Synthesis, characterization, and biological relevance of hydroxypyrone and hydroxypyridinone complexes of molybdenum

Article abstract of DOI:10.1139/v99-111

We have prepared a number of complexes of the type cis-MoO₂L₂ where L represents a hydroxypyronato or hydroxypyridinonato ligand. Both the maltol (3-hydroxy-2-methyl-4-pyrone, Hma) and kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone, Hka) complexes, cis-MoO₂(ma)₂ (1) and cis-MoO₂(ka)₂ (2), have been characterized by X-ray diffraction studies. The pyrone ligands are bound to molybdenum in a cis bidentate fashion via the deprotonated hydroxyl groups and the ketone moieties. Crystals of 1 are orthorhombic, a = 12.107 (1), b = 8.6169 (8), c = 16.472 (1) A, Z = 4, space group Pca2₁, and those of 2 are monoclinic, a = 8.4591 (5), b = 16.3453 (10), c = 10.2954 (7) A, β = 103.0320 (10)°, Z = 4, space group P2₁/c. Hydroxypyridinone molybdenum complexes have been prepared for both maltol and kojic acid derivatives with the substituents Me, n-Pr, CH₂Ph, Ph at the ring nitrogen. Crystals of the 3-hydroxy-2-methyl-1-phenyl-4-pyridinone (Hppp) derivative, MoO₂(ppp)₂ (9), are monoclinic, a = 10.9476 (6), b = 13.5353 (9), c = 17.4877 (10) A, β = 93.465 (4)°, Z = 4, space group P2₁/n. Initial investigations into the effects molybdenum compounds have on diabetic hearts are presented. Both Na₂MoO₄ (used as a control) and 1 were effective in lowering blood glucose and free fatty acid levels. Diabetic rats treated with molybdate showed significant improvements in postischemic cardiac function.

Full text of DOI:10.1139/v99-111

1249
Synthesis, characterization, and biological
relevance of hydroxypyrone and
hydroxypyridinone complexes of molybdenum
Sarah J. Lord, Noah A. Epstein, Robert L. Paddock, Christopher M. Vogels,
Tracy L. Hennigar, Michael J. Zaworotko, Nicholas J. Taylor,
William R. Driedzic, Tom L. Broderick, and Stephen A. Westcott
Abstract: We have prepared a number of complexes of the type cis-MoO2L2 where L represents a hydroxypyronato or
hydroxypyridinonato ligand. Both the maltol (3-hydroxy-2-methyl-4-pyrone, Hma) and kojic acid (5-hydroxy-2-
hydroxymethyl-4-pyrone, Hka) complexes, cis-MoO2(ma)2 (1) and cis-MoO2(ka)2 (2), have been characterized by X-ray
diffraction studies. The pyrone ligands are bound to molybdenum in a cis bidentate fashion via the deprotonated
hydroxyl groups and the ketone moieties. Crystals of 1 are orthorhombic, a = 12.107 (1), b = 8.6169 (8), c = 16.472
(1) Å, Z = 4, space group Pca21, and those of 2 are monoclinic, a = 8.4591 (5), b = 16.3453 (10), c = 10.2954 (7) Å,
β = 103.0320 (10)°, Z = 4, space group P21/c. Hydroxypyridinone molybdenum complexes have been prepared for both
maltol and kojic acid derivatives with the substituents Me, n-Pr, CH2Ph, Ph at the ring nitrogen. Crystals of the 3-
hydroxy-2-methyl-1-phenyl-4-pyridinone (Hppp) derivative, MoO2(ppp)2 (9), are monoclinic, a = 10.9476 (6), b =
13.5353 (9), c = 17.4877 (10) Å, β = 93.465 (4)°, Z = 4, space group P21/n. Initial investigations into the effects
molybdenum compounds have on diabetic hearts are presented. Both Na2MoO4 (used as a control) and 1 were effective
in lowering blood glucose and free fatty acid levels. Diabetic rats treated with molybdate showed significant
improvements in postischemic cardiac function.
Key words: molybdenum, hydroxypyrones, hydroxypyridinones, heart function.
Résumé : On a préparé un certain nombre de complexes du type cis-MoO2L2 dans lesquels L est un ligand
hydroxypyronato ou hydroxypyridinonato. On a caractérisé ces complexes avec le maltol (3-hydroxy-2-méthyl-4-
pyrone, Hma) et l’acide kojique (5-hydroxy-2-hydroxyméthyl-4-pyrone, Hka), cis-Mo(ma)2L2 (1) et cis-MoO2(ka)2
(2) par diffraction des rayons X. Les ligands pyrone sont liés au molybdène d’une façon bidentate cis par le biais des
groupes hydroxyméthyles déprotonés et des portions cétoniques. Les cristaux de 1 sont orthorhombiques, groupe
d’espace Pca21, avec a = 12,107 (1), b = 8,6159 (8) et c = 16,472 (1) Å et Z = 4 alors que ceux de 2 sont
monocliniques, groupe d’espace P21/c, avec a = 8,4591 (5), b = 16,3453 (10) et c = 10,2954 (7) Å, β = 103,0320
(10)° et Z = 4. Les complexes du molybdène et de l’hydroxypyrone ont été préparés avec des dérivés du maltol et de
l’acide kojique portant des substituants Me, Pr, CH2Ph et Ph sur l’azote du cycle. Les cristaux du dérivé 3-hydroxy-2-
méthyl-1-phényl-4-pyridone (Hppp), MoO2(ppp)2 (9), sont monocliniques, groupe d’espace P21/n, avec a = 10,9476 (6),
b = 13,5353 (9) et c = 17,4877 (10) Å, β = 93,465 (4)° et Z = 4. On présente les résultats d’études préliminaires
relatives à l’effet des composés du molybdène sur des coeurs diabétiques. Le Na2MoO4 (utilisé comme contrôle) ainsi
que le composé 1 sont tous les deux efficaces pour diminuer les niveaux de glucose et des acides gras libres dans le
sang. Des rats diabétiques traités au molybdate ont montré des améliorations significatives dans la fonction cardiaque
postischémique.
Mots clés : molybdène, hydroxypyrones, hydroxypyridinones, fonction cardiaque.
[Traduit par la Rédaction] Lord et al. 1261
Received November 16, 1998.
S.J. Lord, N.A. Epstein, R.L. Paddock, C.M. Vogels, and S.A. Westcott.1 Department of Chemistry, Mount Allison University,
Sackville, NB E4L 1G8, Canada.
W.R. Driedzic and T.L. Broderick.2 Department of Biology and Biochemistry, Mount Allison University, Sackville, NB E4L 1G7,
Canada.
N.J. Taylor. Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
T.L. Hennigar and M.J. Zaworotko.3 Department of Chemistry, St. Mary’s University, Halifax, NS B3H 3C3, Canada.
1Author to whom correspondence may be addressed. Telephone: (506) 364-2372. Fax: (506) 364-2313. e-mail: swestcott@mta.ca
2Author to whom correspondence regarding biological studies may be addressed. Current address: Department of Physiology,
Midwestern University, Glendale, AZ 85308, U.S.A. Telephone: (602) 572-3664. Fax: (602) 572-3226.
e-mail: tbrode@arizona.midwestern.edu
3Current address: Department of Chemistry, University of Winnipeg, Winnipeg, MB R3B 2E9, Canada.
Can. J. Chem. 77: 1249–1261 (1999)
© 1999 NRC Canada

