Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 34, Issue 1, Pages 465-478Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2018.1555536
Keywords
Acetohydrazides; quinazolin-4(3H)-one; cytotoxicity; caspase activation
Funding
- National Foundation for Science and Technology of Vietnam (NAFOSTED) [104.01-2017.06]
- Korean Government (NRF) [2017R1A5A2015541]
- Hanoi University of Pharmacy
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In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-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(3H)-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. [GRAPHICS] .
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