Structural characterization of 1,3-propanedithiols that feature carboxylic acids: Homologues of mercury chelating agents

Article abstract of DOI:10.1016/j.poly.2013.05.012

The molecular structures of a series of 1,3-propanedithiols that contain carboxylic acid groups, namely rac- and meso-2,4-dimercaptoglutaric acid (H ₄DMGA) and 2-carboxy-1,3-propanedithiol (H₃DMCP), have been determined by X-ray diffraction. Each compound exhibits two centrosymmetric intermolecular hydrogen bonding interactions between pairs of carboxylic acid groups, which result in a dimeric structure for H₃DMCP and a polymeric tape-like structure for rac- and meso-H₄DMGA. Significantly, the hydrogen bonding motifs observed for rac- and meso-H ₄DMGA are very different to those observed for the 1,2-dithiol, rac-2,3-dimercaptosuccinic acid (rac-H₄DMSA), in which the two oxygen atoms of each carboxylic acid group hydrogen bond to two different carboxylic acid groups, thereby resulting in a hydrogen bonded sheet-like structure rather than a tape. Density functional theory calculations indicate that 1,3-dithiolate coordination to mercury results in larger S-Hg-S bond angles than does 1,2-dithiolate coordination, but these angles are far from linear. As such, κ²-S₂ coordination of these dithiolate ligands is expected to be associated with mercury coordination numbers of greater than two. In vivo studies demonstrate that both rac-H₄DMGA and H ₃DMCP reduce the renal burden of mercury in rats, although the compounds are not as effective as either 2,3-dimercaptopropane-1-sulfonic acid (H₃DMPS) or meso-H₄DMSA.

Full text of DOI:10.1016/j.poly.2013.05.012

Polyhedron 64 (2013) 268–279
Contents lists available at SciVerse ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Structural characterization of 1,3-propanedithiols that feature carboxylic
acids: Homologues of mercury chelating agents q
Wesley Sattler a, Joshua H. Palmer a, Christy C. Bridges b, Lucy Joshee b, Rudolfs K. Zalups b,
Gerard Parkin a,
⇑
a Department of Chemistry, Columbia University, New York, NY 10027, USA
b Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St. Macon, GA 31207, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The molecular structures of a series of 1,3-propanedithiols that contain carboxylic acid groups, namely
rac- and meso-2,4-dimercaptoglutaric acid (H4DMGA) and 2-carboxy-1,3-propanedithiol (H3DMCP), have
been determined by X-ray diffraction. Each compound exhibits two centrosymmetric intermolecular
hydrogen bonding interactions between pairs of carboxylic acid groups, which result in a dimeric
structure for H3DMCP and a polymeric tape-like structure for rac- and meso-H4DMGA. Significantly,
the hydrogen bonding motifs observed for rac- and meso-H4DMGA are very different to those observed
for the 1,2-dithiol, rac-2,3-dimercaptosuccinic acid (rac-H4DMSA), in which the two oxygen atoms of
each carboxylic acid group hydrogen bond to two different carboxylic acid groups, thereby resulting in
a hydrogen bonded sheet-like structure rather than a tape. Density functional theory calculations indicate
that 1,3-dithiolate coordination to mercury results in larger S–Hg–S bond angles than does 1,2-dithiolate
Received 2 March 2013
Accepted 7 May 2013
Available online 16 May 2013
Keywords:
Mercury
Thiolate
Chelating agent
coordination, but these angles are far from linear. As such, j
2-S2 coordination of these dithiolate ligands is
expected to be associated with mercury coordination numbers of greater than two. In vivo studies dem-
onstrate that both rac-H4DMGA and H3DMCP reduce the renal burden of mercury in rats, although the
compounds are not as effective as either 2,3-dimercaptopropane-1-sulfonic acid (H3DMPS) or meso-
H4DMSA.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Therefore, we sought to investigate other compounds that could serve
as potential chelators of mercuric ions in biological systems.
The primary aim of chelation therapy [1–3] is to rid vulnerable
target sites in the body of toxic metals, such as mercury [4],
following exposure. Previous compounds that have been utilized
for chelation therapy include meso-2,3-dimercaptosuccinic acid
(meso-H4DMSA),1 2,3-dimercaptopropane-1-sulfonic acid (H3DMPS),
2,3-dimercaptopropanol (British anti-lewisite; H3BAL), and 2,3-
dimercaptopropionic acid (H3DMPA), as illustrated in Fig. 1. H3DMPS
and H4DMSA are low molecular weight, water soluble, vicinal dithiols
that have proven to be effective in promoting urinary excretion of
ionic forms of mercury and are used throughout the world to treat
mercury intoxication [5,6]. It has been suggested, however, that these
compounds are not ideal chelators for mercury and that the develop-
ment of additional, more effective chelators is necessary [7].
From a chemical design point of view, an ideal chelating agent
is, firstly, one that can gain rapid and efficient access to the intra-
cellular milieu of target cells in the body that are at greatest risk of
being adversely affected by the metal in question. Secondly, the
chelating agent should be able to bind competitively and strongly
to the toxic metal, which is likely to be coordinated to other intra-
cellular molecules. Thirdly, the coordinating agent should not de-
plete intracellular stores of essential metals. In this regard,
although H4DMSA and H3DMPS have the ability to promote rapid
excretion of mercuric species, there is evidence that these dithiols
may also bind to essential elements such as copper, chromium and
zinc [1–3].
In addition to the above requirements, the metal complex
formed should be able to serve as a substrate of membrane trans-
porters that are capable of exporting or eliminating it from the tar-
get cells into an extracellular compartment to be excreted. In this
regard, once internalized into the body, mercury species accumu-
late predominantly along the epithelial cells lining the proximal
tubule in the kidneys, although other target cells in the body also
accumulate and become intoxicated by mercury. The predilection
for mercury species to be taken up so avidly along the renal
q
Dedicated with respect to Professor George Christou on the occasion of his 60th
birthday.
⇑
Corresponding author.
E-mail address: parkin@columbia.edu (G. Parkin).
Dimercaptosuccinic acid is often given the abbreviation DMSA. However, here we
1
use the abbreviation H4DMSA in order to provide a distinction with the deprotonated
derivatives.
0277-5387/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.poly.2013.05.012

W. Sattler et al. / Polyhedron 64 (2013) 268–279
269
Fig. 1. Chelating agents that have been employed in mercury detoxification.
Fig. 2. 1,3-Dithiols that contain carboxylic acid moieties.
proximal tubule relates to the activity of numerous membrane
evidence that neither H3DMPS nor meso-H4DMSA chelate to Hg2+
,
transporters present in both luminal and basolateral plasma mem-
branes of these cells. Similarly, the ability of H3DMPS and H4DMSA
to extract mercury from renal tissue relies on the ability of these
agents to be taken up by carriers such as the organic anion trans-
porters, OAT1 and OAT3, and the sodium dicarboxylate transporter,
NaC3, present in the basolateral membrane of proximal tubular
cells [5,8]. It has been hypothesized that once these coordinating
agents gain access to cells via carriers on the basolateral mem-
brane, they form complexes with intracellular mercury that are ex-
ported from the intracellular compartment into the tubular lumen
for eventual excretion in urine [5].
but rather bind in more complex ways involving mercury binding
to more than one ‘‘chelating agent’’ ligand [7]. The ability of a
dithiol ligand to form a stable chelate complex with a given metal
center is, however, expected to be a function of both the length and
geometry of the spacer between the thiol groups and also the other
supporting ligands attached to the metal. Therefore, we report here
an investigation of 1,3-dithiols that are structurally related to clin-
ically useful mercury chelating agents. In particular, since carbox-
ylic acid groups increase water solubility, attention is focused on
H3DMCP and H4DMGA, which respectively contain one and two
carboxylic acid groups (Fig. 2).
Hence, since glutarate is an avid substrate of OAT1, OAT3, and
NaC3 [5,8,9], an objective of the research described here was to
investigate potential mercury coordinating agents that contain
the glutarate motif. Specifically, it was hypothesized that incorpo-
ration of two thiols into glutaric acid could provide a potential
means to deliver a dithiol binding moiety into one of the primary
cellular targets of mercury species, namely the epithelial cells lining
the renal proximal tubule. Therefore, we describe here an investiga-
tion of a series of 1,3-dithiols, namely rac- and meso-2,4-dimerca-
ptoglutaric acid (H4DMGA) and 2-carboxy-1,3-propanedithiol
(H3DMCP),2 as illustrated in Fig. 2, which are homologues of mercury
chelating agents that feature 1,2-dithiol moieties.
2.1. Molecular structures of 2,4-dimercaptoglutaric acid and 2-
carboxy-1,3-propanedithiol
2,4-Dimercaptoglutaric acid (H4DMGA) is structurally related to
2,3-dimercaptosuccinic acid (H4DMSA) by the formal insertion of a
methylene group. H4DMGA exists as both rac and meso isomers
and both forms were synthesized from 2,4-dibromoglutaric acid
via a modification of the literature methods [17], as illustrated in
Scheme 1. Specifically, rather than converting dimethyl-2,4-
bis(acetylthio)glutarate to 1,2-dithiolane-3,5-dicarboxylic acid by
a sequence involving treatment with (i) KOH(aq), (ii) NH3(aq),
(iii) I2 and KI(aq), and (iv) HCl(aq), the conversion was achieved
by refluxing with KHCO3(aq) in air, followed by treatment with
HCl(aq). The 1,2-dithiolane-3,5-dicarboxylic acids are separated
by crystallization into the rac and meso diastereomers, from which
the respective isomers of 2,4-dimercaptoglutaric acid are obtained
by reduction with zinc in NaHCO3(aq) followed by acidification.