1250
Can. J. Chem. Vol. 77, 1999
Introduction
Experimental
Maltol (3-hydroxy-2-methyl-4-pyrone, Hma) and kojic
acid (5-hydroxy-2-hydroxymethyl-4-pyrone, Hka) are natu-
rally occurring nontoxic compounds that have found recent
applications in bioinorganic chemistry (1). Interest in
maltol and kojic acid arises from their ability to
deprotonate readily (pKa for Hma = 8.38, pKa for Hka =
7.72) and act as anionic chelating, bidentate O,O′ ligands
towards a number of biologically active metals. For in-
stance, iron–maltol complexes have found some potential
in the treatment of iron-deficiency anaemia (2) and maltol
has been examined as a possible chelating agent for lower-
ing aluminum levels in the body (3).
Although metal complexes containing maltol (4) and
kojic acid (5) groups are well known, the most significant
and well-studied example is the vanadium complex,
VO(ma)2 (BMOV) (4h). This remarkable compound dis-
plays potent insulinomimetic properties and has been the
subject of numerous chemical and physiological studies
(6). Indeed, Orvig, McNeill and co-workers have shown
that BMOV is effective in lowering blood glucose levels in
diabetic rats and is relatively nontoxic over a six month ad-
ministration period (6b). BMOV also facilitates the preven-
tion of long-term diabetes-induced pathology and
attenuation of hyperinsulinemia and hypertension in geneti-
cally hypertensive rats (6a). Prevention of cardiac dysfunc-
tion in diabetic rats treated with BMOV is of singular
importance as Type I (Insulin-Dependent Diabetes Mellitus
– IDDM) diabetics are particularly susceptible to heart fail-
ure (7). With the advent of insulin therapy, deaths arising
from cardiovascular complications associated with diabetes
mellitus have risen from 20% to 80% (7). Attempts to de-
velop new compounds for the oral treatment of diabetes
should, therefore, have potent insulinomimetic properties
as well as show improvement in cardiac pump function
over conventional insulin therapy.
Much effort has focused on generating new vanadium
compounds to meet these requirements (8). Vanadium com-
plexes containing 3-hydroxy-2-methyl-pyridinone ligands,
derived from the addition of primary amines to maltol,
have been reported (8c, 8d). Variation of the amine
substituent allows for fine tuning of the hydro-
philic/lipophilic balance of the ligands and, therefore, of
the corresponding metal complexes (2b). The ability to tai-
lor the physical properties of pyridinone ligands has also
been utilized to transport metal ions across biological
membranes (9).
Recent studies have shown that other transition metals
also display certain insulinomimetic properties (10). For ex-
ample, insulin-like effects on blood lipids have been re-
ported recently in diabetic rats treated with sodium
molybdate, Na2MoO4 (10b). With this in mind, we postu-
lated that oxomolybdenum complexes containing organic
ligands may also prove effective for the oral treatment of di-
abetes. As part of our initial investigation, we have prepared
a number of hydroxypyrone and hydroxypyridinone molyb-
denum complexes and report herein on the amelioration of
heart function defects in diabetic rats treated with Na2MoO4
and the molybdenum analogue of BMOV, cis-bis(malto-
lato)dioxomolybdenum(VI) (1).
Materials and methods
Chemicals used were of reagent grade. Maltol, kojic acid,
amines, and 3-hydroxy-1,2-dimethyl-4-pyridinone were ob-
tained from Aldrich Chemicals and molybdic acid was pur-
chased from Strem. NMR spectra were recorded on a JEOL
1
JNM-GSX270 FT-NMR spectrometer. H NMR chemical
shifts are reported in ppm and referenced to residual protons
in CDCl3, D2O, and DMSO-d6 at 270.05 MHz. 13C{1H}
NMR chemical shifts are referenced to internal solvent
peaks at 67.80 MHz. Multiplicities are reported as (s) sin-
glet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet, (br)
broad, and (ov) overlapping. Infrared spectra were obtained
with Nujol on KBr/NaCl plates using a Perkin–Elmer 710B
and a Mattson Polaris spectrometer and are reported in cm–1.
Melting points were measured uncorrected with a Mel-Temp
apparatus. Microanalyses for C, N, and H were carried out at
Desert Analytics (Tucson, Ariz.).
Complex 1 (4a) and complex 3 (11g) were prepared by
established methods using molybdic acid. Compounds
Hhmp (5d), Hhnp (5d), Hbpp (5d), Hnpp (9a), and Hppp
(12b) were all prepared by previously reported methods with
slight modifications. Selected spectroscopic data for these
ligands are reported as follows.
3-Hydroxy-6-hydroxymethyl-1-methyl-4-pyridinone, (Hhmp):
mp 204°C (dec.); IR (Nujol): 870 (m), 1079 (w), 1129 (m),
1225 (w), 1268 (w), 1310 (m), 1454 (s), 1480 (m), 1552 (s),
1627 (m), 2964 (s), 3310 (br); 13C{1H} (in D2O), δ: 43.2,
62.1, 116.5, 131.3, 148.4, 150.6, 173.3.
3-Hydroxy-6-hydroxymethyl-1-propyl-4-pyridinone, (Hhnp):
mp 186°C (dec.); IR (Nujol): 722 (m), 859 (s), 972 (s), 1083
(s), 1131 (s), 1217 (s), 1270 (m), 1454 (s), 1463 (m), 1564
(m), 1643 (m), 2722 (m), 3178 (br); 13C{1H} (in D2O), δ:
12.5, 26.3, 57.3, 62.0, 116.9, 130.1, 148.5, 150.1, 173.3.
Benzyl-3-hydroxy-2-methyl-4-pyridinone, (Hbpp): mp
204°C (dec.); IR (KBr): 855 (m), 1455 (m), 1500 (m), 1570
(s), 1620 (s), 3152 (m); 13C{1H} (in CDCl3), δ: 12.2, 57.4,
111.3, 126.0, 128.5, 128.6, 129.5, 135.4, 137.8, 146.6, 170.0;
1H δ: 2.27 (s, 3H), 4.72 (br s, 1H), 5.09 (s, 2H), 6.45 (d, J = 7
Hz, 1H), 7.01 (br d, J = 7 Hz, 2H), 7.31 (m, 4H).
3-Hydroxy-2-methyl-1-propyl-4-pyridinone, (Hnpp): mp
161°C (dec.); IR (Nujol): 844 (s), 1033 (m), 1223 (s), 1349
(m), 1462 (s), 1504 (m), 1571 (s), 1625 (s), 2971 (s), 3145
(br); 13C{1H} (in D2O), δ: 12.5, 14.0, 25.9, 58.6, 114.8,
137.1, 141.0, 147.3, 171.1.
3-Hydroxy-2-methyl-1-phenyl-4-pyridinone, (Hppp): 13C{1H}
(in CDCl3), δ: 13.8, 111.2, 126.9, 128.9, 129.7, 130.1, 137.5,
141.9, 145.9, 170.4.
Preparation of cis-bis(5-hydroxy-2-hydroxymethyl-4-
pyronato)dioxomolybdenum(VI), MoO2(ka)2, 2
To a stirred suspension of molybdic acid (0.25 g,
0.74 mmol) in 10 mL of water, a 10 mL aqueous solution of
kojic acid (0.42 g, 2.96 mmol) was added dropwise. The ad-
dition of isopropanol to the solution resulted in the crystalli-
zation of white starting material. The yellow product was
crystallized following further addition of isopropanol and
was collected by suction filtration. The product was washed
with ether (2 × 50 mL) and dried under vacuum. Yield:
0.22 g (36%) of a light yellow powder; mp 170°C (dec.). IR
© 1999 NRC Canada

