Synthetic models for the glucose tolerance factor: The spectroscopic characterization and toxicity studies of monomeric and dimeric Cr(III) species

Article abstract of DOI:10.1016/S0277-5387(98)00187-9

A number of chromium(III) complexes with glycine, cysteine, glutamic and nicotinic acids-models for biologically active Cr(III) species have been prepared and characterized with physicochemical methods (UVVis, IR spectra, magnetic moments). Four of them have been also tested for their toxicity. On the basis of CF calculation it was found that only the nicotinates were octahedral Cr(III) species. Other complexes exhibited a tetragonal deformations. Based upon 10 Dq values, the sequence of the ligand field strength was found to be: glycine>cysteine≈glutamic acid>nicotinic acid. The likely structures were proposed for the isolated compounds. The preliminary toxicity studies showed that all tested complexes appeared to be non-toxic and can be potentially applied as chromium nutrition products.

Full text of DOI:10.1016/S0277-5387(98)00187-9

Polyhedron Vol[ 06\ No[ 10\ pp[ 2674Ð2683\ 0887
Þ 0887 Elsevier Science Ltd
Pergamon
All rights reserved[ Printed in Great Britain
9166Ð4276:87 ,08[99¦9[99
\
PII] S9166Ð4276"87#99076Ð8
Synthetic models for the glucose tolerance factor]
the spectroscopic characterization and toxicity
studies of monomeric and dimeric Cr"III# species
Gabriela Galuszka\a Maria Cieslak!Golonka\aꢀ Adam Szelag\b Jan Starostaa
and Agnieszka Wojciechowskaa
aInstitute of Inorganic Chemistry and Metallurgy of Rare Elements\ University of Technology\ 49!269
Wroclaw\ Poland^ bDepartment of Pharmacology\ Medical Academy\ Wroclaw\ Poland
Received 00 February 0887^ accepted 4 May 0887
Abstract*A number of chromium"III# complexes with glycine\ cysteine\ glutamic and nicotinic acids!models
for biologically active Cr"III# species have been prepared and characterized with physicochemical methods
"UV:Vis\ IR spectra\ magnetic moments#[ Four of them have been also tested for their toxicity[ On the basis
of CF calculation it was found that only the nicotinates were octahedral Cr"III# species[ Other complexes
exhibited a tetragonal deformations[ Based upon 09 Dq values\ the sequence of the ligand _eld strength was
found to be] glycine×cysteine¼glutamic acid×nicotinic acid[ The likely structures were proposed for the
isolated compounds[ The preliminary toxicity studies showed that all tested complexes appeared to be non!
toxic and can be potentially applied as chromium nutrition products[ Þ 0887 Elsevier Science Ltd[ All rights
reserved
Keywords] Cr"III# complexes^ glucose tolerance factor^ low molecular weight chromium^ electronic spectra^
toxicity^ amino acids[
———————————————————————————————————————————————
Chromium has been known to be a micronutrient for Cr"III# may not be a component of the GTF ð6Ð09Ł or
almost forty years[ The essential nature of this element that it does not play any biological role at all ð7Ł[
was recognized in 0848 by Mertz and Schwarz ð0Ł[
These results prompted many investigators to study
These authors demonstrated the role of chromium synthetic models for the GTF ð5\ 00Ð03Ł[ In most
in maintaining normal glucose in rats[ Later on\
chromium was shown to be important for normal
mammalian carbohydrate and lipid metabolism ð1Ð3Ł[
Despite these results very little is known about the
composition and structure of the biologically active
form"s# of chromium[ The most con~icting results
have been obtained by studying the problem of the
Cr"III# relationship to the so!called glucose tolerance
factor "GTF#\ an organic Cr"III# containing complex
responsible for stimulating insulin action[ The evi!
dence obtained from the literature suggested that the
GTF contained Cr"III# in the form of a complex with
nicotinate "pyridine 2!carboxylate# and either gluta!
thione or amino acids] glycine\ glutamic acid and cyst!
eine ð4\ 5Ł[ However\ it has also been suggested that
models two nicotinate ligands are coordinated as
monodentate ligands in trans positions via oxygen ð02\
04Ł or nitrogen donor atoms ð00\ 05\ 06Ł[ However\
both biological extracts and synthetic GTF models
have as yet been poorly characterized[
The other pathway in investigating the biological
activity of trivalent chromium was based on Yama!
moto et al[ ð07Ł\ namely isolation of naturally occur!
ring Cr"III# containing protein of low molecular
weight "LMWCr# ½0499 Da[ Recently\ the isolation
of LMWCr in milligram quantities\ together with its
biochemical and physicochemical analysis\ has been
reported ð08Ð11Ł[ The composition of ligands in
LMWCr is similar to the GTF[ One di}erence is the
presence of the aspartate in the former instead of the
nicotinate in the latter ð08Ł[ It is postulated that in
the centre of activity LMWCr contains an assembly
composed of four chromium atoms bridged with
oxygen\ hydroxyl group\ chlorine etc ð08Ł[ The oligo!
ꢀAuthor to whom correspondence should be addressed[
e!mail] golonkaÝichn[ch[pwr[wroc[pl
2674