The molecular structures of both rac- and meso-H4DMGA have
been determined by X-ray diffraction, as illustrated in Figs. 3 and
4. In each case, intermolecular O–Hꢀ ꢀ ꢀO hydrogen bonding be-
tween pairs of carboxylic acid groups results in a polymeric array
in the solid state (Figs. 5 and 6), with Oꢀ ꢀ ꢀO distances of 2.647(2)
and 2.610(2) Å for the rac isomer, and 2.706(2) and 2.611(2) Å
for the meso isomer.
2. Results and discussion
In view of the well-known affinity of mercury for sulfur, as illus-
trated by the fact that mercury forms compounds with a diverse
array of sulfur donor ligands (including thiolate [10–12], thioether
[13] and thione [14,15] derivatives), much attention has been di-
rected towards the use of sulfur-containing ligands in chelation
therapy [1–3]. For example, a common feature of the chelating
agents illustrated in Fig. 1 is the presence of a 1,2-dithiol moiety.
Interestingly, despite the fact that these compounds are referred
to as ‘‘chelating’’ agents, the modes by which these ligands bind
to mercury have not been ascertained by X-ray diffraction,
although several mercury derivatives of H3BAL, H3DMPS, and
H4DMSA have been investigated in solution [16]. In fact, mercury
LIII-edge X-ray absorption spectroscopy has been used to provide
Interestingly, the structures of rac- and meso-H4DMGA are
quite distinct from those that have been reported for rac- and
meso-H4DMSA [18,19]. For example, rather than adopt a structure
that features two hydrogen bonds between pairs of carboxylic acid
groups, the two oxygen atoms of each carboxylic acid group of
rac-H4DMSA hydrogen bond to two different carboxylic acid groups [19].
2
The abbreviation H3DMCP refers to the alternative name 1,3-dimercapto-2-
carboxypropane. 2-Carboxy-1,3-propanedithiol is also referred to as 3-mercapto-2-
(mercaptomethyl)propanoic acid and dihydroasparagusic acid.

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W. Sattler et al. / Polyhedron 64 (2013) 268–279
Scheme 1. Synthesis of rac( )- and meso-2,4-dimercaptoglutaric acid.
Fig. 4. Molecular structure of rac-H4DMGA.
In the case of meso-H4DMSA, only the structure of the 1:2 N,N-
dimethylformamide (DMF) adduct has been reported [18]. In con-
trast to the aforementioned structures, meso-H4DMSAꢀ2DMF does
not possess hydrogen bonding interactions between pairs of car-
boxylic acid groups. Rather, each carboxylic acid group hydrogen
bonds selectively to one DMF molecule, thereby resulting in a dis-
Fig. 3. Molecular structure of meso-H4DMGA.
As
a result, rather than forming a hydrogen bonded tape,
rac-H4DMSA forms a hydrogen bonded sheet (Fig. 7).

W. Sattler et al. / Polyhedron 64 (2013) 268–279
271
Fig. 5. A portion of the polymeric hydrogen bonded structure of meso-H4DMGA. Hydrogen bonding interactions are represented with hollow bonds.
Fig. 6. A portion of the polymeric hydrogen bonded structure of rac-H4DMGA. Hydrogen bonding interactions are represented with hollow bonds.
Fig. 7. Hydrogen bonded sheet-like structure of rac-H4DMSA (coordinates taken from Ref. [19]). Hydrogen bonding interactions are represented with hollow bonds.
crete [DMF–H4DMSA–DMF] unit, as illustrated in Fig. 8 [20]. Each
[DMF–H4DMSA–DMF] moiety is, nevertheless, linked to two others
via S–Hꢀ ꢀ ꢀO interactions [d(S–Hꢀ ꢀ ꢀO) = 2.48 Å; d(Sꢀ ꢀ ꢀO) = 3.52 Å]3
[18,21] to form an extended array; such S–Hꢀ ꢀ ꢀO interactions are,
however, weaker than O–Hꢀ ꢀ ꢀO interactions [22].
have similar S–Cꢀ ꢀ ꢀC–S torsion angles of approximately 120°, with a
range of 116.2–126.0° (Table 1 and Fig. 10). Both the values and the
narrow range of the torsion angles of these 1,3-dithiols provide a
marked contrast with those of the 1,2-dithiols, rac- and
meso-H4DMSA, which exhibit torsion angles of 66.2° and 180°,
respectively.
In addition to the above dicarboxylic acid derivatives, we have
also determined the molecular structure of a 1,3-propanedithiol
that features only a single carboxylic acid group, namely 2-car-
boxy-1,3-propanedithiol (H3DMCP) [23], which is a homologue of
the chelating agent 2,3-dimercaptopropionic acid (H3DMPA) [24].
However, in view of the fact that H3DMCP contains only one car-
boxylic acid group, the compound exists as a centrosymmetric
hydrogen bonded dimer (Fig. 9)4 rather than as a polymeric array
of the type observed for rac- and meso-H4DMGA (Fig. 5 and Fig. 6).
