(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity. (1st January 2019)

• Record Type: Journal Article
• Authors: Huan, Le Cong; Phuong, Cao Viet; Truc, Le Cong; Thanh, Vo Nguyen; Pham-The, Hai; Huong, Le-Thi-Thu; Thuan, Nguyen Thi; Park, Eun Jae; Ji, A Young; Kang, Jong Soon; Han, Sang-Bae; Tran, Phuong-Thao; Nam, Nguyen-Hai
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 465
• Page End: 478
• Publication Date: 2019-01-01
• Subjects: Acetohydrazides -- quinazolin-4(3H)-one -- cytotoxicity -- caspase activation; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2018.1555536
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3 H )-ones (5, 6, 7) . Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3 H )-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l ). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3. Graphical Abstract: