Novel cyclic C5-curcuminoids penetrating the blood-brain barrier: Design, synthesis and antiproliferative activity against astrocytoma and neuroblastoma cells

•Cytotoxicity of cyclic C5-curcuminoids against CNS tumors is described.•Their IC50 value on astrocytoma is in the low nanomolar and picomolar range.•These cyclic C5-curcumunoids penetrate the blood-brain barrier in different ratios.•The antitumoral activity did not show correlation with experimental logP.•The synthesis of these novel C5-curcuminoids is simple and economical in large scale. Novel series of cyclic C5-curcuminoids 17a-j and 19-22 were prepared as cytotoxic agents and evaluated against human neuroblastoma (SH-SY5Y) or human grade IV astrocytoma (CCF-STTG1) cell lines in low (∼0.1 nM - 10 nM) concentrations. Among the tested 21 derivatives, 16 displayed potent antiproliferative activity with IC50 values in the low nanomolar to picomolar range (IC50 = 7.483-0.139 nM). Highly active compounds like N-monocarboxylic derivative 19b with IC50 = 0.139 nM value against neuroblastoma and N-alkyl substituted 11 with IC50 = 0.257 nM against astrocytoma proved some degree of selectivity toward non-cancerous astrocytes and kidney cells. This potent anticancer activity did not show a strong correlation with experimental logPTLC values, but the most potent antiproliferative molecules 11-13 and 19-22 are belonging to discrete subgroups of the cyclic C5-curcuminoids. Compounds 12, 17c and 19b were subjected to blood-brain barrier (BBB) penetration studies, too. The BBB was revealed to be permeable for all of them but, as the apparent permeability coefficient (Papp) values mirrored, in different ratios. Lower toxicity of 12, 17c and 19b was observed toward primary rat brain endothelial cells of the BBB model, which means they remained undamaged under 10 µM concentrations. Penetration depends, at least in part, on albumin binding of 12, 17c and 19b and the presence of monocarboxylic acid transporters in the case of 19b. Permeation through the BBB and albumin binding, we described here, is the first example of cyclic C5-curcuminoids as to our knowledge. : New cyclic C5-curcuminoids are synthesized with superior cytotoxic activity on neuroblastoma and astrocytoma cell lines. IC50 values in low nanomolar and picomolar range, experimental logPTLC, structure-activity relationship, BBB penetration and selective cytotoxicity are described [Display omitted]