Journal of medicinal chemistry · 2026
Synthesis, Biological Evaluation, and Biodistribution of Xinyne, a Novel Quinazoline-carbazole N-methylamine Anticancer Agent Used in Mice Xenograft Models.
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Liu Xinya, Feat-Vetel Justyne, Barbe Peggy, Sayadi Alexandre, Alami Mouad, Tran Christine, Hamze Abdallah, Bignon Jérôme, Rode Guillaume, Gallego-Yerga Laura, Peláez Rafaël, Thomas Mayeul, Berissi Sophie, Cabrera Damien, Ha-Duong Tap, Cano Gregorio Javier, Lucena-Agell Daniel, Díaz José Fernando, Lebrequier Sabrina, Loreau Olivier, Audisio Davide, Keck Mathilde, Provot Olivier
Аннотация
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.