Decane-1,2-diol derivatives as potential antitumor agents for the treatment of glioblastoma

Anisha Viswanathan, Anastasia Zhurina, Benedicta Assoah, Aleksi Paakkunainen, Aliyu Musa, Dinesh Kute, Konda Mani Saravanan, Olli Yli-Harja, Nuno R Candeias, Meenakshisundaram Kandhavelu

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    Abstract

    Glioblastoma remains the most common and aggressive type of malignant brain tumor among adults thus, considerable attention has been given to discovery of novel anti-tumor drugs for its treatment. This study reports the synthesis of a series of twelve novel decane-1,2-diol derivatives and evaluation of its anti-tumor activity in mammalian glioblastoma cell lines, U87 and LN229. Starting from decane-1,2-diol, several derivatives were prepared using a diversity oriented synthesis approach through which a small library composed of esters, silyl ethers, sulfonates, sulfites, sulfates, ketals, and phosphonates was built. The decane-1,2-diol ditosylated derivative, DBT, found to have higher cytotoxicity than the standard drug cisplatin, has IC50 value of 52µM in U87 and 270µM in LN229. Migration analysis of U87 cell line treated with the DBT indicated its ability to effectively suppress proliferation during initial hours of treatment and decrease anti-proliferative property over time. Additionally, DBT was assessed for its role in apoptosis, oxidative stress and caspase 3/7 activation in U87. Interestingly, our experiments indicated that its cytotoxicity is independent of Reactive oxygen species induced caspase 3/7 activity. The compound also exhibited caspase independent apoptosis activity in U87. DBT treatment led to G1/S cell cycle arrest and apoptosis induction of glioma cell lines. In addition, we identified 1,533 genes with significant changes at the transcriptional level, in response to DBT. A molecular docking study accounting for the interaction of DBT with NMDA receptor disclosed several hydrogen bonds and charged residue interactions with 17 amino acids, which might be the basis of the DBT cytotoxicity observed. We conclude that this molecule exerts its cytotoxicity via caspase 3/7 independent pathways in glioblastoma cells. Concisely, simple decane-1,2-diol derivatives might serve as scaffolds for the development of effective anti-glioblastoma agents.

    Original languageEnglish
    Pages (from-to)105-116
    JournalEuropean Journal of Pharmacology
    Volume837
    Early online date1 Sep 2018
    DOIs
    Publication statusPublished - 15 Oct 2018
    Publication typeA1 Journal article-refereed

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