Lord et al.
1251
(Nujol): 701 (s), 876 (m), 919 (m), 1154 (m), 1405 (s), 1520
(s), 1574 (m), 1647 (s), 3112 (m). NMR spectroscopic data
(in DMSO-d6): 1H δ: 4.56 (s, 4H), 5.98 (s, 2H), 6.93 (s, 2H),
8.67 (s, 2H); 13C{1H} δ: 59.8, 106.9, 142.4, 154.1, 173.8,
179.3.
Preparation of cis-bis(1-benzyl-3-hydroxy-2-methyl-4-
pyridinonato)dioxomolybdenum(VI), MoO2(bpp)2, 7
To a 25 mL aqueous solution of molybdic acid (0.14 g,
0.41 mmol), 1-benzyl-3-hydroxy-2-methyl-4-pyridinone (0.39 g,
1.81 mmol) was added as a solid in small portions. After
24 h, a yellow precipitate was collected by vacuum filtration
and washed with water (2 × 10 mL) and methanol (3 ×
10 mL). Yield: 0.38 g (83%) of a yellow solid; mp 295°C
(dec.). IR (KBr): 830 (w), 895 (s), 930 (m), 1270 (s), 1360
(m), 1490 (s), 1550 (s), 1615 (m), 3170 (w). NMR spectro-
Preparation of cis-bis(3-hydroxy-6-hydroxymethyl-1-
methyl-4-pyridinonato)dioxomolybdenum(VI),
MoO2(hmp)2, 4
1
3-Hydroxy-6-hydroxymethyl-1-methyl-4-pyridinone (0.38 g,
2.45 mmol) was added as a solid to a 35 mL aqueous solu-
tion of molybdic acid (0.20 g, 0.59 mmol). After 24 h, the
resulting yellow precipitate was collected by suction filtra-
tion and washed with water (3 × 10 mL) and methanol (2 ×
10 mL). Yield 0.34 g (66%) of a yellow solid; mp 295°C
(dec.). IR (KBr): 900 (s), 935 (s), 1100 (m), 1135 (m), 1255
(m), 1305 (s), 1380 (m), 1470 (s), 1515 (s), 1560 (s), 1620
(m), 3070 (w), 3390 (br). NMR spectroscopic data (in
scopic data (in DMSO-d6): H δ: 2.27 (s, 6H), 5.46 (s, 4H),
6.58 (d, JH–H = 8 Hz, 2H), 7.12–7.44 (ov m, 10H), 8.06 (d,
JH–H = 8 Hz, 2H). 13C{1H} δ: 12.2, 57.4, 108.9, 126.6,
128.2, 129.2, 133.6, 135.9, 139.0, 154.9, 170.3. Anal. calcd.
for MoO6C26H24N2: C 56.12, H 4.35, N 5.03; found: C
56.06, H 4.40, N 5.00.
Synthesis of 1-benzyl-3-hydroxy-6-hydroxymethyl- 4-
pyridinone, (Hhbp)
1
DMSO-d6): H δ: 3.77 (s, 6H), 4.48 (s, 4H), 5.82 (s, 2H),
1-Benzyl-3-hydroxy-6-hydroxymethyl-4-pyridinone was pre-
pared by modification of a known procedure (5d). Kojic acid
(1.40 g, 9.85 mmol) was dissolved in a 3:1 mixture of wa-
ter:ethanol (40 mL) whereupon benzylamine (1.50 g,
14.00 mmol) was added dropwise. The reaction mixture was
heated to reflux under an atmosphere of dinitrogen for 12 h
and then cooled to 5°C. After 3 h, a dark brown precipitate
was collected by vacuum filtration and washed with water (2
× 10 mL) and methanol (3 × 10 mL). Yield: 0.24 g (11%) of
light brown crystals; mp 258°C. IR (Nujol): 879 (m), 1124
(m), 1245 (m), 1377 (m), 1462 (s), 1518 (w), 1563 (m), 1643
(m), 2930 (s), 3196 (br). NMR spectroscopic data (in DMSO-
d6): 1H δ: 4.28 (s, 2H), 5.19 (s, 2H), 6.29 (s, 1H), 7.13 (d, JH–
6.53 (s, 2H), 7.67 (s, 2H); 13C{1H} δ: 41.2, 59.4, 108.9,
126.7, 149.4, 155.7, 172.0. Anal. calcd. for MoO8C14H16N2:
C 38.55, H 3.70, N 6.42; found: C 38.42, H 3.90, N 6.29.
Preparation of cis-bis(3-hydroxy-2-methyl-1-propyl-4-
pyridinonato)dioxomolybdenum(VI), MoO2(npp)2, 5
A 10 mL water solution of molybdic acid (0.16 g,
0.47 mmol) was cooled to 0°C in an ice–water bath. To this
chilled solution, Hnpp (0.35 g, 2.10 mmol) was added in
small portions as a solid. After 18 h of stirring, the solution
was allowed to return to room temperature and the yellow
precipitate collected by vacuum filtration. Complex 5 was
recrystallized from a methylene chloride – hexane solution
and collected by suction filtration. Yield: 0.33 g (76%) of a
yellow solid; mp 283°C (dec.). IR (Nujol): 721 (w), 818 (w),
890 (w), 1268 (m), 1377 (m), 1462 (s), 1496 (m), 1551 (m),
1612 (w), 2940 (s). NMR spectroscopic data (in DMSO-d6):
1H δ: 0.89 (t, JH–H = 5 Hz, 6H), 1.73 (m, JH–H = 5 Hz, 4H),
2.50 (s, 6H), 4.08 (t, JH–H = 5 Hz, 4H), 6.47 (d, JH–H = 5 Hz,
2H), 7.87 (d, JH–H = 5 Hz, 2H); 13C{1H} δ: 10.4, 11.6, 23.3,
54.8, 108.3, 133.0, 137.7, 154.4, 169.6. Anal. calcd. for
MoO6C18H24N2: C 46.95, H 5.25, N 6.09; found: C 46.60, H
5.35, N 5.95.
= 5 Hz, 2H), 7.35 (m, 3H), 7.48 (s, 1H); 13C{1H} δ: 54.2,
H
59.2, 112.2, 123.9, 126.3, 127.6, 128.8, 136.9, 146.8, 147.6,
170.8.
Preparation of cis-bis(1-benzyl-3-hydroxy-6-hydroxy-
methyl-4-pyridinonato)dioxomolybdenum(VI),
MoO2(hbp)2, 8
1-Benzyl-3-hydroxy-6-hydroxymethyl-4-pyridinone (0.40 g,
1.73 mmol) was added in small portions to a stirred 15 mL
aqueous solution of molybdic acid (0.13 g, 0.38 mmol). Af-
ter 24 h, complex 8 had precipitated from solution and was
collected by filtration and washed with water (3 × 10 mL)
and methanol (2 × 15 mL). Yield: 0.40 g (89%) of a yellow
solid; mp 240°C (dec.). IR (KBr): 895 (m), 924 (m), 1172
(m), 1248 (s), 1313 (m), 1468 (s), 1522 (s), 1563 (s), 1614
(s), 1642 (m), 3219 (br). NMR spectroscopic data (in
Preparation of cis-bis(3-hydroxy-6-hydroxymethyl-1-
propyl-4-pyridinonato)dioxomolybdenum(VI),
MoO2(hnp)2, 6
1
DMSO-d6): H δ: 4.44 (t, JH–H = 16 Hz, 4H), 5.41 (s, 4H),
Solid Hhnp (0.12 g, 0.65 mmol) was added in small por-
tions to a stirred 15 mL aqueous solution of molybdic acid
(0.05 g, 0.15 mmol). After 18 h, a yellow precipitate was
collected by vacuum filtration and washed with water (3 ×
10 mL) and diethyl ether (3 × 10 mL). Yield: 0.07 g (47%)
of a yellow solid; mp 238°C (dec.). IR (Nujol): 722 (s), 863
(m), 927 (m), 1106 (s), 1244 (s), 1290 (m), 1454 (s), 1537 (m),
5.84 (br s, 2H), 6.66 (s, 2H), 7.18–7.42 (m, 10H), 7.85 (s,
2H); 13C{1H} δ: 55.7, 58.9, 109.9, 125.9, 126.6, 128.0,
128.7, 135.6, 149.2, 155.6, 172.2. Anal. calcd. for
MoO8C26H24N2·H2O: C 51.49, H 4.32, N 4.62; found: C
51.73, H 4.26, N 4.67.
1
1620 (m), 2883 (s). NMR spectroscopic data (in DMSO-d6): H
Preparation of cis-bis(3-hydroxy-2-methyl-1-phenyl-4-
pyridinonato)dioxomolybdenum(VI), MoO2(ppp)2, 9
To a stirred 30 mL aqueous solution of molybdic acid
(0.20 g, 0.59 mmol), 3-hydroxy-2-methyl-1-phenyl-4-
pyridinone (0.59 g, 2.93 mmol) was added in small portions
as a solid. After 18 h, 9 precipitated from solution and was
δ: 0.92 (t, JH–H = 8 Hz, 6H), 1.77 (d, JH–H = 5 Hz, 4H),
4.02 (s, 4H), 4.50 (s, 4H), 5.76 (br s, 2H), 6.54 (s, 2H),
7.75 (s, 2H); 13C{1H} δ: 10.7, 23.9, 54.4, 59.2, 109.3, 125.3,
148.5, 155.8, 171.9. Anal. calcd. for MoO8C18H24N2·3H2O:
C 39.56, H 5.53, N 5.13; found: C 40.04, H 5.63, N 5.19.
© 1999 NRC Canada

