Prodrugs of a 1-Hydroxy-2-Oxopiperidin-3-Yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation

Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP\u27s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion

Potential of Philippine sunflower variants for the phytoremediation of copper contaminated substrate

Phytoremediation is the process of using plants to remove, degrade, and stabilize contaminants in water and soil. In this study Sunflower (Helianthus annuus) is used for the phytoremediation of copper-contaminated soil since it is fast-growing and can accumulate heavy metals in soil. Three variants of Philippine Sunflower (F1 Vincent 2 Choice, F1 Vincent 2 Fresh, and Sunrich Orange) were evaluated for the phytoremediation of soil with 177.16 ppm Cu as Cu2+ . Among the three variants, F1 Vincent 2 Choice performed the best in terms of Cu uptake at 3574.22 mg Cu/kg dry biomass. It is also noteworthy that with higher Cu concentration and longer exposure time, more Cu is removed from the soil with Cu concentrations ranging 124.84 – 242.16 ppm. It can be observed that H. annuus is a good hyperaccumulator with a bioconcentration factor (BCF) after 3 weeks ranging from 6.7 – 10.2. Also, during the early stages more Cu was found to concentrate within the roots. However, with longer exposure time, Cu was observed to be translocated to the aerial parts, i.e. the shoots. The translocation factor (TF) after 3 weeks ranging from 0.17 – 0.23. The Cu concentration in the roots was always higher than that of the shoots. Interestingly, in the latter stages, the total amount of Cu in the shoots was always higher than that of the roots due to the amount of biomass. The Cu uptake kinetics of H. annuus was evaluated and it was found out that it best fits with an n=0.7 order model with an average R2 value of 0.967 with a rate constant, k, of 0.0475-0.0491 mg0.3 -kg-0.3 -wk-1

Total Synthesis and Structural Confirmation of the Antimalarial Naphthopyrone Lasionectrin

The total synthesis of lasionectrin, a naphthopyrone metabolite of an Acremonium-like fungus collected in Equatorial Guinea, is reported. Divergent access to four stereoisomers confirmed the natural product to be the enantiomer of the originally proposed structure. Highlights of the synthesis include ring opening of a chiral oxetane using a thiol, a highly <i>E</i>-selective Julia–Kocienski olefination, and a modified Sharpless/Upjohn dihydroxylation. Palladium-catalyzed carbonylative lactonization was used to assemble the fused naphthopyrone ring system