Xinya Liu, Justyne Feat-Vetel, Peggy Barbe, Alexandre Sayadi, Mouad Alami, Christine Tran, Abdallah Hamze, Jérôme Bignon, Guillaume Rode, Laura Gallego-Yerga, Rafaël Peláez, Mayeul Thomas, Sophie Berissi, Damien Cabrera, Tap Ha-Duong, Gregorio Javier Cano, Daniel Lucena-Agell, José Fernando Díaz, Sabrina Lebrequier, Olivier Loreau, Davide Audisio, Mathilde Keck, Olivier Provot
Xinyne, a diaryl-N-methylamine analogue of isoCombretastatin A-4 was synthesized via a late-stage Cl-exchange using KCN. Xinyne exhibited potent antiproliferative activity at nanomolar concentrations against various human cancer cell lines, inhibited tubulin polymerization, induced apoptosis, and induced G2/M phase cell cycle arrest in 4T1 cells. To investigate its in vivo behavior, radiolabeled [14C]-Xinyne was prepared using [14C]-KCN. Pharmacokinetic analysis revealed significant sex-based differences: males showed faster absorption and more efficient elimination, whereas females exhibited broader tissue distribution and slower clearance. A biodistribution study demonstrated preferential accumulation of [14C]-Xinyne in the liver and the small intestine, with larger elimination through feces. Finally, the antitumor efficacy of Xinyne was confirmed in a murine breast cancer model.