Because of our ongoing interest in finding new apoptosis-inducing agents, we are particularly intrigued by molecular scaffolds that allow the parallel synthesis of substituted derivatives. Actually, the parallel procedure is suitable for rapidly obtaining variously substituted analogs, particularly when structure-based design strategy is not applicable due to the lack of knowledge of a specific target. Thus, we recently synthesized a small library of resveratrol analogs, bearing the 3,5-dimethoxy motif at the A phenyl ring: many derivatives were more active than resveratrol as apoptosis-inducing agents in HL60 leukemia cells, and some of them were active toward resistant HL60R cells. Given these results, we aimed at increasing the structural diversity of the new molecules by synthesizing a second series of derivatives, which incorporate a phenyl ring as a bioisosteric substitution of the alkenyl bridge. Thus, through a Suzuky cross-coupling we obtained a small series of terphenyls that were tested on several leukemia cell lines. One of the new derivatives, TR9, behaved differently from the others, as it was able to block the cell cycle in G0-G1 phase and also to induce differentiation in acute myelogenous leukemia HL60 cells. Compared to resveratrol, the synthetic terphenyl I showed a more potent apoptotic and differentiating activity. Moreover, it was active on both multidrug resistance and Bcr-Abl expressing cells that were resistant to resveratrol.
Identification of a Terphenyl-Based Small Molecule That Induces Differentiation in Leukemia Cells
ROBERTI, MARINELLA;PIZZIRANI, DANIELA;RECANATINI, MAURIZIO;
2006
Abstract
Because of our ongoing interest in finding new apoptosis-inducing agents, we are particularly intrigued by molecular scaffolds that allow the parallel synthesis of substituted derivatives. Actually, the parallel procedure is suitable for rapidly obtaining variously substituted analogs, particularly when structure-based design strategy is not applicable due to the lack of knowledge of a specific target. Thus, we recently synthesized a small library of resveratrol analogs, bearing the 3,5-dimethoxy motif at the A phenyl ring: many derivatives were more active than resveratrol as apoptosis-inducing agents in HL60 leukemia cells, and some of them were active toward resistant HL60R cells. Given these results, we aimed at increasing the structural diversity of the new molecules by synthesizing a second series of derivatives, which incorporate a phenyl ring as a bioisosteric substitution of the alkenyl bridge. Thus, through a Suzuky cross-coupling we obtained a small series of terphenyls that were tested on several leukemia cell lines. One of the new derivatives, TR9, behaved differently from the others, as it was able to block the cell cycle in G0-G1 phase and also to induce differentiation in acute myelogenous leukemia HL60 cells. Compared to resveratrol, the synthetic terphenyl I showed a more potent apoptotic and differentiating activity. Moreover, it was active on both multidrug resistance and Bcr-Abl expressing cells that were resistant to resveratrol.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
