Synthesis and antitumor activity of novel 3,4-diaryl squaric acid analogs

• Published in: European journal of medicinal chemistry 2013-07, Vol.65, p.187-194
• Main Authors: Liu, Zong-ying, Wang, Yue-ming, Han, Yan-xing, Liu, Ling, Jin, Jie, Yi, Hong, Li, Zhuo-rong, Jiang, Jian-dong, Boykin, David W.
• Format: Article
• Language: English
• Subjects: 3,4-Diaryl squaric acid analogs; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclobutanes - chemical synthesis; Cyclobutanes - chemistry; Cyclobutanes - pharmacology; Cytotoxic agents; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; MCF-7 Cells; Models, Molecular; Molecular Structure; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.04.046

A series of novel 3,4-diaryl squaric acid analogs 4a–r related to combretastatin A-4 (CA4) using squaric acid as the cis-restricted linker were prepared and studied for their anticancer activity against selected human cancer cell lines. New compounds 4g, 4k, 4m, 4n, 4p, 4q and 4r exhibit strong activities against human leukemia cells with IC50 values of ≤20 nM and compounds 4k, 4n, 4p, 4q and 4r showed potent activities against a panel of human tumor cell lines. Compounds 4n and 4p arrest tumor cell cycle in G2-M phase. Computational modeling analysis suggests that the binding mechanism of compound 4n to the colchicine binding site on the microtubules is similar to that of CA4. [Display omitted] •Some novel 3,4-diaryl squaric acid analogs were synthesized.•Compounds were tested for cytotoxic activities against human tumor cell lines.•Compounds 4g, 4k, 4m, 4n, 4p, 4q and 4r exhibit strong activities against human leukemia cells with IC50 values of ≤20 nM.•Compounds 4k, 4n, 4p, 4q and 4r showed potent activities against a panel of human tumor cell lines.