Probing the potential of platinum(II) complexes for the inhibition of thiol-dependent enzymatic activity

Zutphen, Steven van; Kraus, Marianne; Marel, Gijs A. van der; Overkleeft, Herman S.; Reedijk, Jan

doi:10.1016/j.jinorgbio.2005.03.014

Cited by 16 publications

(5 citation statements)

References 23 publications

(28 reference statements)

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“…Perhaps not surprisingly platinum complexes have been investigated as cysteine protease inhibitors, but despite positive results in model reactions they showed no significant inhibitory activity towards cathepsin B. 77 Our hypothesis was that a metal complex could inhibit a cysteine protease by ligand exchange with the thiol of the active site cysteine. The reduced pK a of the active site cysteine thiol results in a completely ionic thiolate group which favors the interaction of thiophilic metals such as gold which have a high affinity for thiolates with a low pK a .…”

Section: Cathepsin Cysteine Proteases As Targets For Metal-based Drug...mentioning

confidence: 87%

Cysteine proteases as targets for metal-based drugs

Fricker

2010

Metallomics

126

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The discovery of the platinum anticancer drug cisplatin provided a major stimulus for research into metal-based drugs. The molecular target for the platinum agents is DNA; however recent developments in inorganic medicinal chemistry have identified several alternative novel targets for metal-based drugs. Biological molecules with essential thiol groups are attractive targets. Thiol-containing molecular targets include the redox enzymes thioredoxin reductase and glutathione reductase, transcription factors, and cysteine proteases such as caspases and cathepsins. Inorganic chemistry offers many opportunities for medicinal chemistry, and alternative targets for metal-based drugs are reviewed, with a focus on cysteine proteases. The cathepsin cysteine proteases have numerous physiological functions, and have been implicated in diseases including cancer, autoimmune and inflammatory, and parasitic diseases. The catalytic mechanism of these enzymes is dependent upon a cysteine at the active site. We postulate that metal complexes can inhibit these enzymes via a ligand substitution with the thiol of the active site cysteine. We have investigated several classes of metal complexes including cyclometalated organo gold(iii) and Pd(ii) complexes, and a series of rhenium(v) mixed ligand oxorhenium complexes as inhibitors of cathepsin cysteine proteases. Mechanistic studies were conducted on the latter supporting the hypothesis of active site-directed inhibition. These data are reviewed below and discussed in the context of possible therapeutic applications including cancer and parasitic disease.

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Section: Cathepsin Cysteine Proteases As Targets For Metal-based Drug...mentioning

confidence: 87%

Cysteine proteases as targets for metal-based drugs

Fricker

2010

Metallomics

126

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“…Although platinum(II) is a well-established pharmacophore for the development of cytotoxic agents [37,225], numerous Pt(II)-based chemotherapeutic strategies being reported to this date; its high thiophilicity is responsible for several severe drawbacks: drugs' inactivation and development of resistance via reaction with endogenous sulphur-containing biomolecules present in high concentrations inside the cell (e.g., cysteine and methionine-rich proteins, glutathione, metallothionein, and albumin [226][227][228][229][230]) and high nephrotoxicity due to interaction with renal thiol enzymes [231,232].…”

Section: Palladium For Platinum Substitution In Polyamine Complexesmentioning

confidence: 99%

Platinum and Palladium Polyamine Complexes as Anticancer Agents: The Structural Factor

Marques

2013

ISRN Spectroscopy

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Since the introduction of cisplatin to oncology in 1978, Pt(II) and Pd(II) compounds have been intensively studied with a view to develop the improved anticancer agents. Polynuclear polyamine complexes, in particular, have attracted special attention, since they were found to yield DNA adducts not available to conventional drugs (through long-distance intra- and interstrand cross-links) and to often circumvent acquired cisplatin resistance. Moreover, the cytotoxic potency of these polyamine-bridged chelates is strictly regulated by their structural characteristics, which renders this series of compounds worth investigating and their synthesis being carefully tailored in order to develop third-generation drugs coupling an increased spectrum of activity to a lower toxicity. The present paper addresses the latest developments in the design of novel antitumor agents based on platinum and palladium, particularly polynuclear chelates with variable length aliphatic polyamines as bridging ligands, highlighting the close relationship between their structural preferences and cytotoxic ability. In particular, studies by vibrational spectroscopy techniques are emphasised, allowing to elucidate the structure-activity relationships (SARs) ruling anticancer activity.

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“…The low activity of compounds 1-5 for the inhibition of cathepsin B could be relatedwith an insufficient targeting of compounds 1-5 for the active site of cathepsin B orwith a lack of reactivity of their metal center for the active site of cathepsin B [63]. It should be noted that a hydrogen bond between the N-H function of compounds 1-5 and the anionic X ligand trans to the metalated carbon atom could render the metal centers of compounds 1-5 less reactive to substitution reactions than expected.…”

Section: Cathepsin B Inhibitionmentioning

confidence: 99%

Cyclopalladated and cycloplatinated benzophenone imines: Antitumor, antibacterial and antioxidant activities, DNA interaction and cathepsin B inhibition

Albert

D’Andrea

Granell

et al. 2014

Journal of Inorganic Biochemistry

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The antitumor, antibacterial and antioxidant activity, DNA interaction and cathepsin B inhibition of cyclo-ortho-palladated and -platinated compounds [Pd(C,N)]2(μ-X)2 [X=OAc (1), X=Cl (2)] and trans-N,P-[M(C,N)X(PPh3)] [M=Pd, X=OAc (3), M=Pd, X=Cl (4), M=Pt, X=Cl (5)] are discussed [(C,N)=cyclo-ortho-metallated benzophenone imine]. The cytotoxicity of compound 5 has been evaluated towards human breast (MDA-MB-231 and MCF-7) and colon (HCT-116) cancer cell lines and that of compounds 1-4 towards the HCT-116 human colon cancer cell line. These cytotoxicities have been compared with those previously reported for compounds 1-4 towards MDA-MB-231 and MCF-7 cancer cell lines. Compound 3 and 4 were approximately four times more active than cisplatin against the MDA-MB-231 and MCF-7 cancer cell lines, and compound 5, was approximately four times more potent than cisplatin against the HCT-116 cancer cell line. The antibacterial activity of compounds 1-5 was in between the ranges of activity of the commercial antibiotic compounds cefixime and roxithromycin. Complexes 1-2 and 4-5 presented also antioxidant activity. Compounds 1-5 alter the DNA tertiary structure in a similar way to cisplatin, but at higher concentration, and do not present a high efficiency as cathepsin B inhibitors. Compound 5 has not been previously described, and its preparation, characterization, and X-ray crystal structure are reported.

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Probing the potential of platinum(II) complexes for the inhibition of thiol-dependent enzymatic activity

Cited by 16 publications

References 23 publications

Cysteine proteases as targets for metal-based drugs

Cysteine proteases as targets for metal-based drugs

Platinum and Palladium Polyamine Complexes as Anticancer Agents: The Structural Factor

Cyclopalladated and cycloplatinated benzophenone imines: Antitumor, antibacterial and antioxidant activities, DNA interaction and cathepsin B inhibition

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