Antibacterial activity of multi-metallic (Ag-Cu-Li) nanorods with different metallic combination ratios against Staphylococcus aureus.

OBJECTIVE: Because of the need to extensively study the synergistic activity of metallic nanoparticles, this study aimed to evaluate the antibacterial activity of mixed metallic nanoparticles, made by differing the weight mixing ratio. We prepared multi-metallic nanorods (NRs) by chemical reduction method, with different ratio combinations of silver Ag and copper Cu, two main batches of nanorods were produced: bimetallic mix made only of Ag-Cu, and trimetallic mix made of Ag-Cu and lithium Li, AgCu NRs and AgCuLi NRs respectively. NaOH was used in the synthesis for the co-reduction of salt precursors. Ag percentage was varied from 10 to 90% in bimetallic NRs but in the trimetallic NRs, which has a fixed ratio of Li (10%), the percentage of silver precursor was from 10 to 80%. The presence of metals was confirmed by energy dispersive X-rays (EDX) analysis. Ion release was detected using inductively coupled plasma spectrometer (ICP) and the values showed that NRs are effective source for ion supply for up to 24 h. The antibacterial activity of metallic NRs was tested against Staphylococcus aureus using Bauer Kirby method. RESULTS: The bi-synergistic mix of Ag and Cu generates more ions than the tri-synergistic mix of Ag, Cu, and Li. Nevertheless, the later was more efficient and showed higher antibacterial activity at lower concentrations. This effect is less likely to be attributed to modality of ion release. Indeed, the results of our work suggest that besides ion release, alloyed nanorods themselves are toxic and the trimetallic mix exhibited more biocidal activity, specifically at Ag salt concentrations of 30%, 50% and 70%.

Solenopsin A and analogs exhibit ceramide-like biological activity.

BACKGROUND: (-)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis. METHODS: Different analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated. RESULTS: In this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (-)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide. CONCLUSIONS: The requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (-)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.

Asymmetric Synthesis of Hydroxy Esters with Multiple Stereocenters via a Chiral Phosphoric Acid Catalyzed Kinetic Resolution.

The kinetic resolution of hydroxy tert-butyl esters through a Brønsted acid catalyzed lactonization is described. The resulting enantioenriched molecules have cyclic backbones and/or multiple stereocenters. DFT calculations explore how small changes in substrate structure can have a large impact on the selectivity of the process.

Facile synthesis of versatile enantioenriched α-substituted hydroxy esters through a Brønsted acid catalyzed kinetic resolution.

An efficient synthesis of enantioenriched α-substituted γ-hydroxy esters via a kinetic resolution event is described. Bulky racemic esters in the presence of a chiral Brønsted acid selectively lactonize to yield a recoverable enantioenriched hydroxy ester and lactone. These esters are highly versatile building blocks that can readily be converted to synthetically useful materials.

Targeting DNA bulged microenvironments with synthetic agents: lessons from a natural product.

Bulged regions of nucleic acids are important structural motifs whose function has been linked to a number of key nuclear processes. Additionally, bulged intermediates have been implicated in the etiology of several genetic diseases and as targets for viral regulation. Despite these obvious ramifications, few molecules are capable of selective binding to bulged sequences. Prompted by the remarkable affinity of a natural product metabolite, we have designed and prepared a series of readily accessible synthetic agents with selective bulge binding activity. Furthermore, by screening a library of bulge-containing oligodeoxynucelotides, correlations between structure and affinity of the agents can be drawn. In addition to potential applications in molecular biology, the availability of these spirocyclic agents now opens the door for rational drug design.