Nevertheless, despite the fact that rac-H4DMGA, meso-H4DMGA
and H3DMCP possess different extended arrays, all three molecules
2.2. Influence of 1,2- versus 1,3-dithiolate substitution on S–Hg–S
bond angles
In order to assess the impact of the spacer length on coordination
of the above molecules to mercury, the molecular structures of a ser-
ies of j
2-S,S derivatives were evaluated by density functional theory
calculations (Figs. 11 and 12).5 As expected for an increased spacer
length [25], the S–Hg–S bond angles for the 1,3-derivatives are larger
than those for the 1,2-derivatives, in various protonation states
(Tables 2 and 3). The bond angles for the 1,3-derivatives are, however,
3
For comparison, the average Sꢀ ꢀ ꢀO distance for structurally characterized
5
j
2-S,O and
j
2-O,O coordination modes were also considered but, in each case
2-S,S
compounds listed in the Cambridge Structural Database (Ref. [22]) is 3.208 Å, with
a range of 2.88–3.32 Å.
examined, the structure with the lowest energy corresponded to that with a
j
4
The hydrogen bonded dimers are only weakly associated with other molecules via
coordination mode. Such observations are in accord with the so-called oxophobicity
S–Hꢀ ꢀ ꢀO interactions, with d(Sꢀ ꢀ ꢀO) = 3.78 Å.
of mercury. See Ref. [13g].

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W. Sattler et al. / Polyhedron 64 (2013) 268–279
Table 1
Torsion angles and Sꢀ ꢀ ꢀS distances for selected dithiol compounds.
Compound
S—Cꢀ ꢀ ꢀC—S
Sꢀ ꢀ ꢀS distance (Å)
Refs.
torsion angle (°)
meso-H4DMGA
rac-H4DMGA
H3DMCP
meso-H4DMSA(DMF)2
rac-H4DMSA
119.6
116.2
126.0
180.0
66.2
4.94
4.30
4.97
4.44
3.44
this work
this work
this work
[18]
[19]
(Q = charge) were investigated computationally to evaluate the feasi-
bility of coordinating Clꢁ to the aforementioned LHg species.
Geometry optimization of the chloride adducts [LHgCl]Q results
in structures with approximately trigonal planar geometries, as
illustrated in Fig. 13 (selected bond lengths and angles are listed in
Table 4). In this regard, well-defined, three-coordinate anionic mer-
cury thiolate compounds are precedented [11,12,28], with the first
structurally characterized mononuclear example, namely
[Hg(SPh)3]ꢁ, having been reported by Christou [11a]. Furthermore,
the [HgS3] coordination environment is present in the MerR metal-
loregulatory protein [29]. In addition to tris(thiolate) compounds,
three-coordinate anionic mercury thiolate compounds in which ha-
lides serve as co-ligands, as illustrated by [(PhS)2HgBr]ꢁ, are also
known [30,31]. Examination of the Cambridge Structural Database
[21] indicates that the coordination geometries of planar, three-
coordinate mercury compounds vary from T–shaped to Y–shaped,
with a variety of bond angles. For example, the S–Hg–S bond angles
in three-coordinate compounds range from at least 88.2° [32,33] to
176.9° [34]. Thus, the S–Hg–S angles computed for [LHgCl]Q are in
accord with literature precedent. Of particular note, the S–Hg–S an-
gles in [Hg(meso–H2DMSA)Cl]ꢁ (90.6°) and [Hg(rac–H2DMSA)Cl]ꢁ
(89.3°) are very similar to the values for the three-coordinate centers
in the 1,2-benzenedithiolate complex, [Hg2(C6H4S2)3]2ꢁ (88.9° and
90.3°), which possesses 5-membered chelate rings [32,35,36]. Fur-
thermore, the Hg–S and Hg–Cl bond lengths in the geometry opti-
mized compounds (Table 4) are comparable to the respective
mean values of 2.547 and 2.528 Å for structurally characterized
compounds listed in the Cambridge Structural Database [21].
Fig. 8. Hydrogen bonding in the 1:2 adduct of meso-H4DMSA and DMF. O–Hꢀ ꢀ ꢀO
hydrogen bonds link together the meso-H4DMSA and DMF, while longer S–Hꢀ ꢀ ꢀO
interactions create an extended array (coordinates taken from Ref. [18]). Hydrogen
bonding interactions are represented with hollow bonds.
2.3. Chelation studies
The ability of rac-H4DMGA and H3DMCP to extract mercuric ions
from biological tissues was investigated by performing in vivo stud-
ies in rats. Interestingly, following injection of HgCl2, treatment of
rats with rac-H4DMGA and H3DMCPresulted in a reduction in the re-
nal burden of mercury (Fig. 14). However, neither compound was as
effective as either H3DMPS or H4DMSA (Fig. 14), which exhibited re-
sults similar to those observed in previous studies [37]. The lower
efficacy of rac-H4DMGA and H3DMCP may be due to their inability
to enter renal tubular cells via carriers in the basolateral plasma
membrane or to the inability of export proteins on the apical plasma
membrane of tubular epithelial cells (e.g. multidrug resistance asso-
ciated protein, MRP2) to transport the mercury coordination com-
pounds out of the cells. Another possible explanation for the lower
efficacy of rac-H4DMGA and H3DMCP is that these molecules are
more susceptible towards oxidation to their 1,2-dithiolanes
[17a,23] than are H3DMPS and H4DMSA.
