Anticancer platinum(II) complexes bearing N-heterocycle rings

doi:10.1016/j.bmcl.2019.03.045

Bioorganic & Medicinal Chemistry Letters

Volume 29, Issue 11, 1 June 2019, Pages 1257-1263

https://doi.org/10.1016/j.bmcl.2019.03.045 Get rights and content

Abstract

Starting from the pioneering discovery of picoplatin and phenanthriplatin, many efforts were realized by different research groups in the synthesis of different platinum(II) complexes, bearing a N-heterocycle moiety active as anticancer agents in different types of solid tumors. This review deals in particular with both the bifunctional and monofunctional platinum drugs, not only in dichloride platinum(II) complexes, but also in recent advances in modern platinum structures, i.e. cationic ones. Both the in vitro and in vivo studies of these anticancer agents are taken into account, with a special consideration for aggressive and orphan in treatment tumors.

Graphical abstract

Section snippets

Bifunctional platinum drugs

Starting from the consideration that DNA represents the well-known primary target for cisplatin, it has been established that it reacts with many other different cellular constituents in the cytoplasm such as cytoskeletal microfilaments, RNA and the extensive pool of thiol-containing proteins, due to the high reactivity of platinum metal center towards soft S-donor nucleophiles.14, 15 Among these, the tripeptide glutathione (GSH), normally present in the cellular environment at high

Monofunctional platinum drugs

Cationic platinum(II)-based anticancer agents containing only one substitution-labile ligand and thus referred to as “monofunctional”, have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum and promising antitumor activity both in vitro and in vivo.47, 48, 2, 49 For such cations no indication of ammonia or N-heterocycle loss was detected so that the characteristic monofunctional DNA adducts may be responsible for the different spectrum of

Conclusion and perspectives

The choice to use different N-heterocycle rings, mainly the aromatic ones, resulted to influence not only the electronic and steric coordination sphere around the platinum metal center but also to offer the possibility to target different biological pathways involved in such a multifactor pathology as cancer. The first attempt was focused on the substitution of one ammonia with a monodentate aromatic amine both in cis and trans configurations, underlining that the cis configuration is not

References (69)

A.J. Di Pasqua et al.
Inorg Chim Acta
(2012)
J.L. Misset et al.
Crit Rev Oncol Hematol
(2000)
L. Bai et al.
Eur J Med Chem
(2017)
Y. Wang et al.
J Photochem Photobiol, B
(2016)
D. Xu et al.
J Inorg Biochem
(2013)
J.-L. Qin et al.
Eur J Med Chem
(2016)
B.A. Miles et al.
Polyhedron
(2016)
V. Brabec et al.
Coord Chem Rev
(2017)
K.-B. Huang et al.
Eur J Med Chem
(2013)
X.-Q. Song et al.
Eur J Med Chem
(2018)

Cited by (42)

