Reactions of proteins with a few organopalladium compounds of medicinal interest

Abstract

Pd compounds form a promising class of experimental anticancer drug candidates whose mechanism of action is still largely unknown; in particular, a few organopalladium compounds seem very attractive.

Reactivity of Palladium(II)-η3-Allyl Complexes with Chalcogenolates: A Density Functional Study of Their Antitumor Implications

“…Importantly, the attack of the chalcogenolate on the palladium metal center was also experimentally observed in a recent ESI-MS study, where a very similar cationic complex [Pd(IMes)(PPh 3 )(allyl)] + was reacted with a C-terminal dodecapeptide of TrxR. 4 Even in that case, no attack at the allyl fragment was noticed. In that case, however, the ESI-MS spectrum suggests the release of the NHC moiety.…”

“…In any case, the qualitative discussion provided for complex 2 remains valid also for protonated complex 2-H + : the reaction at the allyl ligand appears to be the least favored process, while ligand substitution via an interexchange mechanism at the Pd center appears to be the most favorable process, both kinetically and thermodynamically. Importantly, the attack of the chalcogenolate on the palladium metal center was also experimentally observed in a recent ESI-MS study, where a very similar cationic complex [Pd(IMes)(PPh 3 )(allyl)] + was reacted with a C-terminal dodecapeptide of TrxR . Even in that case, no attack at the allyl fragment was noticed.…”

“…However, organometallic palladium complexes can possess the stability required to reach the biomolecular target without undergoing fast degradation, mainly thanks to the strength of the C–Pd bond . Recently, some of us reported that palladium­(II)-η 3 -allyl complexes bearing N -heterocyclic carbene (NHC) ligands can act as potent anticancer agents against cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines and patient-derived tumoroids. , Interestingly, a wide plethora of organopalladium scaffolds appear to be effective as antiproliferative agents, spanning cationic as well as neutral and anionic complexes, with zero, one, or two NHC ligands and with or without a phosphine co-ligand . Also because of this variety, their mechanisms of action are not completely understood, even if it is recognized to be at least partly different from the one of cisplatin and other platinum complexes commonly used in protocols for the treatment of neoplastic diseases.…”

“…To the best of our knowledge, the precise protein target of organopalladium complexes has not been identified. Moreover, different complexes might target different proteins, as recently shown by probing the interaction of four classes of organopalladium complexes against four different proteins: lysozyme, carbonic anhydrase, ribonuclease A, and thioredoxin reductase (TrxR) . Most interestingly, all tested complexes were found to bind to some extent to a C-terminal dodecapeptide of TrxR, a protein well recognized as a plausible target for antitumor therapy. − Additionally, for a selection of allyl palladium complexes, the inhibitory potential against TrxR was evaluated in vitro, and it was found to be comparable to or even better than that of auranofin, a popular gold complex known as a TrxR inhibitor .…”