2675
G[ Galuszka et al[
peptide is probably associated with the kinase active
site of the insulin receptor ð11Ł[
However\ LMWCr of still unknown structure\ may
not be an alternative for the {{old|| GTF\ since the
latter seems to be more a nutrient in an appropriate
organic form suitable for chromium de_cient organ!
isms ð12Ł[ As Cr"III# picolinate used as a dietary chro!
mium supplement has been found to cause
chromosome damage ð13Ł other Cr"III# complexes
suitable for supplementation of this ion should be
investigated ð11Ł[ For example\ Vincent et al[ ð11Ł pro!
posed as a nutrient an inexpensive\ easy to prepare
Cr"III# compound containing a cationic trinuclear
ðCr2O"O1CCH1#5"H1O#2Ł¦ species which was found to
activate the insulin receptor almost identical to that
of LMWCr[
With these facts in mind our studies have been
focused on systematic syntheses of mono! and poly!
meric Cr"III# complexes with {{GTF!like|| ligands and
investigation of their physicochemical properties and
biological activity[ We have prepared and spec!
troscopically analyzed seven Cr"III# mono and dim!
eric complexes with nicotinic "nic# and glutamic "glu#
acids\ cysteine "cys# and glycine "gly#[
To the authors| knowledge\ the complexes I and
IV "Table 0# have been obtained for the _rst time[
Additionally\ for the previously known compound II
ð5Ł a new synthetic procedure has been proposed[
EXPERIMENTAL
Chemicals were used as received[ Stoichiometries of
the complexes were established by microanalysis "C\
N\ S\ H#\ which gave satisfactory results[
Preparation of the complexes
ðCr1nic1"OH#3Ł 3H1O ðIŁ[ From the stock solutions]
Cr"NO2#ꢀ8H1O "09 g in 499 cm2# and nicotinic acid
2
"5[9044 g in 499 cm2# equal volumes of 19 ml each were
mixed together and warmed to 59>C under continuous
stirring[ The acidity had been adjusted to pH 5[9 with
warm NaOH "1 M#[ Addition of NaOH caused the
changes of colours "from green to blue# and simul!
taneous precipitation[ After 37 h the mixture was _l!
tered o}\ washed with water and ethanol[
ðCrnic1OHŁ 2H1O ðIIŁ[ Cr"NO2#2 8H1O "5 g# and
nicotinic acid "2[582 g# were dissolved in a mixture of
methanol "69 cm2# and water "29 cm2#[ The reagent
mixture was heated to re~ux for 5 h[ Solid KOH
"2[25 g# was added to the solution and the resulting
blue precipitate was allowed to remain for 37 h in the
mother liquor[ The precipitate was _ltered\ washed
with water and ethanol and dried[
ðCr1`lu1"OH#1Ł`lu 2H1O ðIIIŁ This compound was
prepared as described elsewhere ð14Ł[
ðCrcys1"OH#"H1O#Ł H1O ðIVŁ CrCl2 5H1O "0[22 g#
was dissolved in a mixture of water "09 cm2# and etha!
nol "1 cm2#[ D\L!Cysteine "0[70 g# dissolved in water

