Nemorubicin

Nemorubicin (Methoxymorpholinyl doxorubicin) is a Doxorubicin derivative with potent antitumor activity. Nemorubicin is highly cytotoxic to a variety of tumor cell lines presenting a multidrug-resistant phenotype. Nemorubicin not only intercalate into the duplex DNA, but also result in significant ligands for G-quadruplex DNA segments, stabilizing their structure. Nemorubicin requirs an intact nucleotide excision repair (NER) system to exert its activity^[1][2][3][4]. In Vitro: Nemorubicin has antitumor activity, with IC₇₀s of 578 nM, 468 nM, 193 nM, 191 nM, 68 nM, and 131 ± 9 nM for HT-29, A2780, DU145, EM-2, Jurkat and CEM cell lines, respectively^[1].
Nemorubicin is CYP3A-activated anticancer prodrug, which can produce a more cytotoxic metabolite, PNU-159682^[1][2].
Nemorubicin acts through nucleotide excision repair (NER) system to exert its activity. Nemorubicin (0-0.3 μM) is more active in the L1210/DDP cells with intact NER than in the XPG-deficient L1210/0 cells. Cells resistant to nemorubicin show increased sensitivity to UV damage^[3].
Nemorubicin is cytotoxic to 9L/3A4 cells, with an IC₅₀ of 0.2 nM, 120-fold lower than that of P450-deficient 9L cells (IC₅₀, 23.9 nM). Nemorubicin also potently inhibits Adeno-3A4 infected U251 cells with IC₅₀ of 1.4 nM. P450 reductase overexpression enhances cytotoxicity of Nemorubicin^[4]. In Vivo: Nemorubicin is converted to PNU-159682 by human liver cytochrome P450 (CYP) 3A4 in rat, mouse, and dog liver microsomes^[2]. Nemorubicin (60 µg/kg) induces sifnificant tumor growth delay in scid mice bearing 9L/3A4 tumors, but shows no obvious effect on the tumor growth delay of 9L tumors in mice by i.v. or intratumoral injection (i.t.). Nemorubicin (40 µg/kg, i.p.) exhibits no antitumor activity and no host toxicity in mice bearing 9L/3A4 tumors^[4].