Nonsteroidal Anti-inflammatory—Organometallic Anticancer Compounds

Abstract

Compounds that combine metal-based drugs with covalently linked targeted organic agents have been shown, in some instances, to exhibit superior anticancer properties compared to the individual counterparts. Within this framework, we prepared a series of organometallic ruthenium(II)- and osmium(II)-p-cymene complexes modified with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and diclofenac. The NSAIDs are attached to the organometallic moieties via monodentate (pyridine/phosphine) or bidentate (bipyridine) ligands, affording piano-stool Ru(II) and Os(II) arene complexes of general formula [M(η(6)-p-cymene)Cl2(N)], where N is a pyridine-based ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate}, [M(η(6)-p-cymene)Cl2(P)], where P is a phosphine ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate, and [M(η(6)-p-cymene)Cl(N,N')][Cl], where N,N' is a bipyridine-based ligand, (4'-methyl-[2,2'-bipyridin]-4-yl)methyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate), (4'-methyl-[2,2'-bipyridin]-4-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate), (bis(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate), or (bis(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate). The antiproliferative properties of the complexes were assessed in human ovarian cancer cells (A2780 and A2780cisR, the latter being resistant to cisplatin) and nontumorigenic human embryonic kidney (HEK-293) cells. Some of the complexes are considerably more cytotoxic than the original drugs and also display significant cancer cell selectivity.

New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

“…The anticancer effects observed for cisplatin suggested that platinum and non-platinum metal-based compounds might be as valuable as organic anticancer drugs [2, 3]. Cisplatin, and a few related platinum complexes, such as carboplatin and oxaliplatin are along with the most commonly used anticancer agents [4].…”

“…The extensive clinical success of platinum compounds has improved the synthesis of other platinum and non-platinum metallodrugs that might demonstrate different cytotoxic properties and characterized by a different prototype of anticancer specificities, active against cisplatin-resistant tumor cells and with an encouraging toxicological profile. Thus, in the span of three to four decades, a variety of metal compounds were investigated as potential anticancer agents based on several non-platinum metals such as ruthenium, palladium, titanium, gold and copper [2–10]. …”

“…There are many examples of gold(III) complexes linked to dithiocarbamate, polyamine, polypyridine and their derivative ligands [2, 3]. In particular, dithiocarbamate ligands were combined with gold(III) complexes to inhibit the interaction of the metal center with thiol-containing renal enzymes and avoid cisplatin-induced nephrotoxicity [16].…”

Selective cytotoxicity of arene tricarbonylchromium towards tumour cell lines

“…The complexes of Fe [20][21][22][23], Ru [24][25][26], Os [27,28] and Ag [29] have been found to be very active against cancer cells. Arene tricarbonylchromium group, for which the oxidation state of chromium is zero, has been attached to biological substances such as β-estradiol molecule to produce complexes that have been mainly studied for their capacity to act as a probe for the detection of biological substances by infrared spectroscopy [30].…”

Cytotoxic hydrogen bridged ruthenium quinaldamide complexes showing induced cancer cell death by apoptosis

“…[6][7][8][9][10][11][12][13][14][15][16] Ruthenium-based complexes are some of the most promising, with reported selective potency in vitro and in vivo. [17][18][19][20][21][22] McGowan et al have synthesised a range of ruthenium metal complexes for their uses as anticancer agents. [23][24][25][26] The work published on ruthenium quinaldamides showed that under inert atmosphere conditions, the filtering over NH4PF6 yielded the ruthenium quinaldamide monomers.…”