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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Exploration of Some Thiazolidine-2,4-dione and 2-Oxoindoline Derivatives Incorporating 3,4,5-Trimethoxybenzyl Moiety as Novel Anticancer Agents

Author(s): Le Cong Huan, Hai Pham-The, Huong Le-Thi-Thu, Tran Phuong Thao, Do Nguyet Que, Nguyen-Thu Trang, Phan Thi Phuong Dung, Minji Pyo, Sang-Bae Han, Nguyen Thi Thuan* and Nguyen-Hai Nam*

Volume 15, Issue 4, 2018

Page: [375 - 387] Pages: 13

DOI: 10.2174/1570180814666170605122552

Price: $65


Background: Combrestastatin A-4 (CA-4) is a potent anticneoplastic and antiangiogenesis natural substance isolated from Combretum caffrum. Over the past two decades, numerous derivatives of CA-4 have been discovered. However, none of these derivatives has reached the clinical stage. Thus, continuing effort is needed in developing CA-4 analogues with improved pharmacological properties.

Methods: In this study, two series of thiazolidine-2,4-dione and 2-oxoindoline derivatives incorporating 3,4,5-trimethoxybenzyl scaffold were designed and synthesized as CA-4 analogues.

Results: Numerous CA-4 analogues bearing thiazolidine-2,4-dione/2-oxoindoline have been synthesized. These compounds were evaluated against several human cancer cell lines. It was found that a series of 5/7-substituted-1-(3,4,5-trimethoxy)benzylindoline-2,3-diones (2a-g) exhibited significant cytotoxicity. Especially compound 2d bearing a 5-bromo substituent showed the best activity with IC50 values in sub-microgram/mL scale in four human cancer cell lines tested. This compound also exhibited potent tubulin polymerization inhibitory activity. A series of (Z)-5-arylidene- 3-(3,4,5-trimethoxybenzyl)thiazolidine-2,4-diones (6a-j), on the other hand, displayed only moderate cytotoxic activities with only compound 6a showing comparable cytotoxicity to 2d. Finally, in silico molecular modeling and drug-likeness profiling revealed that five compounds 2b, 2d, 2e, 3e and 6a bound to tubulin active binding sites with strong binding affinities.

Conclusion: This study discovered some novel CA-4 analogues with cytotoxic potency and antitubulin activity acceptable to be further developed as effective anticancer drug candidates.

Keywords: Thiazolidine-2, 4-dione, indoline-2, 3-dione, combretastatin A-4, synthesis, cytotoxicity, molecular modeling.

Graphical Abstract

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