A Pt(II) complex bearing N-heterocycle ring induced ferroptotic cell death in ovarian cancer
2024, Journal of Inorganic Biochemistry
Cisplatin is a widely used chemotherapeutic agent which interacts with DNA to form Pt-DNA adducts, leading to DNA double-strand breaks and apoptosis. Resistance is the major obstacle in the clinical application of cisplatin. A quinoline derivative based Pt(II) complex PtQ was synthesized and characterized. As an analogue of cisplatin, PtQ demonstrated a novel anticancer mechanism in ovarian cancer. PtQ caused excessive production of reactive oxygen species (ROS), which triggered ferroptotic cell death in ovarian cancer. Cystine/glutamate antiporter SLC7A11 and glutathione peroxidase 4 (GPX4) which alleviate lipid peroxidation were both downregulated in PtQ-treated SKOV3 cells. Furthermore, PtQ induced DNA single-strand breaks and suppressed the expression of single-strand breaks repair protein PARP1. Mechanism studies demonstrated that PtQ can hopefully bypass the signaling pathways mediated cisplatin resistance in ovarian cancer.
Toxicity assessments and transcriptional effects of monofunctionalized Pt(II) complex under dark and light irradiation condition in Caenorhabditis elegans
2022, Journal of Inorganic Biochemistry
Citation Excerpt :
Besides, Pt(IV) species which was not toxic in normal tissues but toxic in tumor tissues have been synthesized. [12,13] On the other hand, novel Pt(II) complexes with improved anti-chemoresistance capabilities have been synthesized. [14–16] The aromatic segment bearing monofunctional Pt(II) bearing complex Pyriplatin synthesized by Lippard showed improved anti-chemoresistance capability in contrast to traditional cisplatin.
In vivo toxicity of aromatic ring (BODIPY, 1,3,5,7,8-pentamethyl dipyrrin borondifluoride) attached monofunctional Pt(II) complexes mCBP {[cis-Pt(NH₃)₂Cl] 8-(para-pyridine-methylene),1,3,5,7-tetramethyl dipyrrin borondifluoride}⁺ Nitrate⁻ and dCBP {[cis-Pt(NH₃)₂Cl]₂8-(1,3-pyrimidine-5-methylene),1,3,5,7-tetramethyl dipyrrin borondifluoride}²⁺ diNitrate²⁻ were tested in Caenorhabditis elegans (C. elegans). dCBP showed promising reactive oxygen ROS (reactive oxygen species) generating capability. This complex resulted reduction of lifespan, body length and egg laying rate under dark and light irradiation in both N2 (wild-type, cisplatin resistant) and ok938 (asna-1, cisplatin sensitive) C. elegans. Expressional change of several key cancer related pathway (JNK (c-Jun N-terminal kinase) and Wnt/β-catenin (Wingless/Integrated/β-catenin)) related genes (for instance, jnk-1, wrm-1 and gst-4) were confirmed by RNA sequencing experiments. These transcriptional alternations could explain physiological parameters change in nematode and partially revealed how both Pt(II) based complexes influence cancer related pathways. Furthermore, these associated genes exhibited the function of apoptosis, reduced chemoresistance of cancer cells and most of those expressional changes were linked to extended survival of cancer patients.
Theoretical hydrolysis mechanism of anticancer Pt(II) and Pd(II) dichloro complexes with N, N bidentate chelator in aqueous medium and their molecular docking
2022, Chemical Physics
Theoretical hydrolysis mechanism of Pt(II) and Pd(II) dichloro complexes with bidentate N, N chelated cis-[Pt(AEP)Cl₂] and cis-[Pd(AEP)Cl₂] (where AEP = 1-(2-Aminoethyl)-pyrrolidine) were studied with the help of DFT. Penta-coordinated transition state (T.S.) of hydrolysis of Pt(II)/Pd(II) complex through S_N2 mechanistic pathway for both the probable reactions were fully optimized. The characterization of T.S of different hydrolysis paths of both the complexes were performed using density functional (DFT) theory at B3LYP, MPW1PW91 and PBEPBE level of theory. Both the steps are exothermic in nature and the computed activation parameters support the hydrolysis process proceeds through SN2 mechanistic pathway in both the Pt(II)/Pd(II) dichloro complexes. The rate constants for hydrolysis process were deduced from the Eyring equation, and the result suggests that the second step required higher activation energy than in the first step, i.e. second step is the rate-determining step. Molecular docking of the complexes with B-DNA has been explored to obtain best bonding with suitable conformation and corresponding interaction forces in their docked structures.
Distinct mechanism of action for antitumoral neutral cyclometalated Pt(II)-complexes bearing antifungal imidazolyl-based drugs
2022, Journal of Inorganic Biochemistry
Citation Excerpt :
