Novel pyrrole derivatives as tubulin polymerization inhibitor agent capable of inducing ferroptosis in glioblastoma and ovarian cancer cells lines

Apoptosis-induced programmed cell death has always been recognized as the only pathway to take off cancer cells. Recently, ferroptosis has been investigated as non-apoptotic programmed cell death mechanisms with potential to overcome the block of apoptosis in mutant cancer cells. Ferroptosis programmed necrosis is mainly triggered by peroxidation of extra-mitochondrial lipid arising from accumulation of iron-dependent ROS, which are produced by excessive iron deriving from abnormalities of major redox systems and aberrant iron metabolism [1]. It has been established that ferroptosis is an effective approach in anticancer therapy for the eradication of residual or resistant cancer cells. A lot of evidence supports the perspective applications of ferroptosis in GBM therapies. On the other hand, OC cells showed susceptibility to ferroptosis since an excess iron gets overloaded in tumor-initiating cells after overexpression of transferrin receptor 1 and decrease of the level of iron efflux pump ferroportin [2]. In this work, we replaced the 1-(methylphenyl) group of 1 with a pyridine or pyrimidine ring and kept fixed hydrogen, phenyl or furan-2-yl (the latter heterocyclic ring has shown a tight interaction with the colchicine binding site at position 4 of the pyrrole). We discovered that a new aroyl diheterocyclyl pyrrole (ARDHEP) derivative, 15, whose mechanism is the inhibition of tubulin polymerization, exhibited the hallmarks of ferroptosis rather than conventional apoptosis expressed by 1, meanwhile the angiogenic effect remained similar for both compounds[3]. References [1] Mou, Y.; Wang, J.; Wu, J.; He, D.; Zhang, C.; Duan, C.; Li, B. J. Hem. Oncol. 12 (2019) 34. [2] Zhu, X.; Zhou, Y.; Ou, Y.; Cheng, Z.; Han, D.; Chu, Z.; Pan, S. Aging 13 (2021) 17655-17672. [3] Puxeddu, M.; Wu, J.; Bai, R.; D’Ambrosio, M. et al. J. Med. Chem. 2022. Accepted