Pyrazolopyrimidinone is a fused nitrogen-containing heterocyclic system, which acts as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. We have tested the synergistic anti-cancer effects of 15 pyrazolopyrimidinones, synthesised in a two-step process, combined with cold atmospheric plasma (CAP), a novel innovation generating reactive species with other unique chemical and physical effects. We identify two pyrazolopyrimidinones that act as prodrugs and display enhanced reactive-species dependent cytotoxicity when used in combination with cold atmospheric plasma. Synergistic activation was evident for both direct CAP treatment on prodrug loaded tumour cells and indirect CAP treatment of prodrug in media prior to adding to tumour cells. Our results demonstrate the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy against cancer.

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Chronic lymphocytic leukaemia (CLL) is the most commonly diagnosed leukaemia in the Western world, with an average age of diagnosis being over 65 years 1, 2. Despite development of new targeted therapeutics; emerging resistance, pharmacoeconomic sustainability and side-effect intolerability remain significant barriers to patient care and potential disease curability Chemical Synthesis Scheme & Figure 1: Synthesis of ethanoanthracene-based analogues with α,β-unsaturated carbonyl motif (blue) via a two-step process involving Claisen Schmidt condensation followed by Diels Alder cycloaddition onto tricyclic anthracene core (red) to create ethanoanthracene derivatives. The tail groups (purple) and head groups (green) used are outlined above. Biochemical Evaluation & SAR Elucidation Prior research with 2-nitrovinylanthracenes showed strong anti-proliferative proapoptototic activity in CLL lines (Fig. 2): PGA-1 (mutated Ig VH; good prognosis) and HG-3 (unmutated Ig VH; poor prognosis).