The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo. Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.

“Weakly coordinating anions” such as tetraarylborates are ubiquitous in applications of inorganic and organometallic chemistry, with great industrial importance. In this work, we probe the ion-pairing ability of these weakly coordinating anions using the highly sensitive chromium­(VI) nitrido bis­(diisopropylamido) system NCr­(N-i-Pr2)2X, with one variable coordination site (X). This system is being used in the quantification of ligand donor ability to high-valent metal centers and has simply been called the ligand donor parameter (LDP). The donor ability of the variable ligand can be measured by solution-state rotational barrier studies via NMR spectroscopy. If the variable ligand is neutral, the chromium complex is cationic, {NCr­(N-i-Pr2)2L}+, with its pendant anion. Despite the weakly coordinating nature of the counteranions employed, a significant amount of ion pairing has been noted in solution, the result of which is substantial enough to perturb the sensitive LDP measurement. These effects have been noted for many commonly used counteranions, including hexafluoroantimonate­(V), hexafluorophosphate­(V), tetraphenylborate, and tetrakis­(bis­(3,5-trifluoromethyl)­phenyl)­borate (BArF24). Using diffusion ordered (DOSY) and rotating-frame Overhauser effect (ROESY) NMR spectroscopy and LDP values, we have shown, predictably, that the extent of ion pairing is solvent dependent and appears to be minimized by increasing the dielectric constant of the NMR solvent utilized. Additionally, we have gained insight into differences in the nature of ion pairing dependent upon the identity of the weakly coordinating anion employed. It was found that the tetraarylborate anions appear to be fully ion paired in CDCl3 but affect amido rotation less in comparison to other anions. We postulate that the smaller effect on the internal rearrangement by these fluorinated tetraarylborate anions is due to a lack of specificity in the interaction with the cation rather than a lack of ion pairing, which may be a general feature of these anions.

Advances in targeted α-therapies have increased the interest in actinium (Ac), whose chemistry is poorly defined due to scarcity and radiological hazards. Challenges associated with characterizing Ac3+ chemistry are magnified by its 5f06d0 electronic configuration, which precludes the use of many spectroscopic methods amenable to small amounts of material and low concentrations (like EPR, UV–vis, fluorescence). In terms of nuclear spectroscopy, many actinium isotopes (225Ac and 227Ac) are equally “unfriendly” because the actinium α-, β-, and γ-emissions are difficult to resolve from the actinium daughters. To address these issues, we developed a method for isolating an actinium isotope (228Ac) whose nuclear properties are well-suited for γ-spectroscopy. This four-step procedure isolates 228Ra from naturally occurring 232Th. The relatively long-lived 228Ra (t 1/2 = 5.75(3) years) radioisotope subsequently decays to 228Ac. Because the 228Ac decay rate [t 1/2 = 6.15(2) h] is fast, 228Ac rapidly regenerates after being harvested from the 228Ra parent. The resulting 228Ac generator provides frequent and long-term access (of many years) to the spectroscopically “friendly” 228Ac radionuclide. We have demonstrated that the 228Ac product can be routinely “milked” from this generator on a daily basis, in chemically pure form, with high specific activity and in excellent yield (∼95%). Hence, in the same way that developing synthesis routes to new starting materials has advanced coordination chemistry for many metals by broadening access, this 228Ac generator has the potential to broaden actinium access for the inorganic community, facilitating the characterization of actinium chemical behavior.

Hydroamination and multicomponent coupling reactions catalyzed by homogeneous Ti(IV) complexes can produce valuable imines, amines, and other nitrogencontaining organic building blocks. Typically catalysts for this transformation are very sensitive to ancillary ligand design and often suffer from catalyst deactivation, necessitating use in a single reaction. Here, we have attempted to address these issues by moving toward a solid-supported Ti catalyst active for these reaction types. We present initial results to synthesize and probe the catalytic reactivity of silica-supported titanium amide precatalysts. With minimal treatment of commercially available fumed silica, Ti(NMe 2 ) 2 /SiO 2 200 can be isolated upon addition of Ti(NMe 2 ) 4 . This species gives high yields and high regioselectivity for hydroamination of a variety of alkynes with anilines. The solid-supported species is also an active catalyst for the formation of tautomers of unsymmetrical 1,3-diimines via three-component coupling of bulky anilines, alkynes, and isonitriles. Reusability and possible catalyst deactivation pathways are also discussed.

To examine structural and electronic differences between iron and ruthenium imido complexes, a series of compounds was prepared with different phosphine basal sets. The starting material for the ruthenium complexes was Ru(NAr/Ar*)(PMe 3 ) 3 (Ru1/Ru1*), where Ar = 2,6-( i Pr) 2 C 6 H 3 and Ar* = 2,4,6-( i Pr) 3 C 6 H 2 , which were prepared from cis-RuCl 2 (PMe 3 ) 4 and 2 equiv of LiNHAr/Ar*. The starting materials for the iron complexes were the analogous Fe(NAr/Ar*)(PMe 3 ) 3 species (Fe1/Fe1*), which were not isolated but could be generated in situ from FeCl 2 , PMe 3 , and LiNHAr/Ar*. With both iron and ruthenium, the PMe 3 starting materials underwent phosphine replacement with chelating ligands to give new group 8 imido complexes in the +2 oxidation state. Addition of 1,2-bis(diphenylphosphino)ethane (dppe) to M1/M1* gave Ru(NAr/Ar*)(PMe 3 )(dppe) and Fe(NAr/ Ar*)(PMe 3 )(dppe). Addition of 1,2-bis(dimethylphosphino)ethane (dmpe) provided Ru(NAr/Ar*)(dmpe) 2 . A triphos ligand, {P(Me) 2 CH 2 } 3 Si t Bu ( t P 3 ), was also examined. Addition of t P 3 to Fe1 provided Fe(NAr)( t P 3 ) (Fe4), but a similar reaction with Ru1 only gave intractable materials. Oxidation of Fe4 with AgSbF 6 gave {Fe(NAr)( t P 3 )} + SbF 6 − (Fe4a). Oxidation of Ru2 with AgSbF 6 gave the unstable cation {Ru(NAr)(PMe 3 )(dppe)} + , which dimerized in the presence of acetonitrile via C−C bond formation at the aryl group C4 positions, affording {Ru(NAr)(PMe 3 )(NCMe)(dppe)} 2 + . This suggested that there was substantial radical character in the imide π system on oxidation and that an aromatic group substituted at the 4-position might provide greater stability. The cations {Fe(NAr*)(PMe 3 )(dppe)} + (Fe2a*), {Ru(NAr*)(PMe 3 )(dppe)} + (Ru2a*), and Fe4a were examined by EPR spectroscopy, which suggested differences in electronic structure depending on the metal and ligand set. CASPT2 calculations on model systems for Ru2a* and Fe2a* suggested that the large differences in electronic structure are related to the energy gap between the π-antibonding HOMO and the π-bonding HOMO-1. Both the geometry of the phosphines, which is slightly different between the iron and ruthenium analogs, and the metal center seem to contribute to this energetic difference.

A square planar Ru(iv) bis(imide) can be synthesized by photolysis of a tetrazene starting material.

A highly dehydrated silica gel, when exposed to Ti(NMe2)4, gives a fast, high-yielding catalyst for multicomponent coupling of an amine, alkyne, and isonitrile to form 1,3-dimine tautomers, iminoamination.

Heteroleptic catalyst stability toward disproportionation was modelled based on ligand donor abilities, which is of critical importance in some catalyses.