Synthetic models for the glucose tolerance factor
"1 cm2# was added and the reagent mixture was heated
RESULTS AND DISCUSSION
2676
and evaporated to half volume[ Solid KOH was added
until the pH was 7[ The pink violet precipitate was
_ltered and washed with water[
mer!ðCr`ly2Ł H1O ðVŁ\ fac!ðCr`ly2Ł H1O ðVIŁ and
ðCr1"OH#1`ly3Ł H1O ðVIIŁ Prepared as described in the
literature ð15Ł[
Thermodynamically\ trivalent chromium ion is the
most stable oxidation state of chromium^ kinetically
Cr"III# compounds are inert with the half!_lled t1g
level "d2 conf[# in octahedral symmetry "Ref ð21Ł\ and
the references therein#[
The prepared complexes together with their physi!
cal properties are listed in Table 1[ The complexes are
blue "IÐII#\ violet "IIIÐIV# and pinkish!red "VÐVII#[
The blue complexes exhibit the presence of CrO5 and
CrO4N chromophores\ respectively[ The pinkish!red
ones have CrO2N2 chromophores with three nitrogen
atoms per chromium atom[ Additional nitrogen in the
coordination sphere of the chromium is consistent
with the blue shift of the bands manifested in the
spectrochemical series "vide infra#[ In complex III
ligand molecules are in inert and in outer coordination
sphere[ It was established through analysis of the
infrared spectra\ i[e[ the presence of the hydroxide ring
ð14Ł and bidentate O\N chelation of the ligand "Table
2\ vide infra#[ These results are in line with our _ndings
and those of others ð37Ł and us ð38Ł on the observation
that in one compound some organic ligands are
directly bound to the central ion and some are situated
outside the coordination sphere[
The analytical results are presented in Table 0[
Physicochemical studies
Infrared spectra were recorded on a Perkin!Elmer
FTIR 0599 spectrophotometer "3999Ð399 cm−0#[ FIR
spectra "399Ð69 cm−0# were recorded on a Perkin!
Elmer 079 spectrophotometer[
The di}use re~ectance spectra "sample in a Li1CO2
pressed pellet# and solution spectra "in 1 M HNO2#
were measured in the spectral range 01999Ð
37999 cm−0 with
a Hitachi 254 UV:Vis spec!
trophotometer with a IBM:PC computer[ The res!
olution processing of the spectra was performed by
applying the variable digital _lter method ð16Ð29Ł[ The
_ltered spectra were used to obtain the band positions
precisely and calculate the crystal _eld parameters\
assuming _rst Oh symmetry and then tetragonality of
the Cr"III# environment[ The energy matrices were
adopted from the paper by Perumareddi ð20Ł[
The e}ective magnetic moments "2[71Ð3[26 B[M[#
for monomers are close to the spin only value for the d2
system in octahedral and pseudooctahedral symmetry
3A1 ground state#[ Lower values of the magnetic
moments "³2 B[M[# were observed for the dimers[
The magnetic measurements were carried out in the
temperature range 79Ð299 K using a Gouy balance
with CoðHg"SCN#3Ł as a calibrant[
Preliminary toxicity studies
Infrared spectra
Four prepared complexes have been checked for
Table 2 presents the major absorption IR fre!
their toxicity "I\ II\ V\ VI#[ The suspensions were pre! quencies of the prepared compounds[ In these com!
pared ex tempore[ Acute toxicity was investigated on plexes the carboxylate groups are involved in the
a group of white mice Balb C[ Mice of both sexes of coordination[ The values of D\ i[e[ the di}erences
19Ð14 g each were studied[ Three doses of the prepared between the two frequencies nas and ns of the carboxyl
compounds were administrated "in mg:kg#] 099\ 499 group "Table 2# pointed to the unidentate coordination
and 1999\ respectively[ The mice were observed for of the carboxylate ion in all complexes ð22Ł\ and is in
13 h[
line with the results found for other Cr"III# complexes
Table 1[ Physical properties of the compounds
m "BM# per
chromium
atom
Ratio
M]L
Refs[
"preparation#
Symbol
Substrates
Formula
Colour
blue
I
II
Cr"NO2#1=8H1O\ nicotinic acid
Cr"NO2#1=8H1O\ nicotinic acid
CrCl2=5H1O\ glutamic acid
CrCl2=5H1O\ cysteine
CrCl2=5H1O\ glycine
CrCl2=5H1O\ glycine
0]1
0]1
0]2
0]2
0]2
0]5
0]5
ðCr1"nic#1"OH#3Ł(3H1O
ðCr"nic#1"OH#Ł(2H1O
ðCr1"glu#1"OH#1Ł(glu(2H1O
ðCr"cys#1OH(H1OŁ(H1O
mer!ðCr"gly#2H1OŁ(H1O
fac!ðCr"gly#2H1OŁ(H1O
ðCr1"gly#3"OH#Ł1(H1O
1[47
3[26
1[46
2[71
2[81
3[23
1[24
this work
this work
ð12Ł
this work
ð13Ł
blue
III
IV
V
VI
VII
dark violet
pinkÐviolet
pinkÐviolet
pinkÐviolet
dark red
ð13Ł
ð13Ł
CrCl2=5H1O\ glycine