H3DMCP was also able to reduce the burden of mercury in the
liver, although rac-H4DMGA was ineffective (Fig. 15A). As ex-
pected, treatment of rats with H4DMSA or H3DMPS resulted in a
reduction of the hepatic burden of mercury (Fig. 15A). The hema-
tologic burden of mercury was unchanged by H3DMCP and actually
increased following treatment with rac-H4DMGA, suggesting that
mercuric ions may be mobilized by the latter compound and se-
creted into blood (Fig. 15B). The distribution between plasma
and cellular components of blood was altered significantly follow-
Fig. 9. Molecular structure of 2-carboxy-1,3-propanedithiol (hydrogen bonded
dimer shown). Hydrogen bonding interactions are represented with hollow bonds.
far from linear, such that the molecules studied in silico are unlikely to
correspond to stable species that would exist in solution [7]. These
coordination geometries, therefore, suggest that the mercury centers
in such species would be predisposed towards binding additional li-
gands [26]. In particular, the possibility of binding chloride is of spe-
cific relevance because the high concentration of chloride in blood
plasma has prompted the suggestion that it is a ligand for Hg2+ in
the body [27]. Therefore, the structures of chloride adducts [LHgCl]Q

W. Sattler et al. / Polyhedron 64 (2013) 268–279
273
Fig. 10. Views of the S–Cꢀ ꢀ ꢀC–S torsion angles of meso-H4DMGA, rac-H4DMGA and H3DMCP.
Fig. 12. Geometry optimized structures of L0HgQ (L0 = meso-DMGA4ꢁ, rac-DMGA4ꢁ
,
DMCP3ꢁ, meso-DMSA4ꢁ and rac-DMSA4ꢁ).
Fig. 11. Geometry optimized structures of LHg (L = meso-H2DMGA2ꢁ
DMGA2ꢁ, HDMCP2ꢁ, meso-H2DMSA2ꢁ and rac-H2DMSA2ꢁ).
, rac-H2-
Table 2
Selected bond lengths and angles for geometry optimized structures of LHg (L = meso-
H2DMGA2ꢁ, rac-H2DMGA2ꢁ, HDMCP2ꢁ, meso-H2DMSA2ꢁ and rac-H2DMSA2ꢁ).
Compound
d(Hg–S1)
(Å)
d(Hg–S2)
(Å)
d(Hgꢀ ꢀ ꢀO)a
(Å)
4.519
2.882
2.788
2.764
5.209
S1–Hg–S2
(°)
117.2
119.4
123.1
96.2
ing treatment with either H3DMCP or rac-H4DMGA. Under control
conditions using saline, mercury was distributed evenly between
plasma and cells. Following treatment with H3DMCP, the distribu-
tion of mercuric ions in blood shifted so that nearly 80% of the
hematologic burden was associated with plasma. Interestingly,
the hematologic distribution of mercury following treatment with
rac-H4DMGA was similar to that of H3DMPS with approximately
35% in cells and 65% in plasma. The significance of these shifts in
distribution is currently unknown. Treatment with H4DMSA did
not alter the distribution of mercuric ions in blood.
The amount of mercury in urine (Fig. 16A) was inversely related
to the renal burden of mercury. For example, the saline-injected
rats had the greatest renal burden of mercury, while the urine from
this group of animals contained the least amount of mercury. Sim-
ilar relationships were observed for all other treatment groups. The
urinary content of mercury was significantly greater in each group
Hg(meso-H2DMGA)
Hg(rac-H2DMGA)
Hg(HDMCP)
Hg(meso-H2DMSA)
Hg(rac-H2DMSA)
2.521
2.512
2.510
2.556
2.544
2.524
2.526
2.511
2.580
2.544
97.4
a
Shortest Hgꢀ ꢀ ꢀO distance.
of rats treated with a chelator than in those of the saline group.
Treatment of rats with H3DMPS resulted in the greatest excretion
of mercury, with an efficacy similar to that induced by treatment
with H4DMSA. The urinary excretion of mercury following treat-
ment of rats with H3DMCP or rac-H4DMGA was less than half of
that for rats treated with H3DMPS or H4DMSA, and only treatment
with H3DMPS resulted in an increase in the content of mercury in

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W. Sattler et al. / Polyhedron 64 (2013) 268–279
Table 3
pairs of carboxylic acid groups. This hydrogen bonding pattern re-
sults in a dimeric structure for H3DMCP and a polymeric tape-like
structure for rac- and meso-H4DMGA. In this regard, the tape-like
hydrogen bonded array of rac- and meso-H4DMGA stands in
marked contrast to the sheet-like structure of the 1,2-dithiol coun-
terpart, meso-H4DMSA, which results from the two oxygen atoms
of each carboxylic acid group hydrogen bonding to two different
carboxylic acid groups. Density functional theory calculations on
Selected bond lengths and angles for geometry optimized structures of L0HgQ
(L0 = meso-DMGA4ꢁ, rac-DMGA4ꢁ, DMCP3ꢁ, meso-DMSA4ꢁ and rac-DMSA4ꢁ).
