Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)- amino]cyclohexane chelators

Structural and electronic properties of the Mn II, FeII, NiII, CuII and Zn II complexes

Matt L. Childers, Fan Su, Ann M. Przyborowska, Bimjhana Bishwokarma, Gyungse Park, Martin W. Brechbiel, Suzy V. Torti, Frank M. Torti, Grant Broker, Jacob S. Alexander, Robin D. Rogers, Karin Ruhlandt, Roy P. Planalp

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Effects of pyridyl-ring alkylation on complexation of MnII, FeII, NiII, CuII and ZnII by chelators based on r-1,c-3,c-5-tri-aminocyclohexane (tach) have been studied. The chelators studied are N,N′,N″-tris[(x-alkyl-2-pyridyl)methyl] derivatives of tach, where the ring substituents are 3-Me, 4-Me, 5-Me, 6-Me or 6-MeO ("tach-x-Rpyr"). Dicationic complexes were synthesized for most combinations of the above five metals and five chelators, using ClO 4 -, NO3 -, Cl-, or CF 3SO3 - as counterions. Their bonding, structure, and aqueous lability were analyzed by UV/Vis/NIR spectroscopy, magnetic moment determination, HPLC, and single-crystal X-ray crystallography. The striking features are seen in the 6-alkylated complexes, where steric repulsions between the 6-substituents at the threefold axis of the pseudo-octahedral coordination sphere result in a substantially weakened metal-ligand interaction. In the [M(tach-6-Rpyr)]2+ series of divalent Mn, Ni, Cu and Zn, effects of these repulsions include bond angle and length distortions, decrease of the coordination number to five, shifts of d-d electronic transitions to lower energies, and spin-free complexes of the bound metal ion. Aqueous lability studies by HPLC agree with the spectroscopic findings. The bonding properties of the other tach-x-Mepyr chelators (x = 3, 4, 5) closely resemble the unalkylated parent tachpyr in solution. Similarly in the X-ray studies, [Zn(tach-3-Mepyr)]2+ resembles [Zn(tachpyr)]2+. The cytotoxicities of the chelators toward human breast cancer cells (MCF7) at a fixed chelator concentration of 16 μM show time-dependent induction of cell death in the order tach-3-Mepyr >≈ tach-4-Mepyr > tach-5-Mepyr > tachpyr, whereas tach-6-Mepyr and tach-6-MeOpyr had no effect on the cells. The depressed cytotoxicities of the latter two are attributed to inability to bind FeII or ZnII strongly.

Original languageEnglish (US)
Pages (from-to)3971-3982
Number of pages12
JournalEuropean Journal of Inorganic Chemistry
Issue number19
DOIs
StatePublished - Oct 7 2005

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Alkylation
Chelating Agents
Electronic properties
Structural properties
Cytotoxicity
Metals
X ray crystallography
Cell death
Magnetic moments
Complexation
Metal ions
Cyclohexane
pyridine
Cells
Single crystals
Spectroscopy
Ligands
Derivatives
X rays
tachpyr

Keywords

  • Antitumor activity
  • Copper
  • Iron
  • Ligand design
  • Tripodal ligands
  • Zinc

ASJC Scopus subject areas

  • Inorganic Chemistry

Cite this

Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)- amino]cyclohexane chelators : Structural and electronic properties of the Mn II, FeII, NiII, CuII and Zn II complexes. / Childers, Matt L.; Su, Fan; Przyborowska, Ann M.; Bishwokarma, Bimjhana; Park, Gyungse; Brechbiel, Martin W.; Torti, Suzy V.; Torti, Frank M.; Broker, Grant; Alexander, Jacob S.; Rogers, Robin D.; Ruhlandt, Karin; Planalp, Roy P.

In: European Journal of Inorganic Chemistry, No. 19, 07.10.2005, p. 3971-3982.

