Rollover Cyclometalated Bipyridine Platinum Complexes as Potent Anticancer Agents: Impact of the Ancillary Ligands on the Mode of Action

Abstract

Platinum-based anticancer coordination compounds are widely used in the treatment of many tumor types, where they are very effective but also cause severe side effects. Organoplatinum compounds are significantly less investigated than the analogous coordination compounds. We report here rollover cyclometalated Pt compounds based on 2,2'-bipyridine which are demonstrated to be potent antitumor agents both in vitro and in vivo. Variation of the co-ligands on the Pt(2,2'-bipyridine) backbone resulted in the establishment of structure-activity relationships. They showed that the biological activity was in general inversely correlated with the reaction kinetics to biomolecules as shown for amino acids, proteins, and DNA. The less stable compounds caused higher reactivity with biomolecules and were shown to induce p53-dependent DNA damage. In contrast, the presence of bulky PTA and PPh ligands was demonstrated to cause lower reactivity and increased antineoplastic activity. Such compounds were devoid of DNA-damaging activity and induced ATF4, a component of the endoplasmic reticulum (ER) stress pathway. The lead complex inhibited tumor growth similar to oxaliplatin while showing no signs of toxicity in test mice. Therefore, we demonstrated that it is possible to fine-tune rollover-cyclometalated Pt(II) compounds to target different cancer pathways and be a means to overcome the side effects associated with cisplatin and analogous compounds in cancer chemotherapy.

New Findings in Metal Complexes with Antiproliferative Activity Containing 1,3,5‐Triaza‐7‐phosphaadamantane (PTA) and Derivative Ligands

“…[27] Other attractive complexes are the neutral [Ru(N-N)-(PTA) 2 Cl 2 ] {N-N = bpy (10), N-N = phen (11)}, monocationic [Ru(N-N)(PTA) 3 Cl]Cl {N-N = bpy (12), N-N = phen(13)} and, di-Scheme 1. [29][30][31] It was showed that the co-ligands bonded to the {Pt(2,2-bpy)} + moiety have a large influence on the reaction kinetics of the complexes with biomolecules such as amino acids, proteins, and DNA. Adapted from ref.…”

“…Structure of Pt and Ru complexes of PTA 7-9. [30] The ligand PTA decreases the reactivity of these metal complexes with biomolecules but increases antineoplas-tic activity. [27] cationic [Ru(N-N)(mPTA) 2 Cl 2 ](BF 4 ) 2 {N-N = bpy (14), N-N = phen (15)} (bpy = 2,2′-bipyridyl; phen = 1,10-phenanthroline; mPTA = N-methyl-1,3,5-triaza-7-phosphaadamantane) (Scheme 2).…”

Increase in the apparent intercalation ability of a platinum complex via multivalency by installation into the sidechain of a graft copolymer and observation of structural changes in the intercalated DNA

“…In this study, 2,2 0 -bipyridine (BPy) group was selected as the ligand graing on the polymer chain because it can form a stable coordinate bond with Pt, and the resulting complex has a planar structure capable of intercalating with DNA strands. 17,18 Considering that the alkyl chain in the ortho-or para-position on the pyridine ring may stabilize the coordinate bond by donating an electron to the nitrogen, 18 here we designed 6-[5-pentan-1-methacrylate]-2,2 0 -bipyridine (BPyMA) as the BPy monomer. The alkyl chain of pentene in the monomer functions as the spacer between the main polymer chain and the BPy-Pt group, and existence of the spacer contributes to an increase in conformational number and accessibility of BPy-Pt units to DNA strands.…”

Three pairs of enantiomers bearing mitochondria‐targeted TPP+ groups as potential anti‐cancer agents

“…The developing of the targeted drugs led to the improvement on the treatment efficiency and the decrease of some side effects . Some traditional drugs has been applied for the field of anticancer treatments, such as cisplatin, carboplatin, and oxaliplatin .…”