Development of an Aryloxazole Derivative as a Brain-Permeable Anti-Glioblastoma Agent

Title
Development of an Aryloxazole Derivative as a Brain-Permeable Anti-Glioblastoma Agent
Authors
배애님김윤경임성수송지연신슬기김도희최민정Changed G. Gadhe박아영
Keywords
aryloxazole derivative; P-glycoprotein inhibition; anti-glioblastoma agent
Issue Date
2019-09
Publisher
Pharmaceutics
Citation
VOL 11-497-14
Abstract
Glioblastoma drug development has been dicult due to the extremely low blood brain barrier (BBB) penetration of conventional anti-cancer agents. P-glycoprotein, an eux membrane transporter, is responsible for the poor brain uptake of small and hydrophobic drug substances. To develop brain-penetrable anti-tumor agents, we designed colchicine derivatives containing an aryloxazole moiety, which is known to inhibit P-glycoprotein. Among those tested, an aryloxazole derivative named KIST-G1 showed the strongest anti-glioblastoma cell proliferation activity (IC50 = 3.2  0.8 nM). Compared to colchicine, KIST-G1 showed dramatically increased BBB-permeable properties presenting 51.7  0.5 (10􀀀 6 cm/s) parallel artificial membrane permeability assay (PAMPA) permeability and 45.0  6.0% of P-gp inhibition. Aid by the BBB-permeable properties, KIST-G1 (5 mg/kg) suppressed glioblastoma cell growth and migration almost completely in the brain of glioblastoma xenograft models by showing 98.2  0.1% reduced tumor area compared with phosphate bu ered saline (PBS)-injected control. In comparison, temozolomide, which is the most widely used drug for glioblastoma, showed only moderate e ects. Our results demonstrate the e ectiveness of an aryloxazole moiety in targeting brain tumors and suggest KIST-G1 as a potent anti-glioblastoma agent.
URI
http://pubs.kist.re.kr/handle/201004/70105
ISSN
1999-4923
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KIST Publication > Article
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