Tropolones are seven-membered non-benzenoid aromatic compounds with a propensity for metal binding. Naturally occurring tropolones, such as beta-thujaplicin (aka hinokitiol) are found to exhibit antiproliferative effects. We synthesized a library of alpha-tropolone derivatives, including alkyl chain series, para-substitutions on the phenyl ring, meta- substitutions on phenyl ring and non-phenyl based tropolone. We screened these alpha-tropolone derivatives towards a panel of blood cancer cell lines, including T cell, B-cell and myeloid malignancies based on cell viability assays. The tropolones appear to be a preference towards cancer cells of T-cell lineage, especially Molt-4 cells with a sub-micromolar GI50. We further studied the potential cellular mechanism of the anti-proliferative effect of two potent alpha-tropolone derivatives. Both compound 1 and 2 upregulate p53. Caspase inhibition using a pan caspase inhibitor Z-VAD-FMK prevents the tropolone-induced anti-proliferative effect. Alpha-substituted tropolones can be potentially used for the development of novel anti-blood cancer agents.

Alpha-substituted tropolones as potential anti-blood cancer therapeutics

256th National Meeting (2018)

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