L‐asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G⁺) and Gram-negative (G⁻) bacteria, taking compound 1 as the lead. Among the target compounds, quinolone coupled hybrid 5d exerted the potential effect against most of the tested G⁺ and G⁻ strains with MIC values of 0.125–8 μg/mL, much better than those of 1. Molecular-docking assay showed that compound 5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound 5d was selected for the further investigation, with an advantage of a dual-target mechanism of action.

N-arylated α-amino acids and pyrazolidin-3-ones are widely being used as chiral building blocks for pharmaceuticals and agrochemicals. Here we report a biocatalytic route for the asymmetric synthesis of various N-arylated aspartic acids applying ethylenediamine-N,N'-disuccinic acid lyase (EDDS lyase) as biocatalyst. This enzyme shows a broad substrate scope, enabling the addition of a variety of arylamines to fumarate with high conversions, yielding the corresponding N-arylated aspartic acids in good isolated yields and with high enantiomeric excess (ee >99%). Furthermore, we developed a chemoenzymatic method towards synthetically challenging chiral 2-aryl-5-carboxylpyrazolidin-3-ones, using arylhydrazines as bisnucleophilic donors in the EDDS lyase-catalyzed hydroamination of fumarate followed by an acid-catalyzed intramolecular amidation, achieving good overall yields and high optical purity (ee >99%). In addition, we successfully combined the EDDS lyase-catalyzed hydroamination and acid-catalyzed cyclization steps in one pot, thus providing a simple chemoenzymatic cascade route for synthesis of enantiomerically pure pyrazolidin-3-ones. Hence, these biocatalytic methods provide convenient alternative routes to important chiral N-arylated aspartic acids and difficult 2-aryl-5-carboxylpyrazolidin-3-ones.