Title:Design, Synthesis and Evaluation of Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-
yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as Antitumor Agents
Volume: 22
Issue: 14
Author(s): Do Thi Mai Dung, Eun Jae Park, Duong Tien Anh, Pham-The Hai, Le Quang Bao, A Young Ji, Jong Soon Kang, Truong Thanh Tung, Sang-Bae Han*Nguyen-Hai Nam*
Affiliation:
- College of Pharmacy, Chungbuk National University,
194-31, Osongsaengmyung-1, Heungdeok, Chungbuk, 28160, Republic of Korea
- Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, 10000, Vietnam
Keywords:
Acetohydrazides, quinazolin-4(3H)-one, cytotoxicity, synthesis, caspase activation, docking simulation.
Abstract:
Background: Herein, we have designed and synthesized a series of the novel (E)-N'-((1-(4-chlorobenzyl)-
1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5) as potent small molecules activating procaspase-
3. The compounds were designed by the amalgamation of structural features of PAC-1 (the first procaspase-3
activator) and oncrasin-1, one potential anticancer agent.
Methods: The target acetohydrazides (5a-m) were prepared via the Niementowski condensation of anthranilic acid (1a)
or 5-substituted-2-aminobenzoic acid (1b-m) and formamide. The compound libraries were evaluated for their cytotoxicity,
caspase-3 activation, cell cycle analysis, and apoptosis. In addition, computational chemistry is also performed.
Results: A biological evaluation revealed that all thirteen compounds designed and synthesized showed strong cytotoxicity
against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) with
eight compounds (5a, 5c-i, 5k), which were clearly more potent than both PAC-1 and oncrasin-1. In this series, four
compounds, including 5c, 5e, 5f, and 5h, were the most potent members with approximately 4- to 5-fold stronger than
the reference compounds PAC-1 and oncrasin-1 in terms of IC50. In comparison to 5-FU, these compounds were even
18- to 29-fold more potent in terms of cytotoxicity in three human cell lines tested. In the caspase activation assay, the
caspase activity was activated to 285% by compound 5e compared to PAC-1, the first procaspase activating compound,
which was used as a control. Our docking simulation revealed that compound 5e was a potent allosteric inhibitor
of procaspase-3 through chelation of inhibitory zinc ion. Physicochemical and ADMET calculations for 5e provided
useful information of its suitable absorption profile and some toxicological effects that need further optimization to
be developed as a promising anticancer agent.
Conclusion: Compound 5e has emerged as a potential hit for further design and development of caspases activators
and anticancer agents.