GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior.

While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2high cell fraction was enriched upon growth of PC cells as tumorspheres and GD2high fraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2high CRPC cell models markedly impaired the in vitro oncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell and epithelial-mesenchymal transition marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.

Determination of nitrogen sources and losses in surface runoff from different lands at a watershed scale.

Nitrogen (N) loss by surface runoff inevitably results in severe N pollution and eutrophication of aquatic ecosystems. In this study, surface runoff from different land uses in the East Tiaoxi River watershed was collected, and the N concentrations, sources and losses were measured using the dual isotope (δ15N-NO3- and δ18O-NO3-), a Bayesian isotopic mixing (SIAR) model and Soil Conservation Service Curve Number (SCS-CN) method. The results showed that the N concentrations in surface runoff from agricultural lands were higher than those from urban areas and forestlands, and nitrate (NO3-), particulate nitrogen (PN) and dissolved organic nitrogen (DON) were the major forms of N in surface runoff in the East Tiaoxi River watershed. The total loss rate of total nitrogen (TN) from surface runoff in the East Tiaoxi River watershed was 5.38 kg·ha-1·a-1, with NO3--N (46%) contributing the most to TN loss. The TN, and NO3--N loss rates in surface runoff from tea planting lands (21.08 kg·ha-1·a-1, 11.98 kg·ha-1·a-1) and croplands (16.93 kg·ha-1·a-1, 10.96 kg·ha-1·a-1) were high, those from vegetable lands and urban areas were medium, and those from economic and natural forestlands were low in the East Tiaoxi River watershed. The NO3--N contributions of chemical fertiliser (CF), soil N (SN), sewage/manure (SM), and atmospheric deposition (AD) in surface runoff in the East Tiaoxi River watershed were 124.32 × 103, 104.84 × 103, 82.25 × 103 and 58.69 × 103 kg·a-1, respectively. The N pollutant losses in surface runoff from agricultural lands (croplands with rice growing, vegetable lands and tea planting lands) were responsible for most of the N pollutants being transported into the East Tiaoxi River systems.

Thiol-Reactive Arylsulfonate Masks for Phenolate Donors in Antiproliferative Iron Prochelators.

Tridentate thiosemicarbazones, among several families of iron chelators, have shown promising results in anticancer drug discovery because they target the increased need for iron that characterizes malignant cells. Prochelation strategies, in which the chelator is released under specific conditions, have the potential to avoid off-target metal binding (for instance, in the bloodstream) and minimize unwanted side effects. We report a prochelation approach that employs arylsulfonate esters to mask the phenolate donor of salicylaldehyde-based chelators. The new prochelators liberate a tridentate thiosemicarbazone intracellularly upon reaction with abundant nucleophile glutathione (GSH). A 5-bromo-substituted salicylaldehyde thiosemicarbazone (STC4) was selected for the chelator unit because of its antiproliferative activity at low micromolar levels in a panel of six cancer cell lines. The arylsulfonate prochelators were assessed in vitro with respect to their stability, ability to abolish metal binding, and reactivity in the presence of GSH. Cell-based assays indicated that the arylsulfonate-masked prochelators present higher antiproliferative activities relative to the parent compound after 24 h. The activation and release of the chelator intracellularly were corroborated by assays of cytosolic iron binding and iron supplementation effects as well as cell cycle analysis. This study introduces the 1,3,4-thiadiazole sulfonate moiety to mask the phenolate donor of an iron chelator and impart good solubility and stability to prochelator constructs. The reactivity of these systems can be tuned to release the chelator at high glutathione levels, as encountered in several cancer phenotypes.

Albumin Conjugates of Thiosemicarbazone and Imidazole-2-thione Prochelators: Iron Coordination and Antiproliferative Activity.

The central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2 : 1 ligand-to-metal complexes. Native mass spectrometry experiments show that the prochelators form stable disulfide conjugates with bovine serum albumin, thus affording novel bioconjugate prochelator systems. Antiproliferative activities at sub-micromolar levels are recorded in a panel of breast, ovarian and colorectal cancer cells, along with significantly lower activity in normal fibroblasts.

Enantioselective Radical-Polar Crossover Reactions of Indanonecarboxamides with Alkenes.

Highly efficient asymmetric intermolecular radical-polar crossover reactions were realized by combining a chiral N,N'-dioxide/NiII complex catalyst with Ag2 O under mild reaction conditions. Various terminal alkenes and indanonecarboxamides/esters underwent radical addition/cyclization reactions to afford spiro-iminolactones and spirolactones with good to excellent yields (up to 99 %) and enantioselectivities (up to 97 % ee). Furthermore, a range of different radical-mediated oxidation/elimination or epoxide ring-opening products were obtained under mild reaction conditions. The Lewis acid catalysts exhibited excellent performance and precluded the strong background reaction.

