Highly potent Platinum(IV) complexes with multiple-bond ligands targeting mitochondria to overcome cisplatin resistance.

The efficacy and resistance of cisplatin-based compounds are very intractable problems at present. This study reports a series of platinum(IV) compounds containing multiple-bond ligands, which exhibited better tumor cell inhibitory activity and antiproliferative and anti-metastasis activities than cisplatin. The meta-substituted compounds 2 and 5 were particularly excellent. Further research showed that compounds 2 and 5 possessed appropriate reduction potential and performed significantly better than cisplatin in cellular uptake, reactive oxygen species response, the up-regulation of apoptosis and DNA lesion-related genes, and drug-resistant cell activity. The title compounds exhibited better antitumor potential and fewer side effects than cisplatin in vivo. Multiple-bond ligands were introduced into cisplatin to form the title compounds in this study, which not only enhanced their absorption and overcame drug resistance but also demonstrated the potential to target mitochondria and inhibit the detoxification of tumor cells.

Discovery of novel phenylhydrazone-based oxindole-thiolazoles as potent antibacterial agents toward Pseudomonas aeruginosa.

With the soaring of bacterial infection and drug resistance, it is imperative to exploit new efficient antibacterial agents. This work constructed a series of unique phenylhydrazone-based oxindole-thiolazoles to combat monstrous bacterial resistance. Some target molecules showed potent antibacterial activity, among which oxindole-thiolimidazole derived carboxyphenylhydrazone 4e exhibited an 8-fold stronger inhibitory ability than norfloxacin on the growth of P. aeruginosa, with MIC value of 1 µg/mL. Compound 4e with imperceptible hemolysis could hamper bacterial biofilm formation and significantly impede the development of bacterial resistance. Subsequent mechanism studies demonstrated that 4e could destruct bacterial cytoplasmic membrane, causing the leakage of cellular contents (protein and nucleic acid). Moreover, metabolic stagnation and intracellular oxidative stress caused by 4e expedited the death of bacteria. Furthermore, molecule 4e existed supramolecular interactions with DNA to block DNA proliferation. These research results provided a promising light for phenylhydrazone-based oxindole-thiolazoles as novel potential antibacterial agents.

Unique Carbazole-Oxadiazole Derivatives as New Potential Antibiotics for Combating Gram-Positive and -Negative Bacteria.

Novel carbazole-oxadiazoles were developed as new potential antibacterial agents to combat dreadful resistance. Some target compounds displayed predominant inhibitory effects on the tested Gram-positive and -negative bacteria, and carbazole-oxadiazoles 5g, 5i-k, 16a-c, and tetrazole analogues 23b-c were found to be efficient in impeding the growth of MRSA and Pseudomonas aeruginosa ATCC 27853 (MICs = 0.25-4 µg/mL). Furthermore, compounds 5g and 23b-c not only possessed rapid bactericidal ability and low tendency to develop resistance but also exhibited low cytotoxic effects toward Hek 293T, HeLa, and red blood cells (RBCs), especially molecule 5g also showed low toxicity in vivo, which showed the therapeutic potential of these compounds. Further exploration indicated that compounds 5g, 5i, and 23b-c could disintegrate the integrity of bacterial cell membranes to leak the cytoplasmic contents, thus exerting excellent antibacterial effects. These facts mean that carbazole-based antibacterial agents might have bright prospects in confronting bacterial infections.

Dieckmann Condensation of Ugi N-Acylamino Amide Product: Facile Access to Functionalized 2,2-Disubstituted Indolin-3-ones.

Structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center have been constructed through a novel C-C bond formation at the C3 position of Ugi N-acylamino amide adducts employing an organic base-mediated Dieckmann condensation. This facile, flexible protocol can be fine-tuned to construct drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center only through the variation of the acid part in Ugi input. This novel and expeditious methodology has a broad scope and can rapidly generate the drug-like indolin-3-one core.

A facile reaction to access novel structural sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents.

A novel type of sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents was constructed via the unique ring-opened reaction of oxiranes by imidazoles for the first time. Some developed target hybrids showed potential antimicrobial potency against the tested microbes. Especially, imidazole derivative 5f could strongly suppressed the growth of MRSA (MIC = 4 µg/mL), which was 2-fold and 16-fold more potent than the positive control sulfathiazole and norfloxacin. This compound exhibited quite low propensity to induce bacterial resistance. Antibacterial mechanism exploration indicated that compound 5f could embed in MRSA DNA to form steady 5f-DNA complex, which possibly hinder DNA replication to exert antimicrobial behavior. Molecular docking showed that molecule 5f could bind with dihydrofolate synthetase through hydrogen bonds. These results implied that imidazole derivative 5f could be served as a promising molecule for the exploration of novel antibacterial candidates.

Facile synthesis and biological evaluation of tryptamine-piperazine-2,5-dione conjugates as anticancer agents.

