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Beschreibung

A cell-permeable, neutrally charged, pyridinium-to-pyridine substituted YM-01 (Cat. No. 500615) and MKT-077 structural analog that exhibits higher HSP70-binding affinity, but reduced tau degradation-promoting potency in cultures (% degradation of p-tau/total tau = 42/64, 88/89, and 81/80 in HeLaC3 with 30 µ,M YM-08, MKT-077, or YM-01, respectively) and weaker anti-cancer activity (IC50 against MDA-MB-231/MCF10A/MCF7 in µ,M = 1.4/3.0/2,2/MKT-077, 2.0/3.3/5.2/YM-01, and 8.5/7.8/10.5/YM-08 in 72 h)., A cell-permeable, neutrally charged, pyridinium-to-pyridine substituted YM-01 (Cat. No. 500615) and MKT-077 structural analog that exhibits higher HSP70-binding affinity than its cationic pyridinium counterparts (IC50 = 0.61 µ,M/YM-08, 3.2 µ,M/YM-01, and 6.4 µ,M/MKT-077, respectively, in competitive binding assays using human Hsc70/HSPA8), but reduced tau degradation-promoting potency in cultures (% degradation of p-tau/total tau/24 h = 42/64, 88/89, and 81/80 in HeLaC3 with 30 µ,M YM-08, MKT-077, or YM-01, respectively) and weaker anti-cancer activity (IC50 against MDA-MB-231/MCF10A/MCF7 in µ,M = 1.4/3.0/2,2/MKT-077, 2.0/3.3/5.2/YM-01, and 8.5/7.8/10.5/YM-08 with 72 h compound treatment). However, only YM-08, but not YM-01 or MKT-077, exhibits detectable blood-brain-barrier permeability in mice (Cmax = 4 µ,g/g, t1/2 = 6.8 h, AUCinf = 260 ng.h/g, 6.6 mg/kg via i.v., 100 µ,L/mouse in 30% H2O/5% Cremophor/5% EtOH/60% PBS) with much reduced accumulation in kidney in vivo.