Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper(I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs.

Breast cancer is the second type of cancer with a high probability of brain metastasis and has always been one of the main problems of breast cancer research due to the lack of effective treatment methods. Demand for developing an effective drug against breast cancer brain metastasis and finding molecular mechanisms that play a role in effective treatment are gradually increasing. However, there is no effective anticancer therapeutic drug or treatment method specific to breast cancer, in particular, for patients with a high risk of brain metastases. It is known that mTOR and HDAC enzymes play essential roles in the development of breast cancer brain metastasis. Therefore, it is vital to develop some new drugs and conduct studies toward the inhibition of these enzymes that might be a possible solution to treat breast cancer brain metastasis. In this study, a series of 1,10-phenanthroline and Prodigiosin derivatives consisting of their copper(I) complexes have been synthesized and characterized. Their biological activities were tested in vitro on six different cell lines (including the normal cell line). To obtain additional parallel validations of the experimental data, some in silico modeling studies were carried out with mTOR and HDAC1 enzymes, which are very crucial drug targets, to discover novel and potent drugs for breast cancer and related brain metastases disease.

Determining the source of unusual xenon isotopes in samples.

Three unusual radioactive isotopes of xenon-125Xe, 127Xe, and 129mXe-have been observed during testing of a new generation radioxenon measurement system at the manufacturing facility in Knoxville, Tennessee. These are possibly the first detections of these isotopes in environmental samples collected by automated radioxenon systems. Unfortunately, the new isotopes detected by the Xenon International sampler can interfere with quantification of the radioactive xenon isotopes used to monitor for nuclear explosions. Xenon International sampling data collected during February through September 2020 were combined with an atmospheric transport model to identify the possible release location. A source-location analyses using sample counts dominated by 125Xe strongly supports the conclusion that the release point is near (within 20 km) the sampler location. Wind patterns are not consistent with releases coming from more distant nuclear power plants. The High Flux Isotope Reactor (HFIR) and the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory are located in the region of most likely source locations. The source-location analysis cannot rule out either facility as a release location, and some of the samples may contain a combination of releases from both facilities. The source-location results using 125Xe are not unexpected because Klingberg et al. (2013) previously published the production rate of radioactive xenon isotopes from neutron activation of stable xenon in the air at the HFIR. Up to 1012 Bq of 125Xe could be produced per operational day and other xenon isotopes would be produced in lesser quantities.

Characterization and photocatalytic behavior of 2,9-di(aryl)-1,10-phenanthroline copper(i) complexes.

The synthesis, characterization, photophysical properties, theoretical calculations, and catalytic applications of 2,9-di(aryl)-1,10-phenanthroline copper(i) complexes are described. Specifically, this study made use of di(aryl)-1,10-phenanthroline ligands including 2,9-di(4-methoxyphenyl)-1,10-phenanthroline (1), 2,9-di(4-hydroxyphenyl)-1,10-phenanthroline (2), 2,9-di(4-methoxy-3-methylphenyl)-1,10-phenanthroline (3), and 2,9-di(4-hydroxy-3-methylphenyl)-1,10-phenanthroline (4). The 2 : 1 ligand-to-metal complexes, as PF6- salts, i.e., ([Cu·(1)2]PF6, [Cu·(2)2]PF6, [Cu·(3)2]PF6, and [Cu·(4)2]PF6) have been isolated and characterized. The structures of ligands 1 and 2 and complexes [Cu·(1)2]PF6 and [Cu·(3)2]PF6 have been determined by single-crystal X-ray analysis. The photoredox catalytic activity of these copper(i) complexes was investigated in an atom-transfer radical-addition (ATRA) reaction and the results showed fairly efficient activity, with a strong wavelength dependence. In order to better understand the observed catalytic activity, photophysical emission and absorption studies, and DFT calculations were also performed. It was determined that when the excitation wavelength was appropriate for exciting into the LUMO+1 or LUMO+2, catalysis would occur. On the contrary, excitations into the LUMO resulted in no observable catalysis. In light of these results, a mechanism for the ATRA photoredox catalytic cycle has been proposed.

Synthesis of metalated pseudorotaxane polymers with full control over the average linear density of threaded macrocycles.

Here we report the synthesis of metalated main-chain polypseudorotaxanes via ring-opening olefin metathesis copolymerization of macrocycles and metalated [2]catenanes. By varying the feed ratio of the macrocycle and the [2]catenate comonomers, we prepared metalated pseudorotaxane polymers with selected, predictable average linear densities of threaded macrocycles that ranged from 0% to 100%, thus allowing, for the first time, both full and fine control over this key parameter.