2677
G[ Galuszka et al[
with the same or similar ligands ð06Ł[ The CrO stretch!
ing vibration has been found in the ca[ 499 cm−0
absorption region ð42Ł[ All complexes except II exhibit
bands at 319Ð369 cm−0\ which have been assigned to
n"CrN# vibrations ð43\ 44Ł[ The proposed structures
have been presented in scheme 0[ Thus\ the nicotinates
have been found to be O!bonded "II# and both N! and
O!bonded in one molecule "I#[ Such bonding is not
very unusual in coordination chemistry ð23\ 24Ł[
Electronic spectra
The spectra for the solutions and the solid state are
shown in Tables 3Ð5[
The complexes were found to be practically insol!
uble in common organic solvents[ As HNO2 was used
for dissolution\ such spectra usually should be less
reliable "i[e[ changed under the acid interaction# than
the solid state spectra[ However\ the blue shift of the
bands on dissolution is ca[ 0999 cm−0\ consistent with
the data found in the literature for water as solvent
ð18Ł and consistent with a signi_cant change in the
environment of the central atom on dissolution[ These
e}ects are connected with a weakening of the strong
hydrogen bonding system operating in the rigid solid
structure ð18\ 25Ł[ Thus\ assuming only hydrogen
bonding e}ects\ the individuality of the complexes
appeared to be larger in the solution[ The "glu# com!
plex "III# was found to be the only one exhibiting a
very large "1999 cm−0# hipsochromic shift on dissol!
ution[ We relate it to the presence of the glutamic acid
molecule in the second coordination sphere "Tables
0Ð1# which may easily dissociate on solvent in~uence[
This e}ect makes the _rst coordination sphere extra
strong in solution[ mer! and fac!Cr"III# glycine com!
plexes contain three bidentate ligands[ These com!
plexes were the only ones with known crystal struc!
tures ð25Ł[ The chromium ion in the mono Cr"III#
glycinate was found to be octahedrally coordinated
with the CrÐO and CrÐN bond length 085 and 195 pm\
respectively[ Unusual bonding forces were present in
these complexes related to the network of hydrogen
bonds operating in the solid state[
In the visible absorption region two broad bands
associated with the dÐd Laporte forbidden quartetÐ
quartet spin allowed transition have been observed
"Tables 3Ð5\ Fig[ 0#[ In the near IR absorption region
weak but sharp band"s# associated with the doubletÐ
quartet spin forbidden transition"s# can be seen in the
"gly# complexes "VÐVII# "Table 3\ Fig[ 0# ð35\ 36Ł[ In
the rest of the compounds the positions of these bands
were found on the _ltration analysis "not shown in
Tabs[ 3Ð5#[ As this analysis "i[e[ _ltration# does not
give the intensity values "only the energy of tran!
sitions# we were not able to discuss the magnitude of
coupling between two chromium"III# nuclei in com!
pounds I and II[
From the crystal structure results available for
Cr"III# glycinate\ the coordination sphere of the metal