A facile and efficient route to synthesize N-heterocyclic fused tryptamine-piperazine-2,5-dione conjugates was developed via a post-Ugi cascade reaction. The targeted compounds were prepared by means of a mild reaction and simple operation procedure, which could be applied to a broad scope of starting materials. Compound 6h was demonstrated to induce significant growth inhibition of AsPC-1 and SW1990 human pancreatic cancer cell lines (IC50 = 6 ± 0.85 µM). Our protocol allows for the construction of a structurally diverse compound library and paves a new avenue for the discovery of pancreatic cancer drug candidates.

Synthesis of Pyridodiindoles with Anticancer Activity by a Three-Component Cascade Condensation.

A novel three-component cascade reaction was discovered and developed to synthesize pyridodiindoles with the assistance of microwave irradiation. A collection of pyridodiindoles was prepared by means of the mild reaction and simple operation procedure, which could be applicable to a broad scope of functional aldehydes. Screening demonstrated that compound 5g exhibited a good potency in HCT116 cell lines, and this work validated the feasibility of this novel reaction for generating promising bioactive compounds.

Functionalized Spiroindolines with Anticancer Activity through a Metal-Free Post-Ugi Diastereoselective One-Pot Cascade Reaction.

A post-Ugi diastereoselective one-pot cascade reaction requiring no metal catalyst was developed. The reaction scope was wide with mild conditions and good yields. A collection of spiroindolines was prepared by the protocol and screening tests in several difficult-to-inhibit cancer cell lines were conducted. The relationship of structure and anticancer activities was promising and in the Huh7 cell lines compound 16 j is more potent than Vinbalstine. The cyclization design strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like heterocycles.

Recent advances in the development of polycyclic skeletons via Ugi reaction cascades.

Isocyanide-based multicomponent reactions are among the most powerful synthetic tools available. Particularly, the isocyanide-based Ugi reaction can allow rapid preparation of [Formula: see text]-aminoacyl amide derivatives and polyazaheterocycles with extensive pharmaceutical applications. Moreover, bridged polyazaheterocycles, including one or more quaternary carbon centers, can be constructed via the Ugi cascade reaction in a few steps. This review will emphasize synthesis and bioactivities of bridged compounds with quaternary centers constructed through Ugi cascade reactions.

Efficient Synthesis of Fused Oxazepino-isoquinoline Scaffolds via an Ugi, Followed by an Intramolecular Cyclization.

A mild and efficient protocol was developed for the synthesis of oxazepino-isoquinolines via a one-pot Ugi four-component reaction, followed by the intramolecular addition of the resulting alcohol to an alkyne moiety under microwave irradiation conditions. Notably, this process only required one purification step, providing facile access to two series of complex and potentially interesting biologically active scaffolds.

Metal-organic frameworks based on rigid ligands as separator membranes in supercapacitor.

Two thermally stable MOFs formulated as CoL(1,4-bdc)·2DMF (L = 3,5-bis(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)pyridine), 1,4-H2bdc = 1,4-benzenedicarboxylic acid) (1) and CdL(4,4'-bpc)·3DMF (4,4'-H2bpc = 4,4'-biphenyldicarboxylic acid) (2) have been solvothermally synthesized and exhibit a similar uninodal 6-connected 3D architecture with {4(12)·6(3)}-pcu topology. MOF1 shows a non-interpenetrated network with larger channel, whereas MOF 2 exhibits a 3-fold interpenetrating framework with smaller pore size. When the two MOFs are used as separator membranes in a supercapacitor, the equivalent series resistance (Res) is larger than the Res in the blank supercapacitor, and the smaller the current density, the more the Res. After being charged and discharged at the low current density, the supercapacitor with MOF 1 as separator membrane (denoted as 1a) possesses a much larger specific capacitance (SC) than the blank supercapacitor, and the amorphous separator membrane 1a shows a more porous morphology than the original MOF membrane 1.

Metal(II) complexes synthesized based on quinoline-2,3-dicarboxylate as electrocatalysts for the degradation of methyl orange.

Based on quinoline-2,3-dicarboxylic acid (H2L), two metal(II) complexes formulated as MnL(phen)(H2O)·H2O (phen = 1,10-phenanthroline) (1) and Co(HL)2(PPA)·4H2O (PPA = N(1),N(4)-di(pyridin-4-yl)terephthalamide) (2) were synthesized and structurally characterized by single-crystal X-ray diffraction. Both complexes 1 and 2 exhibit one-dimensional (1D) chain-like structures, in which stable five-membered rings are observed. Different chains are linked by strong π-π stacking interactions into a three-dimensional (3D) supramolecular architecture. Both complexes can increase the degradation rate of methyl orange (MO), which is expected to be associated with their electrocatalytic activities for the H2 evolution reaction from water.

In vivo characterization of Streptococcus pneumoniae genes involved in the pathogenesis of meningitis by differential fluorescence induction.

