Comparison and Mechanism Study of Antibacterial Activity of Cationic and Neutral Oligo-Thiophene-Ethynylene.

Photodynamic therapy (PDT) is a potential approach to resolve antibiotic resistance, and phenylene/thiophene-ethynylene oligomers have been widely studied as effective antibacterial reagents. Oligomers with thiophene moieties usually exhibit good antibacterial activity under light irradiation and dark conditions. In the previous study, we verified that neutral oligo-p-phenylene-ethynylenes (OPEs) exhibit better antibacterial activity than the corresponding cationic ones; however, whether this regular pattern also operates in other kinds of oligomers such as oligo-thiophene-ethynylene (OTE) is unknown. Also, the antibacterial activity comparison of OTEs bearing cyclic and acyclic amino groups will offer useful information to further understand the role of amino groups in the antibacterial process and guide the antibacterial reagent design as amino groups affect the antibacterial activity a lot. We synthesized four OTEs bearing neutral or cationic, cyclic, or acyclic amino groups and studied their antibacterial activity in detail. The experimental results indicated that the OTEs exhibited better antibacterial activity than the OPEs, the neutral OTEs exhibited better antibacterial activity in most cases, and OTEs bearing cyclic amino groups exhibited better antibacterial activity than those bearing acyclic ones in most cases. This study provides useful guidelines for further antibacterial reagent design and investigations.

Investigating Antibacterial Efficiency and Mechanism of Oligo-thiophenes under White Light and Specific Biocidal Activity against E. coli in Dark.

More strategies are required to develop better photosensitizers for photodynamic therapy (PDT). As oligo(phenylene-ethynylene) electrolytes (OPE), oligo(thiophene)s with primary amine as pendant groups (P-OT), and oligo(thiophene ethynylene) (OTE) exhibit excellent light-induced biocidal activity, we desire to converge the molecular design principles of these three kinds of antibacterial agents to combine their advantages to obtain high efficiency and economic biocides. Thus, four oligo(thiophene)s (OTs) were designed and synthesized in this study. The light-induced and dark antibacterial efficacy of the four OTs against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) were both evaluated. Notably, all the OTs present high biocidal efficacy in the broad spectrum at low (micromolar) concentrations after white-light irradiation. In particular, the low cell cytotoxicity of OTs exhibits their good biocompatibility. These results illustrate that the OTs could work as promising PDT biocides. Interestingly, OT-3 shows a strong and specific dark killing activity against E. coli. The higher biocidal efficacy of T-OTs compared with that of Q-OTs confirms the tertiary amine is a better pendant group for π-conjugated antibacterial agents against E. coli. Mechanistic investigation proves ROS is the necessary element for antibiosis under white light. The interacting efficacy of the OT to the cell membrane, involving synergistic effects between hydrophilic-hydrophobic interactions and electrostatic attractions, is also critical in the killing process. The membrane intercalating activity plays a more essential role, as indicated by the antibacterial activity of OTs. The results provide a unique insight into the relationship between molecular structure and antibacterial activities of this class of antibacterial agents.

Dual-radiolabelling of an injectable hyaluronan-tyramine-bisphosphonate hybrid gel for in vitro and in vivo tracking.

Hyaluronan (HA) have been widely used as the ideal biomaterials. It is important to understand their degradation and distribution for better optimization. From a new aspect of using radiotracers, we designed the HA-tyramine-bisphosphonate derivative for dual-labelling with two radionuclides (99mTc and 131I) simultaneously for in vitro and in vivo tracking. This dual-radiolabelled HA derivative can still be non-covalently crosslinked by hydroxyapatites to form injectable gel. The excellent properties of the gel, such as robust, biodegradable, and self-healing capacity were maintained. We firstly proved the possibility to distinguish different radionuclides in the degraded gel using the high-resolution gamma-ray spectrometry. The radiolabelled gel showed lower toxicity than pure hydroxyapatites against various cell lines, while the in vivo results proved that the 99mTc/131I-labelling of the gel was safe and stable enough for imaging and quantitatively tracking. The present method can also be applied for the development of dual-radiolabelled gels from other polysaccharides.

Biocidal Activity and Mechanism Study of Unsymmetrical Oligo-Phenylene-Ethynylenes.