1252
Can. J. Chem. Vol. 77, 1999
1
collected by vacuum filtration. The resulting solid was
washed with water (5 × 25 mL) and methanol (3 × 5 mL).
Yield: 0.51 g (82%) of a yellow powder; mp 272°C. IR
(Nujol): 895 (s), 1298 (s), 1365 (s), 1480 (s), 1515 (w), 1543
(s), 1610 (m), 2925 (s), 3058 (br). NMR spectroscopic data
NMR spectroscopic data (in DMSO-d6): H δ: 4.09 (s, 4H),
5.68 (s, 2H), 6.73 (s, 2H), 7.60 (s, 8H), 7.72 (s, 2H);
13C{1H} δ: 59.2, 108.0, 125.7, 126.6, 129.8, 130.0, 140.2,
150.0, 155.1, 173.1. Anal. calcd. for MoO8C24H20N2: C
51.44, H 3.60, N 5.00; found: C 51.24, H 3.51, N 4.80.
1
(in DMSO-d6): H δ: 2.09 (s, 6H), 6.64 (s, 2H), 7.61 (m,
10H), 7.90 (s, 2H); 13C{1H} δ: 13.8, 108.6, 126.7, 129.9,
133.3, 138.6, 141.2, 154.1, 170.9. Anal. calcd. for
MoO6C24H20N2: C 54.55, H 3.82, N 5.30; found: C 54.11, H
4.02, N 5.21.
X-ray crystallography
Crystal data for complexes 1, 2, and 9 are provided in Ta-
ble 1. Data for 1 and 9 were collected on a Nicolet LT2
equipped Siemens P4 diffractometer using the ω method
(4° ≤ 2θ ≤ 60°). Data for 2 were collected on a Siemens
SMART/CCD diffractometer equipped with an LT-II low-
temperature device. The data were corrected for absorption
by a faced-indexed analytical method. Three standard reflec-
tions every 100 showed no significant decay. The structures
were solved by Patterson and Fourier methods, and refined
by full-matrix least squares (SHELXTL IRIS). For complex
1, the alternate polarity cell gave R and wR values of 0.0221
and 0.0251. A weighting scheme of w–1 = σ2(F) was used in
the last cycles of refinement. All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were located and
refined using a riding model. Atomic coordinates, thermal
parameters, bond lengths and angles, and alternate views of
the complexes have been deposited as supplementary mate-
rial.4
Synthesis of 3-hydroxy-6-hydroxymethyl-1-phenyl-4-
pyridinone, (Hhpp)
Aniline was added dropwise (1.38 g, 14.82 mmol) to a
25 mL aqueous solution of kojic acid (1.00 g, 7.04 mmol).
The reaction was heated to reflux for 96 h and was filtered
hot to remove a black oil. After the mixture was allowed to
stand for 18 h at 0°C a dark precipitate was collected and
dissolved in 5 mL of methanol. Following the addition of
25 mL of water, a brown solid precipitated and was dis-
carded. The filtrate was collected and solvent removed under
vacuum to afford a red oil and dark solid. This mixture was
dissolved in a minimum of hot methanol and cooled to 2°C.
Within 18 h, Hhpp precipitated and was collected by suction
filtration. Yield: 0.11 g (7%) of a light brown solid; mp
224°C. IR (Nujol): 703 (m), 854(m), 1152 (m), 1314 (m),
1488 (m), 1515 (m), 1573 (s), 1644 (s), 3057 (br), 3219 (br).
1
Animal model and induction of diabetes
NMR spectroscopic data (in DMSO-d6): H δ: 4.02 (s, 2H),
Male Sprague–Dawley rats with an initial body weight of
200 g were used in this study. Diabetes was induced in
ether-anesthetized rats by an intravenous injection of
60 mg/kg of streptozotocin freshly dissolved in 50 mM so-
dium citrate buffer, pH 4.5. Control animals received citrate
buffer only. After 48 h, the induction of diabetes was con-
firmed by glucose testing in the urine using Keto-diastix
(Ames). Animals were caged in groups of two and provided
with food and water ad libitum until the time of experimen-
tation. Animals used in this study were cared for according
to the recommendations in the Canadian Council on Animal
Care’s Guide to the Care and Use of Experimental Animals.
5.91 (br s, 1H), 6.47 (s, 1H), 7.32 (s, 1H), 7.48 (s, 2H), 7.53
(s, 3H); 13C{1H} δ: 59.2, 111.1, 123.6, 126.9, 129.3, 129.7,
140.7, 146.3, 148.2, 171.4. Isolation of Hhpp was problem-
atic. This is presumably due to a significant amount of hy-
drogen bonding between aniline and the resulting pyridinone
compound. Indeed, a pyridinone–aniline adduct (Hhpp·H2NPh)
could be isolated in certain instances from solutions of hot
methanol. IR (Nujol): 700 (m), 745 (m), 863 (m), 1210 (m),
1307 (m), 1487 (m), 1515 (m), 1573 (s), 1640 (m), 3068
1
(br). NMR spectroscopic data (in DMSO-d6): H δ: 3.87 (d,
JH–H = 5 Hz, 2H), 6.25 (s, 1H), 6.34 (s, 1H), 6.52 (d, JH–H
=
8 Hz, 2H), 6.62 (t, JH–H = 8 Hz, 1H), 7.12 (t, JH–H = 8 Hz,
2H), 7.41 (s, 1H), 7.65 (s, 5H); 13C{1H} δ: 43.7, 111.0,
112.1, 116.5, 123.7, 127.0, 129.0, 129.4, 130.0, 140.8,
146.0, 146.3, 147.5, 171.0.
Treatment protocol
After confirmation of diabetes, treatment was initiated by
adding MoO2(ma)2 and sodium molybdate to the drinking
water. Intake of compounds was determined on a molar ba-
sis adjusted for body weight over a 24 h period. During the
6 week treatment period, the average daily intake of
MoO2(ma)2 by diabetic animals was 0.15 mmol/kg per 24 h
and that of molybdate-treated diabetic animals was
0.13 mmol/kg per 24 h. Analytically pure MoO2(ma)2 was
used in this study (Anal. calcd. for MoO8C12H10: C 38.12, H
2.67; found: C 38.08, H 2.66). The pH of the drinking water
was adjusted to 7.4 with sodium hydroxide. Under these
conditions complex 1 formed a salt that could be recovered
Preparation of cis-bis(3-hydroxy-6-hydroxymethyl-1-
phenyl-4-pyridinonato)dioxomolybdenum(VI),
MoO2(hpp)2, 10
To a stirred 10 mL aqueous solution of molybdic acid
(0.02 g, 0.06 mmol), 3-hydroxy-6-hydroxymethyl-1-phenyl-
4-pyridinone (0.06 g, 0.28 mmol) was added in small por-
tions as a solid. After 18 h, 10 precipitated from solution
and was collected by vacuum filtration. The solid was
washed with water (5 × 25 mL) and methanol (3 × 5 mL).
Yield: 0.03 g (45%) of a yellow solid; mp 261°C. IR
(Nujol): 771 (m), 853 (m), 902 (m), 935 (m), 1163 (m),
1305 (s), 1523 (s), 1552 (s), 1590 (m), 1611 (m), 3205 (w).
1
by titration with HCl (as ascertained by H NMR spectros-
copy). Treatment was initiated immediately following the
4 A complete set of data may be purchased from: The Depository of Unpublished Data, Document Delivery, CISTI, National Research Coun-
cil of Canada, Ottawa, ON K1A 0S2, Canada. Tables of atomic coordinates, bond distances and angles, and alternative views of the com-
plexes have also been deposited with the Cambridge Crystallographic Data Centre, University Chemical Laboratory, 12 Union Road,
Cambridge, CB2 1EZ, U.K.
© 1999 NRC Canada

