期刊
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
卷 18, 期 10, 页码 1495-1504出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1871520618666180313151503
关键词
Hybrid compound; hydroxamate; sulfonamide; synthesis; antimetastatic; anticancer; cytotoxic
资金
- National Natural Science Foundation of China [61525503, 61378091, 61620106016]
- National Basic Research Program of China [2015CB352005]
- Guangdong Natural Science Foundation Innovation Team [2014A030312008]
- Hong Kong, Macao and Taiwan cooperation innovation platform & major projects of international cooperation in Colleges and Universities in Guangdong Province [2015KGJHZ002]
- Shenzhen Basic Research Project [JCYJ20150930104948169, JCYJ20160328144746940, GJHZ20160226202139185]
Background: One of the most promising strategies to develop multi-targeted anticancer therapeutics is to introduce to the structure of a potential drug two or more pharmacophores (functional groups or structural structural fragments), which have antiproliferative, proapoptotic or antimetastatic properties acting via different mechanisms. Objective: To design, synthesize and perform screening of a novel hybrid anticancer compound. Method: A novel hybrid compound 4-[(E)-2-phenylethenesulfonamido]-N-hydroxybutanamide, combining butanehydroxamate and styrenesulfonamide moieties, was designed, synthesized and investigated as a potent antimetastatic and antiproliferative agent. The structure and purity of the synthesized compound were confirmed by H-1 NMR, C-13 NMR, LC/MS spectroscopy and elemental analysis. The compound was screened for the anticancer activity in vitro against HeLa and in vivo against Lewis lung carcinoma tumor, using an antitumor metalloenzyme inhibitor GM6001 (Ilomastat, Galardin) and Pifithrin-mu as control anticancer agents. Results: It was found that the application of our compound resulted in a high fraction of apoptotic cells in the cell population, along with disruption in the cell cycle profile manifested as arrest of proliferative phases. Furthermore, changes of the morphological properties (i.e., an enhancement of adhesive properties and reduction of the nuclear-to-cytoplasm ratio) were found. The in vivo screening revealed that the compound significantly inhibited the metastasizing process that was manifested by a reduction in the number and volume of metastases. Conclusions: The obtained results demonstrate that our compound can serve as a base for further structure optimization in order to design new highly-effective antimetastatic and antitumor agents.
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