50 values 6.4-10.2 greek muM. This is one of the few examples when phosphonium salts exhibited both antibacterial activity and cytotoxicity against human cancer cell lines. According to the results obtained the bactericidal effect of the lead compounds, unlike classical surfactants, was not caused by a violation of the integrity of the cytoplasmic membrane of bacteria and their cytotoxic activity is most likely associated both with the induction of apoptosis along the mitochondrial pathway and the arrest of the cell cycle in the G0/G1 phase.

Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues.

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-ß-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-ß-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2',3',5'-tri-O-acetyl-ß-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2',3',5'-tri-O-acetyl-ß-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity.

Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-tri-O-acetyl-D-ß-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC50 = 30 µM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC50 = 15 µM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).

Glycosides and Glycoconjugates of the Diterpenoid Isosteviol with a 1,2,3-Triazolyl Moiety: Synthesis and Cytotoxicity Evaluation.

Several glycoconjugates of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with a 1,2,3-triazolyl moiety were synthesized, and their cytotoxicity was evaluated against some human cancer and normal cell lines. Most of the synthesized compounds demonstrated weak inhibitory activities against the M-HeLa and MCF-7 human cancer cell lines. Three lead compounds, 54, 56 and 57, exhibited high selective cytotoxic activity against M-HeLa cells (IC50 = 1.7-1.9 µM) that corresponded to the activity of the anticancer drug doxorubicin (IC50 = 3.0 µM). Moreover, the lead compounds were not cytotoxic with respect to a Chang liver human normal cell line (IC50 > 100 µM), whereas doxorubicin was cytotoxic to this cell line (IC50 = 3.0 µM). It was found that cytotoxic activity of the lead compounds is due to induction of apoptosis proceeding along the mitochondrial pathway. The present findings suggest that 1,2,3-triazolyl-ring-containing glycoconjugates of isosteviol are a promising scaffold for the design of novel anticancer agents.

Synthesis and anti-cancer activities of glycosides and glycoconjugates of diterpenoid isosteviol.

A series of glycosides and glycoconjugates of diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with various monosaccharide residues were synthesized and their cytotoxicity against some human cancer and normal cell lines was assayed. Most of the synthesized compounds demonstrated moderate to significant cytotoxicity against human cancer cell lines M-HeLa and MCF-7. Three lead compounds exhibited selective cytotoxic activities against M-HeLa (IC50 = 10.0-15.1 µM) that were three times better than the cytotoxicity of the anti-cancer drug Tamoxifen (IC50 = 28.0 µM). Moreover, the lead compounds were not cytotoxic with respect to the normal human cell line Chang liver (IC50 > 100 µM), whereas Tamoxifen inhibited the viability of normal human Chang liver cells with an IC50 value of 46.0 µM. It was determined that the cytotoxicity of the lead compounds was due to induction of apoptosis proceeding along the mitochondrial pathway. The cytotoxic activity of the synthesized compounds substantially depended on the nature of the monosaccharide residue and its position, that is, whether the monosaccharide residue was attached directly to the isosteviol skeleton or was moved away from it by means of a polymethylene linker.

Synthesis and antituberculosis activity of the first macrocyclic glycoterpenoids comprising glucosamine and diterpenoid isosteviol.

The first macrocyclic glycoterpenoids comprising glucosamine and diterpenoid isosteviol moieties were synthesized and evaluated for inhibition activity against Mycobacterium tuberculosis H37Rv.