OBJECTIVE: To further understand the pathogenesis of pneumococcal meningitis, and provide some target candidates for the development of drugs. METHODS: This study was performed at the Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine (Ministry of Education), Chongqing Medical University, Chongqing, China from March 2006 to December 2007. A promoter-trap library of Streptococcus pneumoniae TIGR4, reported by green fluorescent protein was constructed, and used to infect BALB/c mice (n=15) intranasally, to set up a meningitis model. The control group (n=5) were inoculated with sterile phosphate buffered saline. The bacteria containing the promoter fusions induced only in meningitis brain tissue, not in vitro were screened by differential fluorescence induction. The obtained bacteria were prepared to re-infect the mice and re-screened, as above. The sorted bacteria were spread on trypticase soy agar with 5% sheep blood agar plates containing chloramphenicol (2.5 g/mL), and were used for DNA cloning, sequencing, and bioinformatics analysis. RESULTS: A total of 52 genes were obtained. Bioinformatics analysis revealed that these in vivo induced genes were involved in functions such as, adherence, energy metabolism, nutrient substance transport, transcription regulation, DNA metabolism, as well as, cell wall synthesis. In addition, there were some genes encoding for some hypothetical proteins with unknown, or putative functions. CONCLUSION: Pneumococcal genes involved in meningitis identified in this study are potential targets to understand the pathogenesis of pneumococcal meningitis.

Identification of Streptococcus pneumoniae genes specifically induced in mouse lung tissues.

To identify Streptococcus pneumoniae genes expressed specifically during infections, a selection system based on the in vivo expression technology (IVET) was established. galU, which is critical for capsular polysaccharide biosynthesis, and lacZY encoding beta-galactosidase were employed as dual reporter genes to screen in-vivo-induced (ivi) genes of S. pneumoniae. The galU-deficient mutant of S. pneumoniae is incapable of utilizing galactose, thus failing to synthesize capsular polysaccharide, and therefore loses its ability to survive in the host. A promoter-trap library was constructed in S. pneumoniae, which was used to infect BALB/c mice in an intranostril model. Those strains recovered from lung tissue of mice and exhibiting a white colony phenotype on tryptic soy agar containing X-gal (5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside) were collected and identificated. A total of 15 unique sequences were obtained through in vivo screening. The ivi genes of S. pneumoniae are involved in many processes, such as colonization and adherence, energy metabolism, nutrient substance transport, transcription regulation, DNA metabolism, and cell wall synthesis. There are some hypothetical proteins whose functions are not clear. This novel IVET is a useful tool for identifying ivi genes in S. pneumoniae.

[Screen and identification of Streptocococcus pneumoniae genes specifically induced in host].

To identify in vivo-induced genes of S. pneumoniae and search new potential drug targets and vaccine candidates, a selection system was developed based on the in vivo expression technology (IVET). Promoter galU gene which is critical for the capsular polysaccharide biosynthesis and lacZY gene which encodes bea-galactosidase were employed as dual reporter genes. The galU-deficient mutant of S. pneumoniae is incapable of utilizing galactose and synthesizing capsular polysaccharide, therefore can't survival in the host. Firstly, the random pieces of S. pneumoniae chromosomal DNA (200-500 bp), obtained by partial Sau3Al restriction digestion, were subcloned into the Bgl II site of pEVP3-galU. Transformation by this plasmid library yielded promoter-trap library in S. pneumoniae. Then, the library was used to infect animals. Bacteria were harvested from lung tissue. White clones on TSA agar containing X-gal were used to reinfect animals. The sequence of infection and sorting was performed twice, 165 white clones harvested from the final round of infection were analyzed. A total of 15 unique sequences were obtained through in vivo screen. The bioinformatics analysis showed that these ivi genes involved in colonization and adherence, energy metabolism, nutrient substance transport, transcription regulation, DNA metabolism and cell wall synthesis. And there were some hypothetical proteins have unknown functions. Part of these genes may be related with virulence and can be used as vaccine candidates and drug targets.

The effect of transformation on the virulence of Streptococcus pneumoniae.

Although pneumococcus is one of the most frequently encountered opportunistic pathogen in the world, the mechanisms responsible for its infectiveness have not yet been fully understood. In this paper, we have attempted to characterize the effects of pneumococcal transformation on the pathogenesis of the organism. We constructed three transformation-deficient pneumococcal strains, which were designated as Nos. 1d, 2d, and 22d. The construction of these altered strains was achieved via the insertion of the inactivated gene, comE, to strains 1, 2 and 22. We then conducted a comparison between the virulence of the transformation-deficient strains and that of the wild-type strains, via an evaluation of the ability of each strain to adhere to endothelial cells, and also assessed psaA mRNA expression, and the survival of hosts after bacterial challenge. Compared to what was observed with the wild-type strains, our results indicated that the ability of all of the transformation-deficient strains to adhere to the ECV304 cells had been significantly reduced (p < 0.05), the expression of psaA mRNA was reduced significantly (p < 0.05) in strains 2d and 22d, and the median survival time of mice infected with strains 1d and 2d was increased significantly after intraperitoneal bacterial challenge (p < 0.05). The results of our study also clearly indicated that transformation exerts significant effects on the virulence characteristics of S. pneumoniae, although the degree to which this effect is noted appears to depend primarily on the genetic background of the bacteria.