Platinum-Based Modification of Styrylbenzylsulfones as Multifunctional Antitumor Agents: Targeting the RAS/RAF Pathway, Enhancing Antitumor Activity, and Overcoming Multidrug Resistance

Inhibiting/disturbing the RAS/RAF pathway may benefit
the treatment
of cancer and overcome the resistance. Utilizing such a pathway as
the target, nine styrylbenzylsulfone derivatives generated from the
platinum-based modification of the side chain of Rigosertib were designed.
Among them, compound 29 showed the most potent antitumor
activity in vitro with IC50 values at the nanomolar level
against the tested tumor cell lines and 1000-fold higher than cisplatin
against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP
cells), while it showed only moderate cytotoxicity against normal
cells (HEUVC cells). Compound 29 could clearly disturb
signaling transduction between RAS and CRAF by directly bonding to
CRAF and inhibit CRAF activation. Besides, the enhanced intracellular
platinum level made 29 more potent than cisplatin in
DNA damage, reactive oxygen species accumulation, and mitochondrial
membrane potential decrease. Moreover, 29 induced apoptosis
by the endogenous pathway and efficiently inhibited tumor growth in
the A549 xenograft model without side effects.