Compound
d(Hg–S1) (Å) d(Hg–S2) (Å) d(Hgꢀ ꢀ ꢀO)a (Å) S1–Hg–S2 (°)
[Hg(meso-DMGA)]2ꢁ 2.544
[Hg(rac-DMGA)]2ꢁ 2.532
2.616
2.590
2.551
2.658
2.639
2.413
2.434
2.360
2.434
2.444
109.2
112.8
114.3
96.8
[Hg(DMCP)]ꢁ
2.551
[Hg(meso-DMSA)]2ꢁ 2.600
[Hg(rac-DMSA)]2ꢁ
2.600
90.5
a series of mercury species that feature j
2-S2 coordination of these
a
Shortest Hgꢀ ꢀ ꢀO distance.
ligands indicate that 1,3-dithiolate coordination to mercury is
accompanied by larger S–Hg–S bond angles than is 1,2-dithiolate
coordination. However, the angles in the 1,3-dithiolate species
feces (Fig. 16B). This pattern of elimination, in which the amount of
mercury in feces and urine is greatest for rats treated with
H3DMPS, loosely reflects the measured content of mercury in hepa-
tocytes (Fig. 15A).
It should be noted that when a high dose (100 mg per kg body
weight delivered at 50 mg mLꢁ1) of H3DMCP and rac-H4DMGA was
used, rats suffered from significant adverse effects including sei-
zures and aggressive behavior. Reducing the dose of H3DMCP and
rac-H4DMGA to 50 mg per kg body weight (delivered at
25 mg mLꢁ1), significantly reduced, but did not eliminate, un-
wanted side effects. The mechanisms underlying these effects are
currently unknown.
are far from linear, such that
j
2-S2 coordination of these ligands
is expected to be associated with mercury coordination numbers
of greater than two. In vivo studies demonstrate that both
rac-H4DMGA and H3DMCP are capable of reducing the renal
burden of mercury in rats that have been injected with HgCl2,
although the compounds are not as effective as either of the
classical therapeutic agents, H3DMPS and meso-H4DMSA.
4. Experimental section
4.1. General considerations
All manipulations were performed in air unless stated other-
wise. Solvents were purified and degassed by standard procedures.
1H NMR spectra were measured on Bruker 300 DRX, Bruker 400
DRX, and Bruker Avance 500 DMX spectrometers. 1H NMR chemi-
cal shifts are reported in ppm relative to SiMe4 (d = 0) and were ref-
erenced internally with respect to the protio solvent impurity
3. Conclusions
In summary, the 1,3-dithiol-carboxylic acid compounds,
rac-H4DMGA, meso-H4DMGA and H3DMCP, all exhibit two centro-
symmetric intermolecular hydrogen bonding interactions between
Fig. 13. Geometry optimized structures of [LHgCl]Q (L = meso-H2DMGA2ꢁ, rac-H2DMGA2ꢁ, HDMCP2ꢁ, meso-H2DMSA2ꢁ and rac-H2DMSA2ꢁ).
Table 4
Selected bond lengths and angles for geometry optimized structures of [LHgCl]Q (L = meso-H2DMGA2ꢁ, rac-H2DMGA2ꢁ, HDMCP2ꢁ, meso-H2DMSA2ꢁ and rac-H2DMSA2ꢁ).
Compound
d(Hg–S1) (Å)
d(Hg–S2) (Å)
d(Hg–Cl) (Å)
S1–Hg–S2 (°)
S1–Hg–Cl (°)
S2–Hg–Cl (°)
[Hg(meso-H2DMGA)Cl]ꢁ
[Hg(rac-H2DMGA)Cl]ꢁ
[Hg(HDMCP)Cl]ꢁ
2.635
2.629
2.592
2.608
2.599
2.640
2.638
2.630
2.617
2.639
2.548
2.543
2.561
2.539
2.529
96.3
95.8
105.0
90.6
89.3
132.3
132.8
131.6
134.3
139.5
131.4
131.3
123.4
135.1
131.1
[Hg(meso-H2DMSA)Cl]ꢁ
[Hg(rac-H2DMSA)Cl]ꢁ

W. Sattler et al. / Polyhedron 64 (2013) 268–279
275
Fig. 14. Renal burden of mercury in rats exposed to HgCl2 (0.5 lmol per kg body weight, delivered as a 0.25 mM solution) and treated subsequently with saline (2 mL per kg)
or chelator (50 mg per kg body weight, delivered as a 25 mg mLꢁ1 solution). An asterisk (⁄) indicates a value that is significantly different from the mean value for saline-
injected rats (p < 0.05).