Research output: Contribution to journalArticle

Childers, ML, Su, F, Przyborowska, AM, Bishwokarma, B, Park, G, Brechbiel, MW, Torti, SV, Torti, FM, Broker, G, Alexander, JS, Rogers, RD, Ruhlandt, K & Planalp, RP 2005, 'Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)- amino]cyclohexane chelators: Structural and electronic properties of the Mn II, FeII, NiII, CuII and Zn II complexes', European Journal of Inorganic Chemistry, no. 19, pp. 3971-3982. https://doi.org/10.1002/ejic.200500382
Childers, Matt L. ; Su, Fan ; Przyborowska, Ann M. ; Bishwokarma, Bimjhana ; Park, Gyungse ; Brechbiel, Martin W. ; Torti, Suzy V. ; Torti, Frank M. ; Broker, Grant ; Alexander, Jacob S. ; Rogers, Robin D. ; Ruhlandt, Karin ; Planalp, Roy P. / Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)- amino]cyclohexane chelators : Structural and electronic properties of the Mn II, FeII, NiII, CuII and Zn II complexes. In: European Journal of Inorganic Chemistry. 2005 ; No. 19. pp. 3971-3982.
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title = "Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)- amino]cyclohexane chelators: Structural and electronic properties of the Mn II, FeII, NiII, CuII and Zn II complexes",
abstract = "Effects of pyridyl-ring alkylation on complexation of MnII, FeII, NiII, CuII and ZnII by chelators based on r-1,c-3,c-5-tri-aminocyclohexane (tach) have been studied. The chelators studied are N,N′,N″-tris[(x-alkyl-2-pyridyl)methyl] derivatives of tach, where the ring substituents are 3-Me, 4-Me, 5-Me, 6-Me or 6-MeO ({"}tach-x-Rpyr{"}). Dicationic complexes were synthesized for most combinations of the above five metals and five chelators, using ClO 4 -, NO3 -, Cl-, or CF 3SO3 - as counterions. Their bonding, structure, and aqueous lability were analyzed by UV/Vis/NIR spectroscopy, magnetic moment determination, HPLC, and single-crystal X-ray crystallography. The striking features are seen in the 6-alkylated complexes, where steric repulsions between the 6-substituents at the threefold axis of the pseudo-octahedral coordination sphere result in a substantially weakened metal-ligand interaction. In the [M(tach-6-Rpyr)]2+ series of divalent Mn, Ni, Cu and Zn, effects of these repulsions include bond angle and length distortions, decrease of the coordination number to five, shifts of d-d electronic transitions to lower energies, and spin-free complexes of the bound metal ion. Aqueous lability studies by HPLC agree with the spectroscopic findings. The bonding properties of the other tach-x-Mepyr chelators (x = 3, 4, 5) closely resemble the unalkylated parent tachpyr in solution. Similarly in the X-ray studies, [Zn(tach-3-Mepyr)]2+ resembles [Zn(tachpyr)]2+. The cytotoxicities of the chelators toward human breast cancer cells (MCF7) at a fixed chelator concentration of 16 μM show time-dependent induction of cell death in the order tach-3-Mepyr >≈ tach-4-Mepyr > tach-5-Mepyr > tachpyr, whereas tach-6-Mepyr and tach-6-MeOpyr had no effect on the cells. The depressed cytotoxicities of the latter two are attributed to inability to bind FeII or ZnII strongly.",
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TY - JOUR

T1 - Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)- amino]cyclohexane chelators

T2 - Structural and electronic properties of the Mn II, FeII, NiII, CuII and Zn II complexes

AU - Childers, Matt L.

AU - Su, Fan

AU - Przyborowska, Ann M.

AU - Bishwokarma, Bimjhana

AU - Park, Gyungse

AU - Brechbiel, Martin W.

AU - Torti, Suzy V.

AU - Torti, Frank M.

AU - Broker, Grant

AU - Alexander, Jacob S.

AU - Rogers, Robin D.

AU - Ruhlandt, Karin

AU - Planalp, Roy P.

