Synthesis and antiproliferative activity of new derivatives containing the polycyclic system 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]azepino[4,5-f]azocine

• 5,7:7,13-Dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]azepino[4,5-f]azocines were prepared.
• They show the chemical diversity required in drug discovery.
• Some synthesized compounds were selected by the NCI.
• They caused 50% growth inhibition at micromolar concentrations.
• The most active compound caused a block in G0–G1 and favoured pRb dephosphorylation.

The reaction under reflux between 1-phenyl-3-R-5-methylaminopyrazoles and 2,5-hexanedione lead to 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]azepino[4,5-f]azocine derivatives 3b–g. These unusual molecules show the structural complexity of many biologically active natural products and are endowed with the chemical diversity that is required in drug discovery. The compounds 3b,e were reduced by hydrogen in the presence of Palladium on activated charcoal to give the dihydro derivatives 5b,e. Compounds 3b–f and 5b,e were selected by the NCI to evaluate their in vitro antiproliferative activity against 60 human cell lines derived from nine clinically isolated cancer types (leukaemia, lung, colon, melanoma, renal, ovarian, brain, breast, and prostate). The most active compound of this series, caused a block in G0–G1 phase of cell cycle. Analysis of pRb expression showed that this compound favours pRb dephosphorylation.

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