Lord et al.
1253
Table 1. Crystallographic data for 1, 2, and 9.
Complex
Formula
Crystal system
fw
1
2
9
C12H10MoO8·CH2Cl2
Orthorhombic
463.1
C12H10MoO10
Monoclinic
410.14
C24H20MoN2O6·(CH3)2CO
Monoclinic
586.4
Space group
a, Å
b, Å
Pca21
P21/c
P21/n
10.9476(6)
13.5353(9)
17.4877(10)
93.465(4)
2586.6(3)
4
12.107(1)
8.6169(8)
16.472(1)
8.4591(5)
16.3453(10)
10.2954(7)
103.0320(10)
1386.8(2)
4
c, Å
β
V, Å3
1718.4(3)
4
1.790
Z
Dcalcd g cm–3
Size, mm
1.964
0.04 × 0.4 × 0.4
1.506
0.58{100} × 0.60{010} × 0.42{001}
0.21(1§0)(§10) × .36{101} ×
0.38{10§} × 0.40{001}
Temperature, K
µ, cm–1
Max 2θ, deg
Reflections:
Measured
Observeda
Parameters
Data collection method
Max. res.
density/hole, e Å–3
Rb
160
11.11
60
293
10.01
27.90
180
5.56
56.0
2580
2466
229
ω
8458
3214
216
ω
6540
4747
390
ω
0.45/–0.41
0.0210
0.0237
2.69
0.555/–0.762
0.0288
0.0862
0.35/–0.36
0.0255
0.0290
1.93
Rw
GoF
0.713
aFo > 6σ(Fo).
bR = Σ**Fo* – *Fc**/Σ*Fo*; Rw = [Σ(w(*Fo* – *Fc*)2/Σ(w*Fo*)2]1/2
.
Fig. 1. Synthesis of molybdenum hydroxypyrone and
hydroxypyridinone complexes.
confirmation of diabetes for a 6 week period. Control ani-
mals received water only.
O
O
R1
O
O
[Mo2O7]2-
OH
R2
Mo
O
Heart perfusions
O
X
O
R1
X
H2O
Following treatment, hearts from sodium pentobarbital-
anesthetized rats were quickly excised, placed in ice-cold
buffer and immediately perfused retrogradely via the aorta
with Krebs–Henseleit buffer containing 11 mM glucose and
1.75 mM Ca2+ (pH 7.4, gassed with 95% O2 – 5% CO2).
During this perfusion, the hearts were trimmed of excess tis-
sue, the pulmonary arteries were cut, and the openings of the
left atria were cannulated. Hearts were then switched to the
working mode and perfused at a 15 cm H2O left atrial filling
pressure and 100 cm H2O hydrostatic aortic afterload in a
recirculating buffer system containing 11 mM glucose and
1.2 mM palmitate prebound to 3% bovine serum albumin.
Hearts were initially perfused under aerobic conditions for a
15 min period. Global ischemia was induced by clamping
off both aortic and preload lines for a period of 25 min. Fol-
lowing ischemia, flow was restored and hearts were allowed
to recover for a further 30 min period. Throughout the perfu-
sion, heart rate and aortic pressure development were re-
R2
R1
X = O, NR
X
R2
Statistical analysis
A one-way analysis of variance, followed by the
Newman–Keuls test, was used to determine statistical signif-
icance for comparisons between group means. A value of p
<0.05 was considered significant. All data are reported as
mean ± S.E.M.
Results and discussion
Hydroxypyrone complexes
MoO2(ma)2 (1, ma = maltolato) is readily prepared in
high yield (87%) from addition of maltol to molybdic acid,
(NH4)2Mo2O7, in aqueous solutions at neutral pH (Fig. 1,
ref. 4a). IR and NMR spectroscopic data are consistent with
a cis-dioxo complex containing two chelating maltolato lig-
ands. Analogous reactions with kojic acid afford the corre-
sponding complex, MoO2(ka)2 (2), in much lower yields
(36%). Both 1 and 2 are yellow crystalline complexes, stable
indefinitely in the solid state and relatively soluble in water.
corded using
a
Biotronix pressure recorder (model
BL630) interfaced with a Biotronix chart recording system
(model BL882). Aortic flow was measured by timed collec-
tions. At the end of the reperfusion period, hearts were rap-
idly frozen with clamps cooled to the temperature of liquid
nitrogen, and stored at –80oC.
© 1999 NRC Canada

1254
Can. J. Chem. Vol. 77, 1999
Table 2. Atomic coordinates (× 104) and equivalent isotropic displacement parameters (Å2 × 103) for 1 and 2.
U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x
y
z
U(eq)
Compound 1
Mo(1)
O(1)
O(2)
O(3)
O(4)
O(5)
O(6)
O(7)
O(8)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
3148.9(2)
1935(1)
3812(2)
4370(2)
2382(2)
2744(2)
4128(2)
3218(2)
4391(2)
4054(2)
2963(2)
2562(3)
4235(3)
4690(2)
1465(3)
3241(2)
4007(2)
4570(3)
3676(3)
3098(3)
5377(3)
1430(3)
902(1)
2171.0(2)
1167(2)
1581 (3)
4037(2)
4096(2)
3009(2)
948(2)
2500
181.2(5)
251(5)
259(6)
248(6)
230(5)
249(6)
225(5)
419(9)
435(9)
234(7)
236(8)
342(9)
438(12)
329(10)
547(15)
220(8)
201(7)
289(8)
480(13)
362(10)
405(12)
405(11)
666(4)
773(5)
2499(2)
1646(1)
2690(1)
2130(1)
3754(1)
3225(1)
1788(2)
5374(2)
2419(2)
2094(2)
1786(2)
2088(3)
2401(3)
1416(3)
4295(2)
4029(2)
4566(2)
5635(2)
5143(2)
4380(2)
3993(2)
4961(1)
4016(1)
8048(3)
401(4)
5345(3)
5420(3)
6761(4)
8004(4)
6720(3)
7015(5)
2238(3)
1085(3)
198(4)
1452(6)
2410(5)
–1044(5)
6237(4)
5817(2)
7804(2)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
Cl(1)
Cl(2)
2352(1)
Compound 2
Mo(1)
O(1)
O(2)
O(3)
O(4)
O(5)
O(6)
O(7)
O(8)
O(9)
O(10)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
3747(1)
3327(3)
2139(2)
1692(3)
–440(3)
4266(2)
5504(2)
6711(3)
8818(4)
5217(3)
2140(3)
2584(3)
2440(4)
1055(3)
1122(3)
1917(3)
327(4)
1260(1)
398(1)
1870(1)
325(1)
1964(1)
2405(1)
1668(1)
4018(1)
3891(2)
701(1)
7138(1)
8388(2)
8370(2)
11315(2)
12480(2)
6757(2)
8986(2)
8548(2)
11944(3)
6675(3)
5817(2)
9360(3)
10340(3)
11302(3)
10333(3)
9312(3)
12489(3)
7700(3)
7547(3)
9716(3)
9942(3)
8928(3)
10682(3)
36(1)
41(1)
35(1)
45(1)
47(1)
38(1)
38(1)
44(1)
71(1)
57(1)
58(1)
35(1)
43(1)
36(1)
34(1)
32(1)
47(1)
33(1)
43(1)
36(1)
35(1)
31(1)
50(1)
1216(2)
598(2)
89(2)
1080(2)
1629(2)
1412(2)
1211(2)
2833(2)
3618(2)
3646(2)
2856(2)
2416(2)
4218(2)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
5270(3)
5709(4)
7314(3)
6965(3)
5925(3)
8359(4)
Increased solubility observed for 2 in aqueous solutions pre-
sumably arises due to the pendant CH2OH group on the
pyrone ring. Unlike the maltol derivative, however, 2 de-
composes in water at elevated temperatures to give a mix-
ture of molybdates.
kojic acid, decreases in intensity and shifts to a lower
wavenumber (1647 cm–1) upon coordination to the d 0 metal
centre. Likewise, the bands at 1611 cm–1 (strong) and
1578 cm–1 (medium), belonging to the strongly mixed
ν(C=C) and ν(C=O) modes in pyrones (3a, 4a), also shift to
lower energies upon complexation and are observed at
1574 cm–1 and 1520 cm–1, respectively. The band at
As with 1 (4a), the IR spectrum for 2 shows that the
strong band at 1660 cm–1, assigned as mainly ν(C=O) in
© 1999 NRC Canada

