Redox-active antineoplastic ruthenium complexes with indazole: Correlation of in vitro potency and reduction potential

Michael A. Jakupec; Erwin Reisner; Anna Eichinger; Martina Pongratz; Vladimir B. Arion; Markus Galanski; Christian G. Hartinger; Bernhard K. Keppler

doi:10.1021/jm0490742

Redox-active antineoplastic ruthenium complexes with indazole: Correlation of in vitro potency and reduction potential

Michael A. Jakupec, Erwin Reisner, Anna Eichinger, Martina Pongratz, Vladimir B. Arion, Markus Galanski, Christian G. Hartinger, Bernhard K. Keppler

Research output: Contribution to journal › Article › peer-review

Abstract

Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [RuIIICl (6-n)(ind)n](3-n)- (n = 0-4; ind = indazole; counterions = Hind+ or Cl-) and the compound trans-[RuIICl2(ind)4] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order: [RuIIICl6]3- <[RuIIICl 4(ind)2]- <[RuIIICl 5(ind)]2- ≪ [RuIIICl3(ind) 3] <[RuIIICl2(ind)4]+ ≈ [RuIICl2(ind)4]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it. © 2005 American Chemical Society.

Original language	English
Pages (from-to)	2831-2837
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	48
Issue number	8
DOIs	https://doi.org/10.1021/jm0490742
Publication status	Published - 21 Apr 2005

Keywords

Intestine (colon
potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole)
Antitumor agents
Human
Ovary
Reduction potential
Structure-activity relationship (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole)
Biological transport (uptake
antineoplastic ruthenium indazole complex redn potential

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm0490742

CCDC 611341: Experimental Crystal Structure Determination
Jakupec, M. A. (Contributor), Reisner, E. (Contributor), Eichinger, A. (Contributor), Pongratz, M. (Contributor), Arion, V. B. (Contributor), Galanski, M. (Contributor), Hartinger, C. G. (Contributor) & Keppler, B. K. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2006
DOI: 10.5517/ccnj4pz, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccnj4pz&sid=DataCite
Dataset
CCDC 611340: Experimental Crystal Structure Determination
Jakupec, M. A. (Contributor), Reisner, E. (Contributor), Eichinger, A. (Contributor), Pongratz, M. (Contributor), Arion, V. B. (Contributor), Galanski, M. (Contributor), Hartinger, C. G. (Contributor) & Keppler, B. K. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2006
DOI: 10.5517/ccnj4ny, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccnj4ny&sid=DataCite
Dataset

Cite this

@article{65864cd4c620466d94587fa0380c0fd4,

title = "Redox-active antineoplastic ruthenium complexes with indazole: Correlation of in vitro potency and reduction potential",

abstract = "Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [RuIIICl (6-n)(ind)n](3-n)- (n = 0-4; ind = indazole; counterions = Hind+ or Cl-) and the compound trans-[RuIICl2(ind)4] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order: [RuIIICl6]3- <[RuIIICl 4(ind)2]- <[RuIIICl 5(ind)]2- ≪ [RuIIICl3(ind) 3] <[RuIIICl2(ind)4]+ ≈ [RuIICl2(ind)4]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it. {\textcopyright} 2005 American Chemical Society.",

keywords = "Intestine (colon, potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole), Antitumor agents, Human, Ovary, Reduction potential, Structure-activity relationship (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole), Biological transport (uptake, antineoplastic ruthenium indazole complex redn potential",

author = "Jakupec, {Michael A.} and Erwin Reisner and Anna Eichinger and Martina Pongratz and Arion, {Vladimir B.} and Markus Galanski and Hartinger, {Christian G.} and Keppler, {Bernhard K.}",

