Non-platinum chemotherapeutic metallopharmaceuticals.

Ofele and Wanzlick reported the synthesis of the first N-heterocyclic carbene (NHC) metal complexes in 1968.1,2 The isolation of the first free carbene by Arduengo in 1991 set the scene for an ever-growing interest and advancement in the field of N-heterocyclic carbene chemistry.3 Shortly thereafter, the use of these ligands in organometallic chemistry, particularly in catalysis dramatically increased.4,5

N-heterocyclic carbenes are neutral 2-electron donors, with an ability to bond to both hard and soft metals making them more versatile ligands than phosphines.6 As an added advantage, not only are NHCs easier to synthesize and functionalize than phosphines but they also form a stronger bond to metals and therefore form more stable metal complexes than metal phosphine complexes.7,8 The N-heterocyclic carbene ligands interact with metal centers primarily through strong σ-donation and to a lesser degree through π-backdonation (Figure 1).9,10



Figure 1

Orbital diagram of NHC bonding to metal center.



Ghosh and coworkers11,12,13,14,15,16 as well as others17,18,19 took special interest in the exceptional stability of several metal-NHC complexes and conducted in depth analyses in order to gain better insights into the structure and bonding. In particular, the metal-ligand donor-acceptor interactions were inspected using the charge decomposition analysis (CDA). CDA is a tool used to quantitatively estimate the degree of NHC → metal σ-donation, designated by d, and NHC ← metal π-back donation, designated by b.20,21 Thus a higher d/b ratio emphasizes the ability of NHC to function as an effective σ-donor, whereas a lower d/b ratio highlights the greater NHC ← metal π-back donation. Interestingly, in the studies conducted by Ghosh, greater NHC ← metal π-back donation was observed in Pd-NHC complexes exhibiting lower d/b ratios ranging between 2.59 – 3.9913,14 and Au-NHC complexes with d/b ratios ranging between 5.23 – 5.8815,16 as compared to the Ag-NHC complexes with d/b ratios ranging between 7.8 – 12.6811,12,16. This observation could attest to why silver-NHC complexes are particularly better transmetallating agents.

The newly emerging interest in the medicinal applications of stable metal NHCs led us to examine the few accounts available in the literature dealing with this area of research. This review will discuss in detail the medicinal applications of various transition metal-NHC complexes including silver, gold, rhodium, ruthenium, and palladium. The antimicrobial, antitumor, and resistance properties, along with proposed mechanisms of action to suppress the bacterial growth or proliferation of tumor cells will be discussed.

The Medicinal Applications of Imidazolium Carbene Metal Complexes

NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G2/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.

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NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application

Ruthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy

Ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs.

Publisher Summary Biomedical inorganic chemistry “Elemental Medicine” is an important new area of chemistry. Platinum complexes are now among the most widely used drugs for the treatment of cancer. Three injectable Pt(II) compounds have been approved and several other cis -diam(m)ine complexes are on clinical trials, including an oral Pt(IV) complex. Microbial resistance to established organic antibiotics is a potentially serious problem and provides an impetus for the development of novel antimicrobial metal compounds. With appropriate choice of ligands, it is possible to change the mode of Pt binding to DNA and to circumvent acquired resistance of cancer cells to cisplatin; a trinuclear Pt complex with two monofunctional Pt centers has recently been found to exhibit an intriguing new mode of DNA binding and has entered clinical trials. There is potential in the anti-HIV field. Polyoxometallates of the Keggin type bind to viral envelope sites on cell surfaces and interfere with virus adsorption.

Medicinal Inorganic Chemistry

[ImH] + [RuCl 4 Im 2 ] − cristallise dans le systeme monoclinique avec le groupe d'espace C2/c. [(Me-4ImH)] + [Ru(Me-4Im) 2 Cl 4 ] − cristallise dans le systeme monoclinique avec le groupe d'espace P2 1 /a. Affinement de la structure jusqu'a 0,029 et 0,039 respectivement

Synthesis, molecular structure, and tumor-inhibiting properties of imidazolium trans-bis(imidazole)tetrachlororuthenate(III) and its methyl-substituted derivatives

The antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III) against the P388 leukemia and against the B16 melanoma was investigated. The test compound showed high activity against these tumor models. The tumor inhibiting effect was in the range or better than the effects of the compounds cyclophosphamide, cisplatin, or 5-fluorouracil, which were tested as positive controls. The effective substance is a new, water soluble, anionic, nitrogen-heterocyclic coordinated, ruthenium species, exhibiting antitumor activity.

Antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III). A representative of a new class of inorganic antitumor agents.

Le compose du titre cristallise dans le systeme orthorhombique, groupe d'espace Bm2 1 b et sa structure est affinee jusqu'a R=0,038

Synthesis, antitumor activity, and X-ray structure of bis(imidazolium) (Imidazole)pentachlororuthenate(III), (ImH)2(RuImCl5)

Synthesis, Molecular Structure, and Tumor-Inhibiting Properties of Imidazolium trans-Bis(imidazole)tetrachlororuthenate(III) and Its Methyl-Substituted Derivatives.

W. Rupp

Papers

Synthesis, molecular structure, and tumor-inhibiting properties of imidazolium trans-bis(imidazole)tetrachlororuthenate(III) and its methyl-substituted derivatives

Antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III). A representative of a new class of inorganic antitumor agents.

Synthesis, antitumor activity, and X-ray structure of bis(imidazolium) (Imidazole)pentachlororuthenate(III), (ImH)2(RuImCl5)

Synthesis, Molecular Structure, and Tumor-Inhibiting Properties of Imidazolium trans-Bis(imidazole)tetrachlororuthenate(III) and Its Methyl-Substituted Derivatives.

Synthesis, Antitumor Activity, and X-Ray Structure of Bis(imidazolium) (Imidazole)pentachlororuthenate(III), (ImH)2(RuImCl5).