Lord et al.
1255
Table 3. Selected bond lengths (Å) and angles (°) for 1.
Bond lengths
Mo(1)—O(1)
Mo(1)—O(3)
Mo(1)—O(5)
O(3)—C(1)
O(5)—C(7)
O(7)—C(3)
O(8)—C(9)
C(1)—C(2)
C(2)—C(3)
C(4)—C(5)
C(7)—C(11)
C(9)—C(12)
1.705(2)
2.207(2)
2.242(2)
1.207(3)
1.265(4)
1.364(4)
1.360(4)
1.427(4)
1.353(4)
1.339(5)
1.414(5)
1.481(5)
Mo(1)—O(2)
Mo(1)—O(4)
Mo(1)—O6)
O(4)—C(2)
O(6)—C(8)
O(7)—C(4)
O(8)—C(10)
C(1)—C(5)
C(3)—C(6)
C(7)—C(8)
C(8)—C(9)
C(10)—C(11)
1.697(2)
1.997(2)
1.986(2)
1.341(3)
1.336(4)
1.327(5)
1.325(5)
1.413(4)
1.477(6)
1.428(4)
1.353(4)
1.353(6)
Bond angles
O(1)-Mo(1)-O(2)
O(2)-Mo(1)-O(3)
O(2)-Mo(1)-O(4)
O(1)-Mo(1)-O(5)
O(3)-Mo(1)-O(5)
O(1)-Mo(1)-O(6)
O(3)-Mo(1)-O(6)
O(5)-Mo(1)-O(6)
Mo(1)-O(4)-C(2)
Mo(1)-O(6)-C(8)
104.8(1)
91.1(1)
102.5(1)
88.6(1)
77.4(1)
104.2(1)
84.3(1)
75.4(1)
118.4(2)
118.9(2)
O(1)-Mo(1)-O(3)
O(1)-Mo(1)-O(4)
O(3)-Mo(1)-O(4)
O(2)-Mo(1)-O(5)
O(4)-Mo(1)-O(5)
O(2)-Mo(1)-O(6)
O(4)-Mo(1)-O(6)
Mo(1)-O(3)-C(1)
Mo(1)–O(5)-C(7)
161.3(1)
91.2(1)
75.5(1)
164.4(1)
85.0(1)
93.3(1)
154.5(1)
113.3(2)
112.1(2)
Fig. 3. The molecular structure of MoO2(ka)2, 2.
Fig. 2. The molecular structure of MoO2(ma)2, 1.
3168 cm–1 for the OH stretches of kojic acid is observed at
3122 cm–1 for 2. The two strong IR bands present at 919 and
890 cm–1 assigned to νs (Mo=O) and νas(Mo=O) are similar
to those reported previously for 1 and for the tropolone com-
plex, cis-MoO2(trop)2 (12). The wavenumbers observed in
kojic acid and its metal derivatives are lower than those for
the maltol derivatives, presumably because of the electron-
withdrawing nature of the hydroxymethyl group as opposed
to the electron-donating ability of the methyl group in maltol
(5b).
The proton NMR spectra of 2 in D2O indicates a pair of
broad singlets at δ 6.67 and 7.87 due to the ring CH protons.
The singlet at 6.67 ppm is shifted downfield by 0.23 ppm in
comparison with kojic acid while the other ring proton is
shifted upfield by 0.06 ppm. The exocyclic methylene pro-
tons of the hydroxymethyl group appear as a singlet at δ
4.42 in 2 while the chemical shift of the analogous protons
in starting pyrone appear at δ 4.73.
Single crystals of 1 were grown from a wet methylene
chloride solution cooled to 5°C and those for 2 grown from
a H2O–i-PrOH mixture. An X-ray diffraction study of 1 was
carried out to determine unequivocally the nature of the
compound about to undergo biological testing. The molecu-
lar structures of MoO2(ma)2 and MoO2(ka)2 are depicted in
Figs. 2 and 3, respectively, and crystallographic data for
both compounds are given in Table 1. Atomic coordinates
and displacement parameters for 1 and 2 are given in Table
2. Selected bond distances and angles for 1 and 2 are pro-
vided in Tables 3 and 4, respectively. The coordination sphere
about the molybdenum atoms in both cases consists of six
oxygen atoms arranged in a distorted octahedral geometry.
The molecular structures confirm a cis arrangement of dioxo
© 1999 NRC Canada

1256
Can. J. Chem. Vol. 77, 1999
Table 4. Selected bond lengths (Å) and angles (°) for 2.
Bond lengths
Mo(1)—O(10)
Mo(1)—O(5)
Mo(1)—O(6)
O(1)—C(1)
O(3)—C(3)
O(4)—C(6)
O(6)—C(11)
O(7)—C(8)
C(1)—C(2)
C(3)—C(4)
C(4)—C(5)
C(7)—C(11)
C(9)—C(12)
1.694(2)
1.981(2)
2.236(2)
1.337(3)
1.346(3)
1.390(4)
1.278(3)
1.346(4)
1.334(4)
1.352(4)
1.416(4)
1.433(4)
1.499(4)
Mo(1)—O(9)
Mo(1)—O(1)
Mo(1)—O(2)
O(2)—C(5)
O(3)—C(2)
O(5)—C(7)
O(7)—C(9)
O(8)—C(12)
C(1)—C(5)
C(3)—C(6)
C(7)—C(8)
C(9)—C(10)
C(10)—C(11)
1.695(2)
1.994(2)
2.286(2)
1.272(3)
1.357(4)
1.335(3)
1.342(3)
1.378(5)
1.442(3)
1.503(4)
1.355(4)
1.355(4)
1.403(4)
Bond angles
O(10)-Mo(1)-O(9)
O(9)-Mo(1)-O(5)
O(9)-Mo(1)-O(1)
O(10)-Mo(1)-O(6)
O(5)-Mo(1)-O(6)
O(10)-Mo(1)-O(2)
O(5)-Mo(1)-O(2)
O(6)-Mo(1-O(2)
C(5)-O(2)-Mo(1)
C(7)-O(5)-Mo(1)
C(9)-O(7)-C(8)
C(2)-C(1)-C(5)
C(1)-C(2)–O(3)
O(3)-C(3)-C(6)
104.95(13)
104.13(10)
92.82(10)
162.77(10)
75.65(7)
89.64(10)
83.36(7)
76.26(7)
112.0(2)
119.0(2)
120.8(2)
119.9(3)
121.4(3)
111.0(2)
O(10)-Mo(1)-O(5)
O(10)-Mo(1)-O(1)
O(5)-Mo(1)-O(1)
O(9)-Mo(1)-O(6)
O(1)-Mo(1)-O(6)
O(9)-Mo(1)-O(2)
O(1)-Mo(1)-O(2)
C(1)–O(1)-Mo(1)
C(3)–O(3)-C(2)
C(11)–O(6)-Mo(1)
C(2)-C(1)-O(1)
93.15(10)
105.10(10)
151.05(8)
90.64(10)
80.94(8)
162.99(10)
74.64(7)
119.5(2)
120.3(2)
112.6(2)
123.6(2)
116.5(2)
122.2(2)
126.8(3)
O(1)-C(1)-C(5)
O(3)-C(3)-C(4)
C(4)-C(3)-C(6)
ronments have been observed previously in analogous
vanadium–maltol (15) and iron – kojic acid complexes (5d).
As expected, a slight lengthening of the ketone C=O bond
is observed upon complexation, with a mean distance of
1.268 (4) Å in 1 and 1.275 (3) Å in 2 compared with 1.244
Å found in free kojic acid (16). The molybdenum–oxygen
(ketone) bond in this case is somewhat longer (avg. = 2.225
(2) Å, 1; avg. = 2.261 (2) Å, 2) than the Mo – deprotonated
oxygen distance, the average being only 1.992 (2) Å in 1
and 1.989 (2) Å in 2. This observation provides a distinction
between Lewis acid–base versus covalent bonding for these
two types of oxygen atoms. It is interesting to note that the
ketone oxygen–molybdenum bond length is slightly longer
in 2 than in 1, indicating weaker bonding interaction for this
hydroxypyrone. Low metal-binding constants have been re-
ported previously for kojic acid derivatives (5c). Interest-
ingly, average C(6)—O(4) bond lengths of 1.384 (5) Å
observed for the hydroxymethyl groups in 2 are somewhat
shorter than those seen in kojic acid (1.406 Å), presumably
due to a slight reduction in the degree of intermolecular hy-
drogen bonding for the molybdenum complex. Indeed, O–
H···O interactions in 2 occur at 2.887 and 3.069 Å, while
distances of 1.87 and 2.08 Å are reported for kojic acid.
Fig. 4. Hydroxypyrone and hydroxypyridinone ligands and metal
complexes.
ligands as predicted by extended spectroscopic data and
Hückel calculations (13). The Mo=O bond lengths (avg. =
1.701 (2) Å, 1; avg. = 1.695 (2) Å, 2) are comparable to
those found in other oxomolybdenum(VI) complexes (14).
The two ketonic oxygen atoms of the pyrone moieties are
trans to the oxo ligands and the stronger field hydroxyl
oxygens are trans to one another. Similar coordination envi-
Hydroxypyridinone complexes
A series of N-substituted 3-hydroxy-4-pyridinones were
readily prepared (Fig. 4) from the addition of primary amine
(MeNH2, n-PrNH2, PhCH2NH2, and PhNH2) and either
maltol (9) or kojic acid (5d). Functionalization of the ring
© 1999 NRC Canada

