We synthesized a new inhibitor of tubulin polymerization, the pyrrole (1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrrol-3-yl)(3,4,5-trimethoxy-phenyl)methanone 6 (RS6077). Compound 6 inhibited the growth of multiple cancer cell lines, with IC values in the nM range, without affecting the growth of non-transformed cells. The novel agent arrested cells in the G2/M phase of the cell cycle in both transformed and non-transformed cell lines, but single cell analysis by time-lapse video recording revealed a remarkable selectivity in cell death induction by compound 6: in RPE-1 non-transformed cells mitotic arrest induced was not necessarily followed by cell death; in contrast, in HeLa transformed and in lymphoid-derived transformed AHH1 cell lines, cell death was effectively induced during mitotic arrest in cells that fail to complete mitosis. Importantly, the agent also inhibited the growth of the lymphoma TMD8 xenograft model. Together these findings suggest that derivative 6 has a selective efficacy in transformed vs non-transformed cells and indicate that the same compound has potential as novel therapeutic agent to treat lymphomas. Compound 6 showed good metabolic stability upon incubation with human liver microsomes.Copyright © 2022 Elsevier Masson SAS. All rights reserved.
About The Expert
Jessica Sebastiani
Michela Puxeddu
Marianna Nalli
Ruoli Bai
Ludovica Altieri
Paola Rovella
Eugenio Gaudio
Daniela Trisciuoglio
Filippo Spriano
Patrizia Lavia
Cinzia Fionda
Domiziana Masci
Andrea Urbani
Chiara Bigogno
Giulio Dondio
Ernest Hamel
Francesco Bertoni
Romano Silvestri
Giuseppe La Regina
References
PubMed