Bacterial contamination and the spread of antibiotic-resistant bacteria demand alternate methods to deal with bacterial infections. With particular advantages, photodynamic therapy (PDT) is a promising approach. As a kind of photosensitizer for PDT, light-induced antibacterial compounds like oligo-p-phenylene-ethynylenes (OPEs) have been widely investigated while these studies mainly focus on OPEs with quaternary ammonium salts. In our previous study, OPEs with tertiary amino groups (T-OPEs) were reported to exhibit a better antibacterial activity than the corresponding quaternary ammonium salts, which make it important to develop T-OPEs and further investigate their structure-activity relationship. Additionally, the terminal structure of the reported OPEs mainly consists of quaternary ammonium salts or tertiary amino groups, which could not be linked to other materials. Thus, to develop more effective and multifunctional antibacterial agents, we designed and synthesized four unsymmetrical OPEs having terminal amino groups, which could be linked to other functional units by covalent bonds. Their antibacterial activity against Gram-positive and Gram-negative bacteria and the mechanism have been investigated. The OPEs showed effective biocidal activity under fiber light irradiation, and no dark killing was observed. The mechanism study indicates that OPEs could penetrate and perturb the cell membrane and generate ROS under light irradiation, both of which could influence their antibacterial activity. The penetrating ability of OPEs is partly dependent on their lipophilicity and the structure and composition of the cell membrane.

Radiolabeling, quality control, biodistribution, and imaging studies of 177 Lu-ibandronate.

The purposes of this study were as follows: (1) to radiolabel ibandronic acid (IBA, a third-generation bisphosphonate) with 177 Lu, investigating optimal labeling conditions, and (2) to analyze biodistribution and imaging properties of intravenous 177 Lu-ibandronate (177 Lu-IBA) administered in animals. 177 Lu-labeled methylene diphosphonate (177 Lu-MDP) served as a comparator agent. Differing proportions of IBA solution and 177 LuCl3 solution were combined to determine an optimal ratio for radiolabeling purposes, varying pH, temperature, and time to establish ideal reactivity conditions. Radiochemical purity of the labeled compounds was then assessed by paper chromatography. In vitro and in vivo stabilities were also measured at specific time intervals. In Kunming mice, biodistributions of 177 Lu-IBA and 177 Lu-MDP and respective agent activities in various organs were monitored by gamma counter, and we performed single photon computed tomography/computed tomography (SPECT/CT) imaging of 177 Lu-IBA in normal New Zealand White rabbits. Radiolabeling yields for 177 Lu-IBA proved to be >97% within 30 minutes at 90°C, and its radiochemical purity ensured stability in vitro and in vivo. Furthermore, we found that 177 Lu-IBA is readily soluble in water, showing higher skeletal uptake than 177 Lu-MDP but lower uptake by liver and spleen. The image quality of 177 Lu-IBA was so clear that even after 6 days, analysis was still feasible.

Visible light-induced biocidal activities and mechanistic study of neutral porphyrin derivatives against S. aureus and E. coli.

Positive charged porphyrins have long been regarded as effective biocidal agents, however neutral porphyrins have rarely been studied in their ability photoinactivating microbials, and the structure-activity relationship such as correlation of electronic effect and biocidal activity of porphyrins still remains unclear. Herein, four neutral porphyrins with various electronic effects were selected to undergo light-induced biocidal processes. It turned out that the TPPOH and TPPNH2 with electron-donating groups NH2 and OH, respectively, exhibited much more powerful light-induced biocidal activities against E. coli and S. aureus than TPP and TPPNO2 with electron-withdrawing group NO2. This phenomenon suggested that neutral porphyrins may be treated as a new class of biocidal agents and functional groups with various electronic effects on porphyrins can dramatically affect porphyrins' light-induced biocidal activities. Mechanistic studies demonstrate that despite a better light-induced antibacterial ability of TPPOH, its singlet oxygen generation efficacy is a little lower than that of TPPNH2, together with charge characteristics and lipophilicity, it is clear that (1) the oxidative species singlet oxygen and ROS played the key role in the photo-activated antimicrobial processes of porphyrins, and (2) higher singlet oxygen or ROS yields of TPPOH and TPPNH2 may originate from their structural characteristics, namely electron-donating groups OH or NH2, and (3) a synergistic effect of all other factors including the electrostatic and hydrophobic effects must involve in the process and cooperatively determine their biocidal activities.

