Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation

Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug-protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.     

Microwave Promoted Oxidative Addition Reactions of Os3(CO)12: Efficient Syntheses of Triosmium Clusters of the Type Os3(μ-X)2(CO)10 and Os3(μ-H)(μ-OR)(CO)10

Microwave heating allows for the high-yield, one-step synthesis of the known triosmium complexes Os₃(μ-Br)₂(CO)₁₀ (1), Os₃(μ-I)₂(CO)₁₀ (2), and Os₃(μ-H)(μ-OR)(CO)₁₀ with R = methyl (3), ethyl (4), isopropyl (5), n-butyl (6), and phenyl (7). In addition, the new clusters Os₃(μ-H)(μ-OR)(CO)₁₀ with R = n-propyl (8), sec-butyl (9), isobutyl (10), and tert-butyl (11) are synthesized in a microwave reactor. The preparation of these complexes is easily accomplished without the need to first prepare an activated derivative of Os₃(CO)₁₂, and without the need to exclude air from the reaction vessel. The syntheses of complexes 1 and 2 are carried out in less than 15 min by heating stoichiometric mixtures of Os₃(CO)₁₂ and the appropriate halogen in cyclohexane. Clusters 3–6 and 8–10 are prepared by the microwave irradiation of Os₃(CO)₁₂ in neat alcohols, while clusters 7 and 11 are prepared from mixtures of Os₃(CO)₁₂, alcohol and 1,2-dichlorobenzene. Structural characterization of clusters 2, 4, and 5 was carried out by X-ray crystallographic analysis. High resolution X-ray crystal structures of two other oxidative addition products, Os₃(CO)₁₂I₂ (12) and Os₃(μ-H)(μ-O₂CC₆H₅)(CO)₁₀ (13), are also presented.     

Batch and column study: sorption of perfluorinated surfactants from water and cosolvent systems by Amberlite XAD resins

Amberlite XAD resins have been employed to a great extent as the sorbent for removing or concentrating organic compounds from different matrices. We present for the first time a systematic study on the sorption of perfluorochemical (PFC) surfactants, an emerging class of environmental contaminants, by XAD-7HP (moderately polar) and XAD-2 (nonpolar). The results show that XAD-7HP can strongly sorb PFCs at circumneutral pH; the isotherm-determined linear sorption coefficient can reach 10(6)L/kg. On the other hand, the sorption coefficient for XAD-2 was two orders of magnitude lower than that for XAD-7HP. PFC sorption on XAD-7HP increased with an increase of the perfluorocarbon chain length of PFC and a decrease of the solution pH, indicating the importance of hydrophobic and electrostatic effects. The sorption coefficient for XAD-7HP reduced markedly with increasing fraction of the organic cosolvent (methanol) in the water-cosolvent mixture; however, the trend could not be predicted by a log-linear cosolvency model. Furthermore, the statistical analysis of column test results showed that after regeneration XAD-7HP can be used at least eight times without significant loss of performance. Finally, the experimental results imply that XAD-7HP sorption of shorter-chained PFCs (≤5 perfluorinated carbons) from water can be thermodynamically favorable.     

Asymmetric synthesis of cyclobutanones: synthesis of cyclobut-G

A simple, efficient, and stereoselective approach has been developed for obtaining chiral cis- and trans-disubstituted cyclobutanones from readily available alkyl- and functionalized alkyl-substituted enol ethers. The usefulness of these cyclobutanones is illustrated by an enantioselective synthesis of cyclobut-G (Lobucavir).     

High-pressure Diels-Alder approach to natural kainic acid

The first Diels-Alder based synthesis of (-)-kainic acid is described. Danishefsky's diene and a vinylogous malonate derived from 4-hydroxyproline combine under high pressure to afford a key bicyclic intermediate with virtually no loss of enantiopurity. This adduct can be converted into the natural product with complete stereocontrol. [reaction: see text].     

Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes

A catalytic methodology for the enantioselective addition of alkylzirconium reagents to aliphatic aldehydes is reported here. The versatile and readily accessible chiral Ph-BINMOL ligand, in the presence of Ti(OⁱPr)₄ and a zinc salt, facilitates the reaction, which proceeds under mild conditions and is compatible with functionalized nucleophiles. The alkylzirconium reagents are conveniently generated in situ by hydrozirconation of alkenes with the Schwartz reagent. This work is a continuation of our previous work on aromatic aldehydes.     

Augmenting the Performance of Hydrogenase for Aerobic Photocatalytic Hydrogen Evolution via Solvent Tuning

This work showcases the performance of [NiFeSe] hydrogenase from Desulfomicrobium baculatum for solar-driven hydrogen generation in a variety of organic-based deep eutectic solvents. Despite its well-known sensitivity towards air and organic solvents, the hydrogenase shows remarkable performance under an aerobic atmosphere in these solvents when paired with a TiO₂ photocatalyst. Tuning the water content further increases hydrogen evolution activity to a TOF of 60±3 s⁻¹ and quantum yield to 2.3±0.4 % under aerobic conditions, compared to a TOF of 4 s⁻¹ in a purely aqueous solvent. Contrary to common belief, this work therefore demonstrates that placing natural hydrogenases into non-natural environments can enhance their intrinsic activity beyond their natural performance, paving the way for full water splitting using hydrogenases.     

Electrochemical Borylation of Electron-Deficient Alkenes and Allenoates

The electrochemical borylation of electro-deficient alkenes and allenoates is disclosed. In an undivided cell and under galvanostatic conditions a panel of Michael acceptor and allenoates was readily reacted. The reaction offered an access to versatile borylated building blocks in good to excellent yields (20 examples, 47 % to 91 % yields). A plausible reaction mechanism, based on the literature precedent was suggested.     

Photocatalytic and Electrochemical Borylation and Silylation Reactions

Due to their high versatility borylated and silylated compounds are inevitable synthons for organic chemists. To escape the classical hydroboration/hydrosilylation paradigm, chemists turned their attention to more modern and green methods such as photoredox chemistry and electrosynthesis. This account focuses on novel methods for the generation of boryl and silyl radicals to forge C−B and C−Si bonds from our group.