Platinum(II) N -heterocyclic carbene complexes arrest metastatic tumor growth

Abstract

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2′-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

“…The unique properties exhibited by transition-metal complexes as drugs, including their tunability in the oxidation and the coordination states, allow them to enter into many pharmaceutical applications. − In the amyloid context, they can be considered as good starting compounds for the development of novel neuroprotective agents. , The stability and inertness of Pt­(II) and Ru­(III) complexes allowed a wide range of investigations with different amyloid systems: phenanthroline (phen)–Pt­(II) complexes with two monodentate ligands ( e.g. , chlorides) inhibit the aggregation of Aβ 1–40 and its N-terminal region − as well as of prion protein (PrP) fragments. , Polyoxometalate derivatives of Pt and V suppress amyloid aggregation in a mechanism involving multiple interactions: (i) the coordination of the metal, (ii) electrostatic, (iii) hydrogen, and (iv) van der Waals forces.…”

Organometallic anti-tumor agents: targeting from biomolecules to dynamic bioprocesses

“…11(a)) with highly efficient in vitro and in vivo anti-tumor and anti-metastatic activities. 77 In their previous study using clickable photoaffinity probes, six potential protein targets were identified for an NHC–gold( iii ) complex that is isostructural to 2-34 through a multi-faceted approach. 78 Herein, the cellular thermal shift assay and immunoblot analysis were further applied to determine the molecular target of 2-34 from those six proteins.…”

“…In contrast to the covalent binding mode of 2-33 with ASNS, molecular dynamics simulation analysis indicated that 2-34 binds with vimentin via noncovalent interactions through its orthogonal scaffold synergistically arranged by both the [Pt(C^N^N)] plane and NHC unit. 77…”

Spectroscopy, Structure, Biomacromolecular Interactions, and Antiproliferation Activity of a Fe(II) Complex With DPA-Bpy as Pentadentate Ligand

“…Platinum-based drugs have been successfully used in the treatment of various types of cancer in clinic ( Breglio et al, 2017 ; Shaili et al, 2019 ; Karmakar et al, 2020 ; Tham et al, 2020 ; Wan et al, 2021 ). However, these agents exhibit undesired side effects during chemotherapy.…”