From bench to bedside – preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A)

https://stuff.mit.edu/afs/athena/course/5/5.062/oldwww/Fall03/591.pdf

New metal complexes as potential therapeutics.

Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems.

/pdf/the-development-of-anticancer-ruthenium-ii-complexes-from-35e09q82ra.pdf

The development of anticancer ruthenium(II) complexes: from single molecule compounds to nanomaterials

Why Does Cisplatin Reach Guanine-N7 with Competing S-Donor Ligands Available in the Cell?

The antitumor activity of the organometallic ruthenium(II)−arene complexes, RuCl2(η6-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)−arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung m...

In Vitro and in Vivo Evaluation of Ruthenium(II)−Arene PTA Complexes

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(eta(6)-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p-cymene)RuCl(2)(isonicotinamide)] (7), and [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) are reported. They have "piano stool" geometries with eta(6) coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru-Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.

Inhibition of cancer cell growth by ruthenium(II) arene complexes

Reactions of the anticancer drug carboplatin ("Paraplatin") with a variety of sulfur-containing amino acids have been investigated by (1)H and (15)N NMR spectroscopy and by HPLC. Thiols react very slowly and sulfur-bridged species containing four-membered Pt(2)S(2) rings are the predominant products. In contrast, reactions with thioether ligands are much more rapid, and kinetics for the initial stages of the reaction with L-methionine have been determined (k = 2.7 x 10(-)(3) M(-)(1) s(-)(1)). Surprisingly, very stable ring-opened species are formed such as cis-[Pt(CBDCA-O)(NH(3))(2)(L-HMet-S)] which has a half-life for Met-S,N ring-closure of 28 h at 310 K. A study of the formation of the analogous product for N-acetyl-L-methionine and its subsequent ring closure is reported. Reactions such as these may play a role in the biological activity of carboplatin.

Ring-Opened Adducts of the Anticancer Drug Carboplatin with Sulfur Amino Acids.

NMR investigations of the kinetics and thermodynamics of the competitive binding of L-methionine (Met), L-histidine (His), and 5′-monophosphates of guanosine (5′-GMP), adenosine (5′-AMP), thymidine (5′-TMP) and cytidine (5′-CMP) to [Pt(dien)Cl]+(dien = 1,5-diamino-3-azapentane) in aqueous solution show that 5′-GMP selectively displaces S-bound Met, a finding which has implications for DNA platination by anticancer drugs in vivo.

/pdf/intermolecular-displacement-of-s-bound-l-methionine-on-3td2ib0dvp.pdf

Intermolecular displacement of S-bound L-methionine on platinum(II) by guanosine 5′-monophosphate: implications for the mechanism of action of anticancer drugs

The Ru(II) organometallic antitumor complex [(η6-biphenyl)RuCl(en)][PF6] (1) reacts slowly with the amino acid l-cysteine (l-CysH2) in aqueous solution at 310 K. Reactions were followed over periods of up to 48 h using HPLC, electronic absorption spectroscopy, LC-ESI-MS, and 1D or 2D 1H and 15N NMR spectroscopy. Reactions at a 1 mM/2 mM (Ru/l-CysH2) ratio were multiphasic in acidic solutions (pH 5.1) and appeared to involve aquation as the first step. Initially, 1:1 adducts involving substitution of Cl by S-bound or O-bound l-CysH2, [(η6-biphenyl)Ru(S-l-CysH)(en)]+ (4a) and [(η6-biphenyl)Ru(O-l-CysH2)(en)]2+ (4b) formed, followed by the cystine adduct [(η6-biphenyl)Ru(O-Cys2H2)(en)]2+ (3), and two dinuclear complexes from which half or all of the chelated ethylenediamine had been displaced, [(η6-biphenyl)Ru(H2O)(μS,N-l-Cys)Ru(η6-biphenyl)(en)]2+ (5) containing one bridging cysteine, and [(η6-biphenyl)Ru(O,N-l-Cys-S)(S-l-Cys-N)Ru(η6-biphenyl)(H2O)] (6) containing two bridging cysteines. The unusual cluster...

Reactions of a Ruthenium(II) Arene Antitumor Complex with Cysteine and Methionine

L-Methionine (L-HMet) increased the rate of reaction of the anticancer drug cisplatin, cis-[PtCl2(NH3)2], with guanosine 5′-monophosphate (5′-GMP) at pH 7. The course of the reaction has been elucidated by 1H and [1H, 15N] NMR spectroscopy. Novel intermediates detected and characterized include cis-[Pt(5′-GMP-N7)(L-HMet-S)(NH3)2]2+ and [Pt(L-Met-S,N)(5′-GMP-N7)(NH3)]+(charges on 5′-GMP ignored), the formation of which involves ammine release. Monodentate S-bound L-HMet can co-ordinate reversibly, whereas S,N-chelated L-Met is much less reactive. Thus methionine residues in peptides and proteins could play a role in the transfer of Pt onto DNA. Comparative reactions of [Pt(en)Cl2](en = 1,2-diaminoethane) have also been investigated.

L-Methionine increases the rate of reaction of 5′-guanosine monophosphate with the anticancer drug cisplatin: mixed-ligand adducts and reversible methionine binding

Piedad del Socorro Murdoch

Papers

Inhibition of cancer cell growth by ruthenium(II) arene complexes

Ring-Opened Adducts of the Anticancer Drug Carboplatin with Sulfur Amino Acids.

Intermolecular displacement of S-bound L-methionine on platinum(II) by guanosine 5′-monophosphate: implications for the mechanism of action of anticancer drugs

Reactions of a Ruthenium(II) Arene Antitumor Complex with Cysteine and Methionine

L-Methionine increases the rate of reaction of 5′-guanosine monophosphate with the anticancer drug cisplatin: mixed-ligand adducts and reversible methionine binding