Description
Furamidinedihydrochloride (DB75dihydrochloride) is a selective and cell-permeable inhibitor of protein arginine methyltransferase 1 (PRMT1) with IC50 of 9.4 μM. Furamidinedihydrochloride is more selective for PRMChemicalbookT1 than PRMT5, PRMT6 and PRMT4(CARM1) (IC50 of 166μM, 283μM and >400μM, respectively). Furamidinedihydrochloride is a potent, reversible and competitive inhibitor of tyrosyl DNA phosphodiesterase 1 (TDP-1).
Chemical Properties
Yellow Solid
Uses
Furamidine is a diphenylfuran compound belonging to an important class of antimicrobial and antiparasitic agents. Furamidine and its analogues also display antitumor activities and showed antiproliferative activities against various tumor cell lines.
General Description
Furamidine dihydrochloride is an analog of the aromatic drug pentamidine and a substrate of the organic cation transporter 1 (OCT1). A number of prodrugs of furamidine dihydrochloride are being synthesised and are in clinical trial stages.
Biochem/physiol Actions
Furamidine (DB75) binds to strings of AT base pair sequences in DNA′s minor groove. Furamidine was originally developed as an anti-parasitic compound for a variety of diseases including Chagas′ disease. Furamidine targets AT rich sequences in trypanosome kinetoplast minicircle DNA (kDNA), resulting in subsequent destruction of the kinetoplast and cell death. Furamidine has also been found to inihbit tyrosyl-DNA phosphodiesterase (Tdp1) and act as a selective protein arginine methyltransferase 1 (PRMT1) inhibitor with an IC50 of 9.4μM.
in vitro
Furamidine (compound 1; 20 μM; 72 hours; leukemia cell lines) inhibits cell growth for most of the leukemia cell lines except HEL cells which have JAK2V617F mutations.Furamidine (compound 1; 20 μM; 15 hours; 293T cells) treatment significantly reduces the expression level of the methylated GFP-ALY protein in 293T cells.Furamidine binds duplex DNA in the DNA minor groove selectively at AT rich sites [(A/T)4]. Furamidine can also intercalate between GC base pairs of duplex DNA. Furamidine could therefore interfere with DNA processing enzymes such as TDP-1.
in vivo
Furamidine (1 mg/kg; intraperitoneal injection; 3 times a week and repeated every 4 weeks; for 34 weeks; female NZB/NZW mice) and Irinotecan combined treatment suppresses proteinuria and prolongs survival of lupus-prone NZB/NZW mice. The combination treatment does not change the levels of anti-dsDNA antibodies.
