PNU-142586 sodium

PNU-142586 sodium is the primary metabolite of Linezolid. It inhibits the activity of DNA topoisomerase 2-α (TOP2A) and DNA topoisomerase 2-β (TOP2B). By blocking the binding of DNA to TOP2 and inhibiting ATP hydrolysis, PNU-142586 interferes with DNA replication and transcription, leading to antiproliferative and cytotoxic effects, including mitochondrial dysfunction. It is useful for studying Linezolid-induced hematotoxicity and its molecular mechanisms.

PNU-142586 sodium, when used in concentrations ranging from 0.1 to 2.5 mM for 30 minutes, potently suppresses human TOP2A-mediated kDNA decatenation in cell-free systems, with an IC50 of approximately 150 μM. It also inhibits human TOP2A-mediated scDNA relaxation under the same conditions, with an IC50 around 1.425 mM. Similarly, the compound exhibits potent inhibition of human TOP2B-mediated kDNA decatenation in cell-free systems, with an IC50 of about 150 μM, and restrains human TOP2B-mediated scDNA relaxation with an IC50 around 1.875 mM. Through tryptophan fluorescence quenching, PNU-142586 sodium at concentrations of 31.25 to 500 μM shows direct binding to human TOP2A DNA-binding and ATPase domains, with Kd values of 310.6 ± 89.2 μM and 300.8 ± 31.3 μM, respectively. Additionally, PNU-142586 sodium (50 nM-100 μM) exhibits a concentration-dependent inhibition of human HL-60 promyelocytic cell proliferation, achieving a maximum inhibition rate of approximately 25% after 144 hours at 100 μM. The compound induces concentration-dependent cytotoxicity and proliferation inhibition in both HL-60 promyelocytic cells and THP-1 monocytic cells following 144-hour exposure. Furthermore, at concentrations of 5 μM or higher, and incubation times of 48 hours or more, it suppresses the transcription, gene, and protein expression of mitochondrial MT-CO1 gene in HL-60 and THP-1 cells.

PNU-142586 sodium exhibits dose-dependent morphological toxicity in Xenopus laevis oocytes following 168 hours of incubation at concentrations ranging from 0.015625 to 1 mM, also inhibiting topoisomerase II-mediated kDNA decatenation. At a concentration of 0.5 mM, approximately 43% of the oocytes exhibit malformations. Additionally, PNU-142586 sodium induces dose-dependent pericardial edema in zebrafish embryos when incubated at concentrations from 0.0005 to 0.5 mM, from 24 hours post-fertilization (hpf) to 120 hpf, and inhibits the expression of the mitochondrial mt-co1 gene at concentrations ≥0.5 μM.