Synthesis of benzoxazole-based vorinostat analogs and their antiproliferative activity

• Published in: Bioorganic chemistry Vol. 114; p. 105132
• Main Authors: Mantzourani, Christiana, Gkikas, Dimitrios, Kokotos, Alexandros, Nummela, Pirjo, Theodoropoulou, Maria A., Wu, Kai-Chen, Fairlie, David P., Politis, Panagiotis K., Ristimäki, Ari, Kokotos, George
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2021
• Subjects: Amino-benzoxazole; Cancer cells; Hydroxamic acid; Pseudomyxoma peritonei; Vorinostat; Amino-benzoxazole; Hydroxamic acid; Vorinostat; Pseudomyxoma peritonei; Cancer cells
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105132

[Display omitted] •Synthesis of hydroxamic acid analogs of vorinostat containing the benzoxazole moiety.•Antiproliferative activity of benzoxazole-based analogs on cancer cell lines.•Identification of GK601 analog presenting similar inhibitory activity to vorinostat.•GK601inhibited the growth of cancer cell lines resembling pseudomyxoma peritonei. Hydroxamic acid derivatives constitute an interesting novel class of antitumor agents. Three of them, including vorinostat, are approved drugs for the treatment of malignancies, while several others are currently under clinical trials. In this work, we present new vorinostat analogs containing the benzoxazole ring as the cap group and various linkers. The benzoxazole-based analogs were synthesized starting either from 2-aminobenzoxazole, through conventional coupling, or from benzoxazole, through a metal-free oxidative amination. All the synthesized compounds were evaluated for their antiproliferative activity on three diverse human cancer cell lines (A549, Caco-2 and SF268), in comparison to vorinostat. Compound 12 (GK601), carrying a benzoxazole ring replacement for the phenyl ring of vorinostat, was the most potent inhibitor of the growth of three cell lines (IC50 1.2–2.1 μΜ), similar in potency to vorinostat. Compound 12 also inhibited human HDAC1, HDAC2 and HDAC6 like vorinostat. This new analog also showed antiproliferative activity against two colon cancer cell lines genetically resembling pseudomyxoma peritonei (PMP), namely HCT116 GNAS R201C/+ and LS174T (IC50 0.6 and 1.4 μΜ, respectively) with potency comparable to vorinostat (IC50 1.1 and 2.1 μΜ, respectively).