Lord et al.
1257
Table 5. Atomic coordinates (× 104) and equivalent isotropic displacement parameters (Å2 × 103) for 9. U(eq)
is defined as one third of the trace of the orthogonalized Uij tensor.
x
y
z
U(eq)
Mo(1)
O(1)
O(2)
O(3)
O(4)
O(5)
O(6)
C(1)
C(2)
C(3)
N(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
N(17)
C(18)
C(19)
C(20)
C(21)
C(22)
C(23)
C(24)
C(25)
C(26)
5232.4(2)
6479(1)
4160(2)
4011(1)
6079(1)
6050(1)
4444(1)
4415(2)
5560(2)
6093(2)
5471(2)
4376(2)
3842(2)
5954(2)
5827(3)
6335(3)
6975(2)
7066(2)
6551(2)
7323(2)
5812(2)
6343(2)
6054(2)
5219(2)
4638(2)
4939(2)
4965(2)
3808(2)
3598(2)
4537(3)
5685(3)
5911(2)
3736(2)
733.9(1)
829(1)
150(1)
2715.4(1)
3344.8(9)
3224.1(9)
1676.1(9)
2153.2(9)
1869.4(9)
2850.2(9)
1243(1)
1491(1)
1081(1)
422(1)
21.49(5)
30.4(5)
30.6(5)
24.6(5)
23.0(5)
24.5(5)
24.8(5)
21.6(6)
21.2(6)
23.0(6)
24.9(6)
28.6(7)
26.6(7)
26.2(7)
40.4(9)
48(1)
38.2(8)
34.8(8)
29.4(8)
33.4(8)
20.0(6)
23.0(7)
25.0(7)
21.5(5)
21.3(7)
20.4(6)
23.3(7)
29.8(7)
35.2(8)
38.0(9)
40.7(9)
31.1(8)
31.8(8)
442(1)
–326(1)
1697(1)
2058(1)
–238(2)
–672(2)
–1398(2)
–1731(1)
–1336(2)
–594(2)
–2573(2)
–3505(2)
4303(2)
4168(2)
–3240(2)
–2428(2)
–1812(2)
2619(2)
3410(2)
4349(2)
4550(1)
3802(2)
2846(2)
5587(2)
5965(2)
6965(2)
7570(2)
7185(2)
6183(2)
4049(2)
165(1)
557(1)
17(1)
323(2)
–28(2)
–679(1)
–988(1)
–641(1)
1316(1)
1967(1)
1591 (1)
1787(1)
2316(1)
2690(1)
2517(1)
2462(1)
2283(1)
2385(2)
2658(2)
2834(2)
2742(1)
3273(1)
50:50 disordered acetone of solvation
O(7A)
O(7B)
3184(8)
2927(9)
2746(7)
2101(10)
2515(18)
1931(17)
1537(15)
884(8)
5291(5)
5049(7)
5189(10)
5064(10)
5070(10)
5180(8)
5277(6)
4912(8)
87(3)
154(7)
98(8)
85(7)
148(11)
93(5)
C(27A)
C(27B)
C(28A)
C(28B)
C(29A)
C(29B)
4131 (22)
4009(20)
4695(22)
4394(17)
5096(10)
5017(14)
3322(11)
2573(12)
112(6)
101(5)
nitrogen in the hydroxypyridinones allows for fine tuning of
physical properties such as water solubility, hydrolytic sta-
bility, and lipophilicity without compromising thermody-
namic binding constants (9b). Indeed, the corresponding
pyridinone complexes are somewhat less water soluble and
slightly more lipophilic than the pyrone complexes 1 and 2.
For instance, although the N–Me complex MoO2(dpp)2 3 is
only sparingly soluble in dimethyl sulfoxide, the kojic acid –
aniline derivative 10 is readily soluble in methylene chlo-
ride. While metal complexes containing N-substituted 3-
hydroxy-4-pyridinones are well known (2b, 8c–8d, 9, 11),
the only molybdenum complex reported containing these bi-
ologically relevant ligands is the 3-hydroxy-1,2-dimethyl- 4-
pyridinone (Hdpp) derivative, MoO2(dpp)2 3 (11g).
Upon complexation with molybdenum, the four-band in-
frared spectral pattern between 1400 and 1610 cm–1, charac-
teristic of pyrone and pyridinone ligands (4a, 17), is also
observed, along with an expected bathochromatic shift.
These four bands are assigned collectively as ν(C=C) and
ν(C=O). Of the four possible isomers for complexes of the
type cis-MoO2L2 (18), the most likely isomer is the one in
which both ketone oxygens of the pyridinone ligands are
trans to the molybdenum oxo groups (13). A single-crystal
X-ray diffraction study was carried out on the 3-hydroxy- 2-
methyl-1-phenyl-pyridinone derivative 9 to confirm this as-
signment.
The molecular structure of 9 is shown in Fig. 5, atomic
coordinates and displacement parameters in Table 5, and
© 1999 NRC Canada

1258
Can. J. Chem. Vol. 77, 1999
Table 6. Selected bond lengths (Å) and angles (°) for 9.
Bond lengths
Mo(1)—O(1)
Mo(1)—O(3)
Mo(1)—O(5)
O(3)—C(1)
O(5)—C(14)
C(1)—C(2)
C(2)—C(3)
C(3)—C(13)
N(4)—C(7)
1.705(2)
2.226(2)
2.202(2)
1.287(3)
1.288(3)
1.427(3)
1.369(3)
1.493(3)
1.458(3)
1.380(3)
1.376(4)
1.373(4)
1.401(3)
1.359(3)
1.380(3)
1.373(3)
1.385(3)
1.386(3)
1.378(4)
Mo(1)—O(2)
Mo(1)—O(4)
Mo(1)—O(6)
O(4)—C(2)
O(6)—C(19)
C(1)—C(6)
C(3)—N(4)
N(4)—C(5)
C(5)—C(6)
C(7)—C(12)
C(9)—C(10)
C(11)—C(12)
C(14)—C(19)
C(16)—N(17)
N(17)—C(20)
C(18)—C(26)
C(20)—C(25)
C(22)—C(23)
C(24)—C(25)
1.709(2)
1.999(2)
2.009(1)
1.343(3)
1.345(3)
1.406(3)
1.379(3)
1.364(3)
1.367(3)
1.372(3)
1.386(4)
1.391(4)
1.430(3)
1.366(3)
1.457(3)
1.500(3)
1.379(3)
1.377(4)
1.390(4)
C(7)—C(8)
C(8)—C(9)
C(10)—C(11)
C(14)—C(15)
C(15)—C(16)
N(17)—C(18)
C(18)—C(19)
C(20)—C(21)
C(21)—C(22)
C(23)—C(24)
Bond angles
O(1)-Mo(1)-O(2)
O(2)-Mo(1)-O(3)
O(2)-Mo(1)-O(4)
O(1)-Mo(1)-O(5)
O(3)-Mo(1)-O(5)
O(1)-Mo(1)-O(6)
O(3)-Mo(1)-O(6)
O(5)-Mo(1)-O(6)
Mo(1)-O(4)-C(2)
Mo(1)-O(6)-C(19)
O(3)-C(1)-C(6)
O(4)-C(2)-C(1)
C(1)-C(2)-C(3)
C(2)-C(3)-C(13)
C(3)-N(4)-C(5)
C(5)-N(4)-C(7)
C(1)-C(6)-C(5)
N(4)-C(7)-C(12)
C(7)-C(8)-C(9)
104.3(1)
86.9(1)
106.1(1)
92.7(1)
78.7(1)
100.9(1)
90.7(1)
O(1)-Mo(1)-O(3)
O(1)-Mo(1)-O(4)
O(3)-Mo(1)-O(4)
O(2)-Mo(1)-O(5)
O(4)-Mo(1)-O(5)
O(2)-Mo(1)-O(6)
O(4)-Mo(1)-O(6)
Mo(1)-O(3)-C(1)
Mo(1)-O(5)-C(14)
O(3)-C(1)-C(2)
C(2)-C(1)-C(6)
O(4)-C(2)-C(3)
C(2)-C(3)-N(4)
N(4)-C(3)-C(13)
C(3)-N(4)-C(7)
N(4)-C(5)-C(6)
N(4)-C(7)-C(8)
C(8)-C(7)-C(12)
C(8)-C(9)-C(10)
163.4(1)
89.7(1)
75.2(1)
160.6(1)
82.8(1)
92.2(1)
156.0(1)
113.3(1)
113.0(1)
116.3(2)
117.1(2)
122.0(2)
117.9(2)
120.0(2)
119.1(2)
121.1(2)
118.6(2)
121.4(2)
120.1(3)
75.3(1)
119.3(1)
118.0(1)
126.6(2)
115.9(2)
122.1(2)
122.1(2)
121.8(2)
119.0(2)
119.9(2)
120.0(2)
119.4(3)
ketone C(1)—O(3) bonds. Resonance forms for pyridinone
ligands have been described in detail elsewhere (11, 19). A
N(4)—C(7) bond distance of 1.458 (3) Å, however, is
slightly shorter than that reported for the free ligands 3-
Fig. 5. The molecular structure of MoO2(ppp)2, 9.
hydroxy-1-p-methoxyphenyl-2-methyl-4-pyridinone
(cf.
1.474 (1) Å) (19) and 3-hydroxy-1,2-dimethyl-4-pyridinone
(cf. 1.482 (4) Å) (20). Average C-N-C angles of 120.0° are
similar to those reported earlier (11, 19, 20).
Biological relevance
bond distances and angles are provided in Table 6. Similar
Mo—O bond distances are observed in 9 and the parent
pyrone complex 1. The bond distances within the pyridinone
ring also display trends similar to those described for 1 and
other metal–pyridinone complexes (11). A pronounced lo-
calization of the formal double bonds in the ring, albeit to a
lesser extent than that observed for the pyrone systems, is
clearly indicated by the short C(2)—C(3), C(5)—C(6), and
We have begun our investigation into the effect of molyb-
denum complexes on heart function in diabetic rats and re-
port our findings herein. Initial work was conducted using 1,
the molybdenum analogue of BMOV, because of the effi-
cacy of this latter compound as an insulin mimic, along with
the control (10) sodium molybdate, Na2MoO4. Confirming
the diabetic state, plasma glucose and free fatty acid levels
© 1999 NRC Canada