Synthetic models for the glucose tolerance factor
2678
ion is octahedral ð25Ł[ Generally\ many Cr"III# com! Oh symmetry and "ii# tetragonal distortion around
plexes are octahedrally coordinated ð21Ł[ However\ Cr"III# ion[
The criterion of proper _tting was the RMS value
found on calculation[
The results showed that the complexes belonged to
two general groups]
the fact that the complexes are dimeric with two OH
bridges "I\ III and VII#\ their coordination is via vari!
ous donor atoms] O\ N\ S "I\ IIIÐVII# and the coor!
dination is via oxygen atoms but from various ligands
"II#\ makes the symmetry lowering possible[ Thus\ we
"0# Octahedrally coordinated "the nicotinates I and
have calculated crystal _eld parameters assuming "i# II# Table 4[

2689
G[ Galuszka et al[
Table 3[ Electronic spectra of Cr"III# complexes "cm−0
#
Compound
Spectrum
Band position
I
Absorption
Di}use re~ect[
Absorption
Di}use re~ect[
Absorption
Di}use re~ect[
Absorption
Di}use re~ect[
Absorption
Di}use re~ect[
Absorption
Di}use re~ect[
Absorption
Di}use re~ect[
06499
05599
06499
06099
07299
05499
07799
07199
08999
07699
07799
07899
08199
08599
13299
12799
13199
12699
14599
13199
14199
13599
14499
14599
14199
14599
14399
15999
27999
27999
27499
26799
22499
27799
22499
27099
22399
28999
22399
27899
22399
27299
II
III
IV
V
03399
03599
03099
03199
03599
03799
VI
VII

Synthetic models for the glucose tolerance factor
2680
Table 4[ The dÐd band positions and crystal _eld parameters for Cr"III# nicotinates[ "Filter parameters] step ꢁ 099\ a ꢁ 299\
N ꢀ 19#
Compound Chromophore
Spectrum
3T1g"F#
3T0g"F# 3T0g"G# 09 Dq ðcm−0
Ł
B ðcm−0
Ł
RMS
I
ðCrO4NŁ
ðCrO5Ł
Absorption
Di}use re~ect
06499
05699
13979
12799
27979
26199
06499
05699
549
619
0[5
03[1
II
Absorption
Di}use re~ect
06499
05899
13199
12599
27199
26099
06499
05899
554
556
9[8
09[6
"1# Tetragonally coordinated "the glutamate "III#\ Cr"III# species have been rationalised taking into
cysteinate "IV# and glycinates "VÐVII# Table 5[
account the 09 Dq value as a criterion "Table 3#[ The
energy of the _rst spin allowed dÐd transition "09 Dq#
for Cr"III# monomeric complexes increases in the
sequence
The reasonable explanation for these results may
be based on the di}erences in the MÐL interaction
between the nicotinates and the other ligands[ It is
manifested in the crystal _eld strength calculated for
the absorption spectra "Tables 4Ð5#[ For the _rst
CrO5 ³ CrO3N1 ³ CrO2N2 ³ CrN5
group of the complexes the Dq values are smaller The value for CrN5 chromophore was taken from the
which is evidence for weaker Cr!nic interaction in literature ð21Ł[ This sequence also re~ects the gradually
comparison to the other ligands studied[ However\ changes of the colour from blue "CrO5# through violet
this e}ect is not a very strong one[ Moreover\ the Dt "CrO3N1# to red CrO2N2 "VII# and CrN5 ð21Ł[
values for complexes "IIIÐVII# are small indicating
The greyÐgreen colour of LMWCr concentrated
only slight tetragonality around the Cr"III# ion[ Assum! solutions and the energies of two distinct visible dÐd
ing an octahedral and pseudooctahedral environment\ bands and UV shoulder ð26Ł resemble water solutions
nicotinic acid is evidently the last ligand in the spectro! of anionic type binary and ternary complexes of the
chemical series for the Cr"III# ion] glycine × ðCr"A#"H1O#Łn− and ðCr"AB#Łn− type where A\ B!non
cysteine ¼ glutamic acid × nicotinic acid[
enzymatic cellular reductants] ascorbic acid\ cysteine\
The electronic spectroscopic data for monomeric glutathione ð18\ 29\ 27Ł[ It was found that the S!con!
Fig[ 0[ Di}use re~ectance spectra of monomeric Cr"III# nicotinate "II#\ cysteinate "IV# and glycinate "VI#[