Fig. 15. Hepatic (A) and hematologic (B) burden of mercury in rats exposed to HgCl2 (0.5 lmol per kg body weight, delivered as a 0.25 mM solution) and treated subsequently
with saline (2 mL per kg) or chelator (50 mg per kg body weight, delivered as a 25 mg mLꢁ1 solution). An asterisk (⁄) indicates a value that is significantly different from the
mean value for saline-injected rats (p < 0.05).

276
W. Sattler et al. / Polyhedron 64 (2013) 268–279
Fig. 16. Amount of mercury in urine (A) and feces (B) of rats exposed to HgCl2 (0.5 lmol per kg body weight, delivered as a 0.25 mM solution) and treated subsequently with
saline (2 mL per kg body weight) or chelator (50 mg per kg body weight, delivered as a 25 mg mLꢁ1 solution). An asterisk (⁄) indicates a value that is significantly different
from the mean value for saline-injected rats (p < 0.05).
(d 2.50 for d6-acetone and 4.79 for D2O) [38]. Coupling constants
are given in hertz. All reagents were obtained from Aldrich, with
the exception of potassium thioacetate, which was obtained from
Acros Organics, and formic acid and hydrobromic acid, which were
obtained from Fluka. 2,4-Dibromoglutaric acid [39] and 2-carboxy-
1,3-propanedithiol [23a] were prepared by the literature methods,
and crystals of the latter suitable for X-ray diffraction were ob-
tained by cooling of a hexanes solution.
taric acid (mixture of diastereomers, 10.3 g, 35.53 mmol) in
methanol (ca. 70 mL) was treated with HCl (1.0 M in Et2O, 10.0 mL,
10.0 mmol) and the mixture was stirred for 2 days at room temper-
ature. After this period, the volatile components were removed in
vacuo and the residue obtained was dissolved in Et2O and washed
witha saturatedsolutionof NaHCO3(aq). Theorganic layer was dried
with MgSO4, after which the mixture was filtered and the solvent re-
moved in vacuo to give dimethyl 2,4-dibromoglutarate (9.77 g, 87%,
rac:meso ratio 1.7:1). Rac isomer 1H NMR (d6-acetone): d 2.72 [m, 2H,
CH2{(CHBr)(CO2CH3)}2], 3.78 [s, 6H, CH2{(CHBr)(CO2CH3)}2], 4.59 [t,
3JH–H = 7 Hz, 2H, CH2{(CHBr)(CO2CH3)}2]. Meso isomer 1H NMR
(d6-acetone): d 2.60 [m, 1H, CH2{(CHBr)(CO2CH3)}2], 2.95 [m, 1H,
CH2{(CHBr)(CO2CH3)}2], 3.78 [s, 6H, CH2{(CHBr)(CO2CH3)}2], 4.54
[t, 3JH–H = 7 Hz, 2H, CH2{(CHBr)(CO2CH3)}2].
4.2. X-ray structure determinations
X-ray diffraction data were collected on a Bruker Apex II diffrac-
tometer. Crystal data, data collection and refinement parameters
are summarized in Table 5. The structures were solved using direct
methods and standard difference map techniques, and were re-
fined by full-matrix least-squares procedures on F2 with SHELXTL
(Version 6.1) [40].
4.3.2. Dimethyl-2,4-bis(acetylthio)glutarate
Dimethyl-2,4-bis(acetylthio)glutarate was prepared by a modi-
fication of the literature method [17]. A solution of potassium thio-
acetate (11.85 g, 103.8 mmol) in methanol (ca. 50 mL) was added
slowly to a solution of dimethyl-2,4-dibromoglutarate (15.28 g,
48.0 mmol) in methanol (ca. 50 mL) at 0 °C, thereby resulting in a
color change from red to yellow, accompanied by precipitation of
4.3. Synthesis of rac- and meso-2,4-dimercaptoglutaric acids
4.3.1. Dimethyl-2,4-dibromoglutarate
Dimethyl-2,4-dibromoglutarate [39] was synthesized by esteri-
fication of 2,4-dibromoglutaric acid. A solution of 2,4-dibromoglu-

W. Sattler et al. / Polyhedron 64 (2013) 268–279
277
Table 5
ca. 95%, meso ca. 90%) was sufficient for the synthesis of the dithiol
compounds, which could be purified via crystallization from
Crystal, intensity collection and refinement data.