Significant enhanced uranyl ions extraction efficiency with phosphoramidate-functionalized ionic liquids via synergistic effect of coordination and hydrogen bond.

The influence of the linking group between the phosphoryl and bridging moieties in phosphoryl-containing task-specific ionic liquids (TSILs) on the extraction of uranyl ions was experimentally and theoretically investigated. A novel phosphoramidate-based TSIL with an amine group as the linking moiety resulted in a higher uranyl ion extraction efficiency compared with that of other phosphoryl-based TSILs. A distribution ratio of 4999 ± 51 can be achieved for uranyl ions. The uranyl ions (76.7 ± 1.5%) were stripped from the loaded ionic liquid phase in a single stage using 0.05 M diethylenetriamine pentaacetic acid in a 1.0 M guanidine carbonate solution. The extraction stoichiometry of the uranyl ions was determined by a slope analysis of the extraction data. Furthermore, the fundamental nature of the interaction between the phosphoramidate-based TSIL and uranyl ions was theoretically studied for the first time. The theoretical calculations demonstrated that the synergistic effect of the complexation interaction and H-bond formation between the phosphoramidate-functional ionic liquid and uranyl nitrate led to the higher extraction efficiency. These results provide a basis for rational design, synthesis and potential applications of novel TSILs for uranyl extraction.

Assessing the Biocidal Activity and Investigating the Mechanism of Oligo-p-phenylene-ethynylenes.

A number of oligo-p-phenylene-ethynylenes (OPEs) have exhibited excellent biocidal activity against both Gram-negative and Gram-positive bacteria. Although cell death may occur in the dark, these biocidal compounds are far more effective in the light as a result of their abilities to generate cell-damaging reactive oxygen species. In this study, the interactions of four OPEs with Escherichia coli and Staphylococcus aureus have been investigated. Compared to the OPEs with quaternary ammonium salts (Q-OPE), the OPEs with tertiary ammonium (T-OPE) effectively kill many more bacterial cells under light irradiation, presumably by severe perturbations of the bacterial cell wall and cytoplasmic membrane. According to the findings from this study, such intriguing light-induced antibacterial behavior is probably attributed to the combination of bacterial membrane disruption and the interfacial or intracellular generation of singlet oxygen or other ROS. Singlet oxygen was proved to be formed from irradiation of the OPEs, whereas the varying cell membrane perturbation abilities of OPEs enhance antibacterial activity.

Mechanisms of the InCl3-catalyzed type-I, II, and III cycloisomerizations of 1,6-enynes.

InCl3-catalyzed cycloisomerizations of 1,6-enynes can give either type-I dienes and cyclohexenes (type-III dienes), or type-II dienes, depending on the substitutions in the substrates. Previously, we studied how the type-II diene products were generated and found that the real catalytic species for the cycloisomerizations is InCl2(+) (J. Org. Chem. 2012, 77, 8527-8540). In the present paper, we used density functional theory (DFT) calculations to reveal how the type-I and type-III dienes were generated. A unified model to explain how substituents affect the regiochemistry of type-I, II, and III cycloisomerizations has been provided. Experimental and computational investigation of the InCl3-catalyzed cycloisomerization of 1,6-enynes with both substituents at the alkyne and alkene parts has also been reported in the present study.

Mild-condition synthesis of allenes from alkynes and aldehydes mediated by tetrahydroisoquinoline (THIQ).

A practical 1,2,3,4-tetrahydroisoquinoline (THIQ)-mediated synthesis of 1,3-disubstituted allenes from terminal alkynes and aldehydes under mild conditions in the presence of CuBr first and then ZnI2 was reported. This telescoped allene synthesis reaction includes three consecutive steps and two reactions: first, a room-temperature CuBr-catalyzed synthesis of propargylamines, exo-yne-THIQs, from terminal alkynes, aldehydes, and THIQ, then filtration of the CuBr catalyst, and finally the ZnI2-mediated allene synthesis from the generated exo-yne-THIQs under mild conditions (either at room temperature or heating at 50 or 75 °C). A wide range of aliphatic or aromatic aldehydes and terminal alkynes are tolerated, affording the allene products in up to 92% yield. Especially, temperature-sensitive aldehydes can be used in the reaction system. Preliminary exploration of the asymmetric allene synthesis has also been conducted, and a moderate enantioselectivity has been achieved. Finally, the relative reactivities of several secondary amines were compared with THIQ, showing that THIQ is the best of these amines in the synthesis of allenes under mild reaction conditions.