Asymmetric Baeyer-Villiger oxidation: classical and parallel kinetic resolution of 3-substituted cyclohexanones and desymmetrization of meso-disubstituted cycloketones.

Regioselectivity is a crucial issue in Baeyer-Villiger (BV) oxidation. To date, few reports have addressed asymmetric BV oxidation of 3-substituted cycloketones due to the high difficulty of controlling regio- and stereoselectivity. Herein, we report the asymmetric BV oxidation of 3-substituted and meso-disubstituted cycloketones with chiral N,N'-dioxide/Sc(iii) catalysts performed in three ways: classical kinetic resolution, parallel kinetic resolution and desymmetrization. The methodology was applied in the total and formal synthesis of bioactive compounds and natural products. Control experiments and calculations demonstrated that flexible and adjustable catalysts played a significant role in the chiral recognition of substrates.

Catalytic Asymmetric Construction of ß-Azido Amides and Esters via Haloazidation.

A catalytic regio- and enantioselective haloazidation reaction with a chiral iron(II) complex catalyst under mild reaction conditions was reported. By this approach, the stereoselective α-halo-ß-azido difunctionalization of both α,ß-unsaturated amides and α,ß-unsaturated esters was achieved. This method enabled the construction of a broad spectrum of valuable functionalized amides and esters, including enantiomerically enriched ß-azido amides, aziridine amides, α-amino amide derivatives, ß-triazole amides, functionalized peptide derivatives, and α-halo-ß-azido-substituted esters.

Catalytic asymmetric Meerwein-Ponndorf-Verley reduction of glyoxylates induced by a chiral N,N'-dioxide/Y(OTf)3 complex.

An asymmetric Meerwein-Ponndorf-Verley (MPV) reduction of glyoxylates was for the first time accomplished via an N,N'-dioxide/Y(OTf)3 complex with aluminium alkoxide and molecular sieves (MSs) as crucial additives. A variety of optically active α-hydroxyesters were obtained with excellent results. A possible reaction mechanism was proposed based on the experiments.

The assignment of the configuration for α-hydroxy acid esters using a CEC strategy.

A simple and efficient (1)H NMR method for determining the absolute configuration of chiral α-hydroxy acid esters using a competing enantioselective conversion (CEC) strategy was developed. The α-hydroxy acid esters were acylated in the presence of Feng's chiral N,N'-dioxide-scandium(iii) complex, and the faster reaction was identified when one enantiomer of the chiral α-hydroxy acid ester was treated with both enantiomers of the ligand by NMR analysis of the reaction mixture without further purification. A mnemonic is presented to aid the assignment of the absolute configuration of the substrates.

Synthesis of Chiral Tetrahydrofurans via Catalytic Asymmetric [3 + 2] Cycloaddition of Heterosubstituted Alkenes with Oxiranes.

An efficient diastereo- and enantioselective [3 + 2] cycloaddition of heterosubstituted alkenes with oxiranes via selective C-C bond cleavage of epoxides has been developed. The reaction was catalyzed by a chiral N,N'-dioxide/Ni(II) catalyst, and a variety of chiral highly substituted tetrahydrofurans were obtained in up to 99% yield, 92/8 dr, and 99% ee.

Chiral N,N'-dioxide-FeCl3 complex-catalyzed asymmetric intramolecular Cannizzaro reaction.

An environmentally benign catalyst, the N,N'-dioxide-FeCl3 complex, has been developed for the asymmetric intramolecular Cannizzaro reaction. Aryl and alkyl glyoxal monohydrates were applied to obtain α-hydroxy acid esters with excellent results. Deuterium-label and control experiments shed light on the reaction mechanism.

Kinetic resolution of racemic mandelic acid esters by N,N'-dioxide-scandium-complex-catalyzed enantiomer-selective acylation.

A simple and efficient acylative kinetic resolution of racemic mandelic acid esters was accomplished with a chiral N,N'-dioxide-scandium(III) complex under mild and base-free reaction conditions. A variety of mandelic acid esters performed well in the reaction, obtaining both acylated products (up to 49% yield, 97% ee) and recovered substrates (up to 49% yield, 95% ee) in high enantioselectivities with perfect selectivity factors (up to 247). The enantioselective recognition and catalytic models were also proposed for the catalytic KR reaction.

Regio- and enantioselective Baeyer-Villiger oxidation: kinetic resolution of racemic 2-substituted cyclopentanones.

A kinetic resolution of racemic 2-substituted cyclopentanones via highly regio- and enantioselective Baeyer-Villiger oxidation has been successfully developed. The reaction could afford the normal 6-substituted δ-lactones in up to 98% ee and >19/1 regioselectivity. Meanwhile, the unreacted ketones were recovered in excellent ee values (up to 98%). It represents the best results of the kinetic resolution of racemic 2-substituted cyclopentanones via nonenzymic asymmetric BV oxidation.