2681
G[ Galuszka et al[
taining Cr"III# complexes exhibited the absorption in
the 159 nm "ca[ 27999 cm−0# with the Cr3S ð49\ 40Ł
band intensity of 2999Ð4999 dm2 mol−0 cm−0[ The
159 nm band was also found in the LMWCr ð08\ 26Ł[
However\ as this band was also present in the apo "i[e[
Cr!free# form of the protein ð08\ 41Ł only the detailed
analysis of this spectral region might explain the origin
of this absorption in the LMWCr[
Toxicity
The literature data on chromium toxicity are incom!
plete and inconsistent ð28Ł[ The toxicity expressed by
the lethal dose "LD49# values is dependent on the chro!
mium oxidation state\ di}erent species of animals and
route of exposure ð39Ð32Ł[ Generally\ oral toxicities of
Cr"III# compounds appear to be 09Ð0999 times lower
than for the hexavalent chromium compounds ð27Ł[
The toxicology of chromium"III# varies greatly among
a variety of di}erent chromium compounds ð28Ł[ For
example\ in genotoxical bacterial tests on a series of
hexacoordinate Cr"III# complexes\ out of 06 com!
plexes 01 were positive ð33Ł[
The results of our studies are presented in Table
6[ All compounds appeared to be non!toxic in this
examination[ The completion of the results as well as
their extension into other groups of animals are under
way[
SUMMARY AND CONCLUSIONS
The interaction between the Cr"III# ion and glycine\
cysteine\ glutamic and nicotinic acids gives a series of
monomeric and dimeric complexes\ models for the
glucose tolerance factor "GTF#[ The composition of
the species is strongly dependent on the metalÐligand
interaction and conditions of the experiment "tem!
perature\ time\ etc[#[ The breaking of the strong hydro!
gen bonding network operating in the solid state may
be responsible for the blue shift of the electronic dÐd
bands in solution[ Despite the various types of chro!
mophores and number of the central atoms in the
complexes\ the coordination sphere for chromium nic!
otinates was found to be a full octahedron[ The rest
of the complexes studied can be better described
assuming a tetragonally distorted octahedron[ The
reason for such behaviour was related to the strength
of the ligand _eld around the central metal ion\ this
being weakest in the nicotinic acid[
The tentative results for the toxicity studies of the
complexes are very promising[ They are practically
non toxic and can be potentially apply as chromium
nutrition products[
Acknowled`ements*The authors are indebted to Dr D[
Goodall for reading the manuscript and helpful comments[
Financial support from the Wroclaw University of Tech!
nology "grant No[ 220!392# is gratefully acknowledged[

Synthetic models for the glucose tolerance factor
2682
Table 6[ LD49 values for Cr"III# inorganic compounds taken from the literature and the results of this work
Compound
Animal
LD49 "in mg:kg# Method
Toxicity
Refs[
ðCr1nic1"OH#3Ł=3H19
ðCrnic1"OH#Ł = 2H19
mer!ðCrgly2H1OŁ=H1O
fac!ðCrgly2H1OŁ=H1O
CrCl2
CrCl2
CrCl2
Cr1"SO3#2
Cr1"SO3#2
mouse
mouse
mouse
mouse
mouse
frog
rabbit
mouse
frog
×1999
×1999
×1999
×1999
790
076
177
135[7
26
intraperitoneally
non!toxic
non!toxic
non!toxic
non!toxic
slightly toxic
moderately toxic
moderately toxic
moderately toxic
very toxic
This work
This work
This work
This work
ð34Ł
intraperitoneally
intraperitoneally
intraperitoneally
intravenous
intravenous
intravenous
ð34Ł
ð34Ł
ð34Ł
ð34Ł
intravenous
intravenous
Cr1"SO3#2
Cr1O2
rabbit
dog
104
229
intravenous
hypodermic
moderately toxic
moderately toxic
ð34Ł
ð34Ł
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