Synthesis of Z-alkenes from Rh(I)-catalyzed olefin isomerization of ß,γ-unsaturated ketones.

Developing olefin isomerization reactions to reach kinetically controlled Z-alkenes is challenging because formation of trans-alkenes is thermodynamically favored under the traditional catalytic conditions using acids, bases, or transition metals as the catalysts. A new synthesis of Z-alkenes from Rh(I)-catalyzed olefin isomerization of ß,γ-unsaturated ketones to α,ß-unsaturated ketones was developed, providing an easy and efficient way to access various Z-enones.

DFT and experimental exploration of the mechanism of InCl3-catalyzed type II cycloisomerization of 1,6-enynes: identifying InCl2(+) as the catalytic species and answering why nonconjugated dienes are generated.

InCl(3) and other In(III) species have been widely applied as catalysts in many reactions. However, what are the real catalytic species of these reactions? Through DFT calculations and experimental investigation of the mechanism and regioselectivity of InCl(3)-catalyzed cycloisomerization reactions of 1,6-enynes (here all discussed 1,6-enynes are ene-internal-alkyne molecules), we propose that the catalytic species of this reaction is the in situ generated InCl(2)(+). Further electrospray ionization high-resolution mass spectroscopy (ESI-HRMS) supported the existence of InCl(2)(+) in acetonitrile solution. This finding of InCl(2)(+) as the catalytic species suggests that other reactions catalyzed by In(III) species could also have cationic In(III) species as the real catalysts. DFT calculations revealed that the catalytic cycle of the cycloisomerization of 1,6-enynes catalyzed by InCl(3) starts from InCl(2)(+) coordination to the alkyne of the substrate, generating a vinyl cation. Then nonclassical cyclopropanation of the vinyl cation to the alkene part of the substrate gives a homoallylic cation, which undergoes a novel homoallylic cation rearrangement involving a [1,3]-carbon shift to give the more stable homoallylic cation 15. Finally InCl(2)(+) cation coordination assisted nonconjugated [1,2]-hydride shifts deliver the final nonconjugated diene products. The preference of generating nonconjugated dienes instead of conjugated dienes in the cycloisomerization reaction is mainly due to two reasons: coordination of the InCl(2)(+) to the alkene part in [1,2]-H shift transition states disfavors the conjugated [1,2]-H shifts that generate cations adjacent to the positively charged alkene, and coordination of InCl(2)(+) to the nonconjugated diene product is stronger than coordination to the conjugated diene, making nonconjugated [1,2]-H shift transition states lower in energy than conjugated [1,2]-H shift transition states, on the basis of the Hammond postulate. DFT calculations predicted that the conjugated [1,2]-H shifts could become favored if the electron-donating methyl substituent in the alkyne moiety of the 1,6-enyne is replaced by a H atom. This prediction of producing a conjugated diene has been verified experimentally. Rationalization about why type II rather than type I products were obtained using InCl(3) as the catalyst in the cycloisomerization of 1,6-enynes has also been investigated computationally.

Highly enantioselective hydrogenation of quinolines using phosphine-free chiral cationic ruthenium catalysts: scope, mechanism, and origin of enantioselectivity.

Asymmetric hydrogenation of quinolines catalyzed by chiral cationic η(6)-arene-N-tosylethylenediamine-Ru(II) complexes have been investigated. A wide range of quinoline derivatives, including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (-)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and hydrogen addition undergoes a stepwise H(+)/H(-) transfer process outside the coordination sphere rather than a concerted mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η(6)-arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO(-) anion.

Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-yne/ene-vinylcyclopropanes and CO: homologous Pauson-Khand reaction and total synthesis of (+/-)-alpha-agarofuran.

A novel Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition, which can be regarded as a homologous Pauson-Khand reaction, was developed to synthesize bicyclic cyclohexenones and cyclohexanones, enabling a new approach for synthesis of six-membered carbocycles ubiquitously found in natural products and pharmaceutics. The significance of the Rh-catalyzed [(3 + 2) + 1] cycloaddition has been demonstrated by the total synthesis of a furanoid sesquiterpene natural product, alpha-agarofuran, in which the bicyclic skeleton was constructed by the [(3 + 2) + 1] reaction of 1-yne-VCP and CO.