DNA is identified as the biological target for these complexes, interacting by minor-groove [28]. Organometallic Pt(II) complexes containing monodentate N-donor ligands or cyclometalated ligands that can modify their anticancer mechanism of action have been recently reported [29,30,31] being DNA and serum proteins the most common targets. Several neutral cyclometalated complexes described in the literature displayed a different antiproliferative mechanism to DNA binding, being reactive oxygen species (ROS) generation a suitable strategy to induce programmed cell death in anticancer therapy [32,33].
Three neutral Pt(II) complexes containing 1-Methylimidazole and the antifungal imidazolyl drugs Clotrimazole and Bifonazole have been prepared. The general formula of the new derivatives is [Pt(κ²-(C^N)Cl(L)], where C^N stands for ppy = 2-phenylpyridinate, and L = 1-Methylimidazole (MeIm) for [Pt-MeIm]; L = Clotrimazole (CTZ) for [Pt-CTZ] and L = Bifonazole (BFZ) for [Pt-BFZ]). The complexes have been completely characterized in solution and the crystal structures of [Pt-BFZ] and [Pt-CTZ] have been resolved. Complexes [Pt-MeIm] and [Pt-BFZ] present higher cytotoxicity than cisplatin in SW480 (colon adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian cancer) cell lines. [Pt-MeIm] shows the highest accumulation in A549 cells, in agreement with its inability to interact with serum albumin. By contrast, [Pt-CTZ] and [Pt-BFZ] interact with serum proteins, a fact that reduces their bioavailability. The strongest interaction with bovine serum albumin (BSA) is found for [Pt-BFZ], which is the least internalized inside the cells. All the complexes are able to covalently interact with DNA. The most cytotoxic complexes, [Pt-MeIm] and [Pt-BFZ] induce cellular accumulation in G0/G1 and apoptosis by a similar pathway, probably involving a reactive oxygen species (ROS) generation mechanism. [Pt-BFZ] turns out to be the most efficient complex regarding ROS generation and causes mitochondrial membrane depolarization, whereas [Pt-MeIm] induces the opposite effect, hyperpolarization of the mitochondrial membrane. On the contrary, the least cytotoxic complex, [Pt-CTZ] cannot block the cell cycle or generate ROS and the mechanism by which it induces apoptosis could be a different one.
The literature of heterocyclic chemistry, Part XIX, 2019
2022, Advances in Heterocyclic Chemistry
An overview of anticancer platinum N-heterocyclic carbene complexes
2021, Coordination Chemistry Reviews
Citation Excerpt :
The anticancer efficacy of cisplatin, however, was significantly compromised owing to its severe adverse effects, including nausea, vomiting, loss of hearing and kidney damage [2-5]. Work has thus never stopped in search of other platinum agents or nonplatinum metal complexes (e.g., copper, gold and ruthenium) with improved pharmacological properties [6-32]. These efforts have yielded several encouraging results, such as the approval of carboplatin in 1989 and oxaliplatin in 1996 [33-35].
N-Heterocyclic carbenes (NHCs) have been introduced as a new platform for the development of anticancer metal complexes for several decades. NHCs as strong σ-donors can coordinate firmly with different noble metals, thereby giving rise to many types of metal NHC complexes. Among them, platinum NHC complexes are regarded as the direct descendants of cisplatin as they have the same central metal ions. Inspiringly, platinum NHC complexes showed comparable activities as cisplatin in many human cancer cell lines while maintaining their activity in cisplatin-resistant cell lines. This lies in the fact that platinum NHC complexes can elicit different mechanisms of action other than those known for conventional platinum complexes. Additionally, platinum NHC complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as a type II ICD inducer. Herein, platinum NHC complexes are categorized according to their structural features, and their anticancer activities are also discussed in detail. Meanwhile, other types of carbene structures are introduced that may be able to be used as platforms for the next generation of platinum NHC complexes.

View all citing articles on Scopus

View full text

DigestAnticancer platinum(II) complexes bearing N-heterocycle rings

Abstract

Graphical abstract

Section snippets

Bifunctional platinum drugs

Monofunctional platinum drugs

Conclusion and perspectives

Inorg Chim Acta

Crit Rev Oncol Hematol

Eur J Med Chem

J Photochem Photobiol, B

J Inorg Biochem

Eur J Med Chem

Polyhedron

Coord Chem Rev

Eur J Med Chem

Eur J Med Chem

Bioorg Med Chem

Bioorg Med Chem

Eur J Med Chem

Eur J Med Chem

Inorg Chim Acta

Bioorg Med Chem

J Inorg Biochem

J Inorg Biochem

Bioorg Med Chem

Eur J Med Chem

Biomed Pharmacother

Free Radical Biol Med

J Inorg Biochem

J Clin Oncol

Chem Rev

Jpn J Cancer Res

Cancer Res

Mol Cancer Ther

Mol Pharmacol

Nat Med

Chem Rev

Appl Organomet Chem

Cancer Chemother Pharmacol

Drug Metab Dispos

Digest
Anticancer platinum(II) complexes bearing N-heterocycle rings