Resveratrol 1 (3,4',5-trihydroxy-trans-stilbene), a phytoalexin present in grapes and other food products, has recently been suggested as a potential cancer chemopreventive agent based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This triphenolic stilbene has also displayed in vitro growth inhibition in a number of human cancer cell lines. In this context, a series of cis- and trans-stilbene-based resveratrols were prepared with the aim of discovering new lead compounds with clinical potential. All the synthesized compounds were tested in vitro for cell growth inhibition and the ability to induce apoptosis in HL60 promyelocytic leukemia cells. The tested trans-stilbene derivatives were less potent than their corresponding cis isomers, except for trans-resveratrol, whose cis isomer was less active. The best results were obtained with compounds 11b and 7b, the cis-3,5-dimethoxy derivatives of rhapontigenin 10a (3,5,3'-trihydroxy-4'methoxy-trans-stilbene) and its 3'-amino derivative 10b, respectively, which showed apoptotic activity at nanomolar concentrations. The corresponding trans isomers 12b and 8b were less active both as antiproliferative and as apoptosis-inducing agents. Of interest, 11b and 7b were active toward resistant HL60R cells and their activity was higher than that of several classic chemotherapeutic agents. The flow cytometry assay showed that at 50 nM compounds 7b or 11b were able to recruit almost all cells in the apoptotic sub-G(0)-G(1) peek, thus suggesting that the main mechanism of cytotoxicity of these compounds could be the activation of apoptosis. These data indicate unambiguously that structural alteration of the stilbene motif of resveratrol can be extremely effective in producing potent apoptosis-inducing agents.

The expression of acid ceramidase (AC) – a cysteine amidase that hydrolyses the proapoptotic lipid ceramide – is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea. Here we show that the antineoplastic drug carmofur, which is used in the clinic to treat colorectal cancers, is a potent AC inhibitor and that this property is essential to its anti-proliferative effects. Modifications in the chemical scaffold of carmofur yield new AC inhibitors that act synergistically with standard antitumoral drugs to prevent cancer cell proliferation. These findings identify AC as an unexpected target for carmofur, and suggest that this molecule can be used as starting point for the design of novel chemosensitizing agents.

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Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-D-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cellbased assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDAinduced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC 50 = 0.28 nM).