note = "CAN 142:385348 1-6 Pharmacology Institute of Inorganic Chemistry,University of Vienna,Vienna,Austria. Journal 849938-93-8P; 849938-94-9P Role: PRP (Properties), SPN (Synthetic preparation), PREP (Preparation) (crystal structure; potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 22541-88-4D (Ruthenium(III) Role: BSU (Biological study, unclassified), BIOL (Biological study) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 186179-42-0; 186179-44-2; 332405-33-1 Role: PAC (Pharmacological activity), BIOL (Biological study) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 124875-20-3; 849938-92-7 Role: PAC (Pharmacological activity), RCT (Reactant), BIOL (Biological study), RACT (Reactant or reagent) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 332405-35-3P Role: PAC (Pharmacological activity), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 271-44-3 (Indazole) Role: RCT (Reactant), RACT (Reactant or reagent) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole)",

year = "2005",

month = apr,

day = "21",

doi = "10.1021/jm0490742",

language = "English",

volume = "48",

pages = "2831--2837",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "8",

}

TY - JOUR

T1 - Redox-active antineoplastic ruthenium complexes with indazole: Correlation of in vitro potency and reduction potential

AU - Jakupec, Michael A.

AU - Reisner, Erwin

AU - Eichinger, Anna

AU - Pongratz, Martina

AU - Arion, Vladimir B.

AU - Galanski, Markus

AU - Hartinger, Christian G.

AU - Keppler, Bernhard K.

N1 - CAN 142:385348 1-6 Pharmacology Institute of Inorganic Chemistry,University of Vienna,Vienna,Austria. Journal 849938-93-8P; 849938-94-9P Role: PRP (Properties), SPN (Synthetic preparation), PREP (Preparation) (crystal structure; potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 22541-88-4D (Ruthenium(III) Role: BSU (Biological study, unclassified), BIOL (Biological study) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 186179-42-0; 186179-44-2; 332405-33-1 Role: PAC (Pharmacological activity), BIOL (Biological study) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 124875-20-3; 849938-92-7 Role: PAC (Pharmacological activity), RCT (Reactant), BIOL (Biological study), RACT (Reactant or reagent) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 332405-35-3P Role: PAC (Pharmacological activity), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole); 271-44-3 (Indazole) Role: RCT (Reactant), RACT (Reactant or reagent) (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole)

PY - 2005/4/21

Y1 - 2005/4/21

N2 - Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [RuIIICl (6-n)(ind)n](3-n)- (n = 0-4; ind = indazole; counterions = Hind+ or Cl-) and the compound trans-[RuIICl2(ind)4] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order: [RuIIICl6]3- <[RuIIICl 4(ind)2]- <[RuIIICl 5(ind)]2- ≪ [RuIIICl3(ind) 3] <[RuIIICl2(ind)4]+ ≈ [RuIICl2(ind)4]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it. © 2005 American Chemical Society.

AB - Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [RuIIICl (6-n)(ind)n](3-n)- (n = 0-4; ind = indazole; counterions = Hind+ or Cl-) and the compound trans-[RuIICl2(ind)4] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order: [RuIIICl6]3- <[RuIIICl 4(ind)2]- <[RuIIICl 5(ind)]2- ≪ [RuIIICl3(ind) 3] <[RuIIICl2(ind)4]+ ≈ [RuIICl2(ind)4]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it. © 2005 American Chemical Society.

KW - Intestine (colon

KW - potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole)

KW - Antitumor agents

KW - Human

KW - Ovary

KW - Reduction potential

KW - Structure-activity relationship (potency and redn. potential of redox-active antineoplastic ruthenium complexes with indazole)

KW - Biological transport (uptake

KW - antineoplastic ruthenium indazole complex redn potential

U2 - 10.1021/jm0490742

DO - 10.1021/jm0490742

M3 - Article

SN - 0022-2623

VL - 48

SP - 2831

EP - 2837

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Redox-active antineoplastic ruthenium complexes with indazole: Correlation of in vitro potency and reduction potential

Abstract

Keywords

UN SDGs

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Datasets

CCDC 611341: Experimental Crystal Structure Determination

CCDC 611340: Experimental Crystal Structure Determination

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