Synthesis of benzoxazole-based vorinostat analogs and their antiproliferative activity

Christiana Mantzourani; Dimitrios Gkikas; Alexandros Kokotos; Pirjo Nummela; Maria A Theodoropoulou; Kai-Chen Wu; David P Fairlie; Panagiotis K Politis; Ari Ristimäki; George Kokotos

doi:10.1016/j.bioorg.2021.105132

Synthesis of benzoxazole-based vorinostat analogs and their antiproliferative activity

Bioorg Chem. 2021 Sep:114:105132. doi: 10.1016/j.bioorg.2021.105132. Epub 2021 Jun 28.

Affiliations

¹ Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece; Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
² Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
³ Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
⁴ Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.
⁵ Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶ Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece; Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. Electronic address: gkokotos@chem.uoa.gr.

PMID: 34229198
DOI: 10.1016/j.bioorg.2021.105132

Abstract

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).

Keywords: Amino-benzoxazole; Cancer cells; Hydroxamic acid; Pseudomyxoma peritonei; Vorinostat.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzoxazoles / chemistry
Benzoxazoles / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured
Vorinostat / chemical synthesis
Vorinostat / chemistry
Vorinostat / pharmacology*

Substances

Antineoplastic Agents
Benzoxazoles
Vorinostat