Single molecule fluorescence correlation spectroscopy of single apoptotic cells using a red-fluorescent caspase probe.

The detection of single molecules in single cells has enabled biochemical analyses to be conducted with high sensitivity and high temporal resolution. In this work, detection of apoptosis was studied by single molecule fluorescence correlation spectroscopy (FCS) in single living cells. Caspase activity was assayed using a new red fluorogenic probe that avoids the spectral overlap of green fluorescent probes and cell autofluorescence. This new probe, 2SBPO-Casp, was synthesized by coupling a water-soluble Nile Blue derivative (2SBPO) to an aspartic acid residue. Upon apoptosis induction and caspase activation, free 2SBPO dye is shown to accumulate inside the cell after probe cleavage. In previous work in our lab, single molecule fluorescence in single apoptotic cells was detected 45 min after induction using a rhodamine 110-based probe. However, significant statistical analysis was needed to exclude false positives. The use of 2SBPO-Casp overcomes the autofluorescence problem and offers a steady fluorescence signal. In our single molecule FCS measurements, Ramos cells were determined apoptotic on the basis of their correlation coefficient value (R(2)). Cells that contain an R(2) ≥ 0.65 were identified as highly correlated and therefore determined to be apoptotic. Single apoptotic cells identified in this manner were found as early as 30 min after induction and the number of apoptotic cells reached a peak value at the 3rd hour, which is consistent with other techniques. Using single molecule techniques and a new apoptosis probe, the temporal dynamics were elucidated with better sensitivity and resolution than in previous studies.

Actuator prototype: capture and release of a self-entangled [1]rotaxane.

A conformationally dynamic chain compound that rapidly and reversibly samples both self-entangled and disentangled conformations, yet favors disentangled conformations, and an exclusively self-entangled [1]rotaxane were separately prepared and characterized. The conformationally dynamic state and the conformationally locked state were shown to reversibly and controllably interconvert under appropriate conditions, with an accompanying observable change in size that was calculated to approximate a 35% contraction in length upon capture of the self-entangled state.

Polypseudorotaxanes via ring-opening metathesis polymerizations of [2]catenanes.

A bis-phenanthroline [2]catenane copper complex, consisting of one olefinic macrocycle and one nonolefinic macrocycle, underwent an entropy-driven ring-opening olefin metathesis polymerization (ROMP) to provide a polypseudorotaxane. The polymerization featured an average degree of polymerization of ca. 63 wherein the polymer was effectively saturated with threaded macrocycles. Removal of the copper led to near complete release of the macrocycles from the polymer backbone.

Synthesis of a soluble ureido-naphthyridine oligomer that self-associates via eight contiguous hydrogen bonds.

[structure; see text] An iterative synthetic route to organic-soluble ureido-naphthyridine oligomers has been developed. Use of this protocol allowed synthesis of a short ureido-naphthyridine oligomer, which presents a self-complementary DDAADDAA hydrogen bonding array (D = hydrogen bond donor, A = hydrogen bond acceptor). Strong self-association via eight hydrogen bonds was observed in organic solution.

Catalytic Preparation of Aziridines with an Iron Lewis Acid.

The iron Lewis acid, [(eta(5)-C(5)H(5))Fe(CO)(2)(THF)](+)[BF(4)](-), was found to be an effective catalyst for the preparation of aziridines. This new method provides a facile, one-step route to predominantly cis-aziridines, with yields up to 95%, from compounds with a diazo functionality and a variety of substituted N-benzylidene imines with N-aryl or N-alkyl groups. The reaction mechanism is believed to proceed through an electrophilic iminium ion intermediate. To support this idea, the iron Lewis acid-imine complex [(eta(5)-C(5)H(5))Fe(CO)(2)(PhCH=NPh)](+)[BF(4)](-) was prepared, characterized, and reacted with different diazo compounds to provide the resultant cis-aziridines. Alternatively, it may be possible that the aziridines were derived from an electrophilic carbenoid intermediate, as is often proposed. Thus, the iron carbene [(eta(5)-C(5)H(5))Fe(CO)(2)(CHPh)](+)[SO(3)CF(3)](-) was prepared and treated with N-benzylideneaniline; however, the resultant aziridine was not formed.