Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4-9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25-35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD.

译文

非甾体类抗炎药(NSAIDs)已被建议用于神经退行性疾病的治疗,例如阿尔茨海默氏病(AD)。但是,长时间使用NSAID会产生胃肠道(GI)毒性。为了克服这个严重的局限性,本研究的目的是开发新的NSAID衍生的药物共轭物(抗炎性脂基衍生物,AL4-9),该共轭物保留了NSAIDS的有益作用而不会引起GI问题。这样,我们通过亚烷基二胺接头将选定的众所周知的NSAID,例如(S)-萘普生和(R)-氟比洛芬与(R)-α-硫辛酸(LA)缀合。抗氧化剂LA的选择基于氧化应激在AD的发展和/或进展中的拟议作用。我们的探索性研究表明,在合成的化合物中,在(R)-氟比洛芬和LA之间包含二氨基乙烯连接基的AL7具有最有利的化学和体外酶稳定性。经预处理后,该化合物在佛波醇12-mirateate 13-醋酸盐(PMA)刺激的U937细胞(人类的淋巴母细胞肺)和经Aβ(25-35)处理的THP-1细胞(白血病单核细胞)中表现出出色的抗氧化活性。此外,AL7还调节了这些细胞系中COX-2,IL-1β和TNF-α的表达,表明其具有抗炎活性。两者合计,AL7已成为潜在的铅,值得在合适的AD体内模型中进行进一步的表征和测试。

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