PY - 2005/10/7

Y1 - 2005/10/7

N2 - Effects of pyridyl-ring alkylation on complexation of MnII, FeII, NiII, CuII and ZnII by chelators based on r-1,c-3,c-5-tri-aminocyclohexane (tach) have been studied. The chelators studied are N,N′,N″-tris[(x-alkyl-2-pyridyl)methyl] derivatives of tach, where the ring substituents are 3-Me, 4-Me, 5-Me, 6-Me or 6-MeO ("tach-x-Rpyr"). Dicationic complexes were synthesized for most combinations of the above five metals and five chelators, using ClO 4 -, NO3 -, Cl-, or CF 3SO3 - as counterions. Their bonding, structure, and aqueous lability were analyzed by UV/Vis/NIR spectroscopy, magnetic moment determination, HPLC, and single-crystal X-ray crystallography. The striking features are seen in the 6-alkylated complexes, where steric repulsions between the 6-substituents at the threefold axis of the pseudo-octahedral coordination sphere result in a substantially weakened metal-ligand interaction. In the [M(tach-6-Rpyr)]2+ series of divalent Mn, Ni, Cu and Zn, effects of these repulsions include bond angle and length distortions, decrease of the coordination number to five, shifts of d-d electronic transitions to lower energies, and spin-free complexes of the bound metal ion. Aqueous lability studies by HPLC agree with the spectroscopic findings. The bonding properties of the other tach-x-Mepyr chelators (x = 3, 4, 5) closely resemble the unalkylated parent tachpyr in solution. Similarly in the X-ray studies, [Zn(tach-3-Mepyr)]2+ resembles [Zn(tachpyr)]2+. The cytotoxicities of the chelators toward human breast cancer cells (MCF7) at a fixed chelator concentration of 16 μM show time-dependent induction of cell death in the order tach-3-Mepyr >≈ tach-4-Mepyr > tach-5-Mepyr > tachpyr, whereas tach-6-Mepyr and tach-6-MeOpyr had no effect on the cells. The depressed cytotoxicities of the latter two are attributed to inability to bind FeII or ZnII strongly.

AB - Effects of pyridyl-ring alkylation on complexation of MnII, FeII, NiII, CuII and ZnII by chelators based on r-1,c-3,c-5-tri-aminocyclohexane (tach) have been studied. The chelators studied are N,N′,N″-tris[(x-alkyl-2-pyridyl)methyl] derivatives of tach, where the ring substituents are 3-Me, 4-Me, 5-Me, 6-Me or 6-MeO ("tach-x-Rpyr"). Dicationic complexes were synthesized for most combinations of the above five metals and five chelators, using ClO 4 -, NO3 -, Cl-, or CF 3SO3 - as counterions. Their bonding, structure, and aqueous lability were analyzed by UV/Vis/NIR spectroscopy, magnetic moment determination, HPLC, and single-crystal X-ray crystallography. The striking features are seen in the 6-alkylated complexes, where steric repulsions between the 6-substituents at the threefold axis of the pseudo-octahedral coordination sphere result in a substantially weakened metal-ligand interaction. In the [M(tach-6-Rpyr)]2+ series of divalent Mn, Ni, Cu and Zn, effects of these repulsions include bond angle and length distortions, decrease of the coordination number to five, shifts of d-d electronic transitions to lower energies, and spin-free complexes of the bound metal ion. Aqueous lability studies by HPLC agree with the spectroscopic findings. The bonding properties of the other tach-x-Mepyr chelators (x = 3, 4, 5) closely resemble the unalkylated parent tachpyr in solution. Similarly in the X-ray studies, [Zn(tach-3-Mepyr)]2+ resembles [Zn(tachpyr)]2+. The cytotoxicities of the chelators toward human breast cancer cells (MCF7) at a fixed chelator concentration of 16 μM show time-dependent induction of cell death in the order tach-3-Mepyr >≈ tach-4-Mepyr > tach-5-Mepyr > tachpyr, whereas tach-6-Mepyr and tach-6-MeOpyr had no effect on the cells. The depressed cytotoxicities of the latter two are attributed to inability to bind FeII or ZnII strongly.

KW - Antitumor activity

KW - Copper

KW - Iron

KW - Ligand design

KW - Tripodal ligands

KW - Zinc

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JO - European Journal of Inorganic Chemistry

JF - European Journal of Inorganic Chemistry

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