Synthesis, Characterization and in vitro Anticancer Evaluation of 5‐Sulfinyl(sulfonyl)‐4‐arylsulfonyl‐Substituted 1,3‐Oxazoles

• Published in: ChemMedChem 2023-07, Vol.18 (14), p.e202300161-n/a
• Main Authors: Zyabrev, Vladimir, Pilyo, Stepan, Demydchuk, Bohdan, Kachaeva, Maryna, Semenyuta, Ivan, Zhirnov, Victor, Velihina, Yevheniia, Brovarets, Volodymyr
• Format: Article
• Language: English
• Subjects: 5-Sulfinyl(sulfonyl)-4-arylsulfonyl substituted 1,3-oxazoles; @ibopc_nas, @Y_Velihina; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antiproliferation; Antitumor activity; Antitumor agents; Bioorganic chemistry; Cancer; Cell Line, Tumor; Cell Proliferation; COMPARE correlations; Cytotoxicity; DNA topoisomerase; Drug development; Drug Screening Assays, Antitumor; Mathematical analysis; Oxazol; Oxazoles; Oxazoles - pharmacology; Structure-Activity Relationship; Substitutes; Synthesis; Toxicity; Tumor cell lines
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300161

A novel series of 5‐sulfinyl(sulfonyl)‐4‐arylsulfonyl‐substituted 1,3‐oxazoles has been synthesized, characterized and subjected to NCI in vitro assessment. Cancer cell lines of all subpanels were most sensitive to 2‐{[4‐[(4‐fluorophenyl)sulfonyl]‐2‐(2‐furyl)‐1,3‐oxazol‐5‐yl]sulfinyl}acetamide (3 l). Its antiproliferative and cytotoxic activity averaged over each subpanel was manifested in a very narrow range of concentrations (GI50: 1.64–1.86 μM, TGI: 3.16–3.81 μM and LC50: 5.53–7.27 μM), i. e. practically did not depend on the origin of the cancer cell line. The COMPARE matrix using TGI vector showed a high positive correlation of 3 l (r=0.88) with the intercalating agent aclarubicin, which inhibits topoisomerases. The absence in the database of standard agents that have a high correlation with the cytotoxicity of this compound suggests that it may have a unique mechanism of action. According to the results of the docking analysis, the most promising anticancer target for compound 3 l is DNA topoisomerase IIβ. The obtained results indicate the anticancer activity of 5‐sulfinyl(sulfonyl)‐4‐arylsulfonyl‐substituted 1,3‐oxazoles, which may be useful for the development of new anticancer drugs. 2‐{[4‐[(4‐Fluorophenyl)sulfonyl]‐2‐(2‐furyl)‐1,3‐oxazol‐5‐yl]sulfinyl}acetamide (3 l), as the most active, can be recommended for further in‐depth studies. High anticancer activity of 5‐sulfinyl(sulfonyl)‐4‐arylsulfonyl substituted 1,3‐oxazoles has been demonstrated in a total panel of NCI tumor cell lines. 2‐{[4‐[(4‐Fluorophenyl)sulfonyl]‐2‐(2‐furyl)‐1,3‐oxazol‐5‐yl]sulfinyl}acetamide 3 l appeared to be the most active compound. The COMPARE matrix using the TGI vector showed a high positive correlation of 3 l (r=0.88) with aclarubicin, which inhibits topoisomerases. A possible binding mode of 3 l to DNA topoisomerase IIβ has been suggested.