Lord et al.
1259
Table 7. Physical characteristics and blood profile of control and diabetic rats.
Glucose
(mM)
Free fatty acids
(mM)
Body weight
(g)
Fluid intake
(mL/kg per 24 h)
Group
Control
Diabetic
+ molybdate
+ MoO2(ma)2
6.1 ± 0.1
0.37 ± 0.04
492 ± 8
43 ± 2
23.2 + 1.5a,c
13.2 + 1.4a,b
16.3 + 1.3a,b
0.51 + 0.09a,c
0.17 + 0.02a,b
0.13 + 0.02a,b
291 + 19a
286 + 12a
328 + 17a
163 + 22a,c
90 + 12a,b
115 + 13a,b
Values are presented as mean ± S.E.M. for six to eight animals in each group. Average daily intake of MoO2(ma)2 by diabetic animals was 0.15
mmol/kg per 24 h, whereas that of molybdate was 0.13 mmol/kg per 24 h.
aSignificant vs. control.
bSignificant vs. diabetic.
cSignificant vs. diabetic treated with molybdate.
Table 8. Effects of MoO2(ma)2 and sodium molybdate treatment on heart function.
HR
(beats/min)
PSP
(mmHg)
RPP (beats
DP
(mmHg)
AF
(mL/min)
Perfusion condition
mmHg min–1)
Aerobic perfusion
Control
Diabetic
+ molybdate
+MoO2(ma)2
Reperfusion following ischemia
Control
Diabetic
+ molybdate
+ MoO2(ma)2
250 ± 8
92 ± 5
94 ± 4
97 ± 3
87 ± 5
23 ± 1
19 ± 1a
23 ± 2
18 ± 1
59 ± 2
63 ± 2
62 ± 3
63 ± 4
42 ± 4
200 ± 13a
243 ± 20
214 ± 12
20 ± 3a
36 ± 4b
17 ± 3a,c
190 ± 21
164 ± 25
235 ± 11
114 ± 14c
87 ± 9
16 ± 2
14 ± 2
22 ± 1
9 ± 3c
57 ± 5
61 ± 9
64 ± 2
35 ± 12
16 ± 6
6 ± 2a
25 ± 3b
3 ± 2ac
74 ± 11
94 ± 3
45 ± 16c
Values are presented as mean ± S.E.M. for six to eight animals in each group. HR, heart rate; PSP, peak systolic pressure; RPP, heart rate pressure
product; DP, diastolic pressure; AF, aortic flow. Hearts were perfused under aerobic conditions for 15 min, then subjected to 25 min of global ischemia
followed by 30 min of aerobic reperfusion. Reperfusion data obtained at the end of the 30 min.
aSignificant vs. control.
bSignificant vs. diabetic.
cSignificant vs. diabetic treated with molybdate.
were markedly elevated in the diabetic rats (Table 7). Body
weight, as expected, was lower in diabetic rats than in the
controls. Food and fluid intake was maintained during the
6 week period. Treatment of diabetic animals with either so-
dium molybdate or MoO2(ma)2 (1) significantly reduced lev-
els of plasma glucose but proved to have weaker insulin-like
effects when compared to BMOV (4h, 5, 6). It is interesting
to observe that treatment with MoO2(ma)2 and sodium
molybdate also reduced plasma glucose and free fatty acid
levels in diabetic rats. Rats treated with both molybdenum
complexes suffered from initial weight loss although those
given complex 1 gained weight at the end of the treatment.
No animals suffered from diarrhea and all survived treat-
ment with these molybdenum complexes.
The 6 week period of diabetes was selected because alter-
ations in heart function occur within this period (21–23). As
shown in Table 8, if hearts from diabetic rats are perfused
under aerobic conditions, significant differences in function
are noted. Diabetic rat hearts show a significant depression
in rate–pressure product as a result of a decrease in heart
rate. Aortic flow in these rats is also depressed compared to
that in control hearts. Treatment of diabetic rats with sodium
molybdate, however, prevented this depression in aortic flow
from occurring, an effect not observed in diabetic rats
treated with MoO2(ma)2. During reperfusion of previously
ischemic hearts, the benefits of sodium molybdate on me-
chanical function of diabetic rat hearts are also clearly ob-
served. These are associated with significant and dramatic
increases in aortic flow. No benefits of MoO2(ma)2 treat-
ment on reperfusion recovery of diabetic hearts were seen.
Preventing the diabetes-induced depressions in heart func-
tion can be accomplished with agents that decrease circulat-
ing levels of lipids and glucose (21–24), which could
possibly explain the benefits of molybdate on reperfusion on
recovery of diabetic hearts. Diabetic hearts exposed to low
levels of fatty acids can oxidize glucose as an additional
substrate (24) since the poorly controlled state is character-
ized by energy requirements met primarily from the oxida-
tion of fatty acids (25). Although conjectural, the possibility
exists that molybdate-treated diabetic hearts oxidized more
glucose during reperfusion, allowing them to be less sensi-
tive to ischemia (26).
Conclusions
A series of hydroxypyrone and hydroxypyridinone com-
plexes of molybdenum have been prepared and were charac-
terized by a number of physical methods including X-ray
diffraction studies. Initial biological data demonstrate that
treatment of diabetic animals with sodium molybdate not
only reduces plasma levels of glucose and fatty acids, but
also prevents the depression in cardiac function from occur-
© 1999 NRC Canada

1260
Can. J. Chem. Vol. 77, 1999
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also showed some improvement in blood glucose and free
fatty acid levels but had no effect on heart function. We are
currently investigating the physical properties necessary to
generate a more active molybdenum complex for the treat-
ment of cardiac dysfunction associated with diabetes.
Acknowledgements
Thanks are gratefully extended to the Heart and Stroke
Foundation of New Brunswick (S.A.W.), the Medical Re-
search Fund of New Brunswick (T.L.B.), the University of
Waterloo, St. Mary’s University, and Mount Allison Univer-
sity for financial support. We also thank Dan Durant, Roger
and Marilyn Smith, and Jacqueline Jacob for their expert
technical assistance, as well as Dr. John Bailey for many
helpful discussions.
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