Et2O (vide infra). Rac isomer 1H NMR (d6-acetone):
d 2.74
meso-H4DMGA
rac-H4DMGA
H3DMCP
3
3
[t, JH–H = 6 Hz, 2H, CH2{(CHS–)(CO2H)}2], 4.55 [t, JH–H = 6 Hz, 2H,
Lattice
Formula
Formula weight
Space group
Unit cell dimensions
a (Å)
triclinic
C5H8O4S2
196.23
monoclinic
C5H8O4S2
196.23
monoclinic
C4H8O2S2
152.22
CH2{(CHS–)(CO2H)}2]. Meso isomer 1H NMR (d6-acetone): d 2.83
3
3
[t, JH–H = 7 Hz, 2H, CH2{(CHS–)(CO2H)}2], 4.44 [t, JH–H = 7 Hz, 2H,
CH2{(CHS–)(CO2H)}2].
ꢀ
P21/n
P21/n
P1
6.8623(5)
7.8506(5)
8.5151(10)
97.5080(10)
91.8010(10)
114.5930(10)
411.67(6)
2
125(2)
0.71073
1.583
0.610
30
7168
2807
110
0.0400
0.1031
0.0510
0.1102
1.039
6.8561(8)
12.4153(15)
10.0971(12)
90
106.796(2)
90
822.81(17)
4
125(2)
0.71073
1.584
0.611
32.43
13928
2867
110
9.719(5)
6.930(3)
10.475(5)
90
110.663(7)
90
660.1(6)
4
125(2)
0.71073
1.532
4.3.4. Rac-2,4-dimercaptoglutaric acid
b (Å)
c (Å)
Rac-2,4-dimercaptoglutaric acid has been previously reported
[17], but an alternative route was used here. A suspension of rac-
1,2-dithiolane-3,5-dicarboxylic acid (555 mg, 2.86 mmol) in water
(ca. 10 mL) was treated with NaHCO3 (264 mg, 3.14 mmol), there-
by resulting in evolution of CO2. Zn powder (1.00 g, 15.3 mmol)
was added, and the mixture was stirred for 30 min. After this per-
iod, HCl(aq) (1.0 M, 32.0 mL, 32.0 mmol) was added and the mix-
ture was filtered into a flask containing HCl(aq) (1.0 M, 8.0 mL,
8.0 mmol) to prevent regeneration of rac-1,2-dithiolane-3,5-dicar-
boxylic acid. The solution was extracted with ethyl acetate and the
organic layer was dried with Na2SO4, after which the volatile com-
ponents were removed in vacuo to give colorless rac-2,4-dimerca-
ptoglutaric acid that was recrystallized from Et2O (400 mg, 71%;
a
(°)
b (°)
c
(°)
V (Å3)
Z
T (K)
k (Å)
q
l
(g cmꢁ3
(Mo K
)
a
) (mmꢁ1
)
0.715
32.25
8634
2258
hmax (°)
No. of data collected
No. of data
No. of parameters
R1 [I > 2
wR2 [I > 2
R1 [all data]
85
r
(I)]
r
0.0482
0.1343
0.0687
0.1491
1.058
0.0457
0.1085
0.0845
0.1305
1.023
(I)]
3
literature yield 58% [17]). 1H NMR d6-acetone: d 2.28 [t, JH–H
3
= 8 Hz, 2H, CH2{(CHSH)(CO2H)}2], 3.60 [t, JH–H = 8 Hz, 2H,
wR2 [all data]
Goodness-of-fit (GOF)on F2
CH2{(CHSH)(CO2H)}2].
4.3.5. Meso-2,4-dimercaptoglutaric acid
KBr. After the addition was complete, the reaction was allowed to
warm to room temperature, and the mixture was stirred overnight.
The mixture was filtered and the volatile components were re-
moved from the filtrate in vacuo. The residue obtained was ex-
tracted into Et2O and washed with H2O. The organic layer was
isolated and dried with MgSO4, after which the volatile
components were removed in vacuo to give dimethyl 2,4-bis(acet-
ylthio)glutarate as a dark yellow oil (12.58 g, 85.0%) as a mixture of
isomers of sufficient purity to be used directly for the synthesis of
the 1,2-dithiolane-3,5-dicarboxylic acids (see below). 1H NMR
Meso-2,4-dimercaptoglutaric acid has been previously reported
[17], but an alternative route was used here. A suspension of meso-
1,2-dithiolane-3,5-dicarboxylic acid (525 mg, 2.70 mmol, ca. 90%
meso) in water (ca. 10 mL) was treated with NaHCO3 (250 mg,
2.98 mmol), thereby resulting in evolution of CO2. Zn powder
(900 mg, 13.76 mmol) was added, and the mixture was stirred
for 2 h. After this period, HCl(aq) (1.0 M, 32.0 mL, 32.0 mmol)
was added and the mixture was filtered into a flask containing
HCl(aq) (1.0 M, 8.0 mL, 8.0 mmol) to prevent regeneration of
meso-1,2-dithiolane-3,5-dicarboxylic acid. The solution was ex-
tracted with Et2O and the organic layer was dried with Na2SO4,
after which the volatile components were removed in vacuo to give
colorless crystals of meso-2,4-dimercaptoglutaric acid that were
washed with cold Et2O (150 mg, 28%; literature 8% [17]), together
with a small amount of the rac isomer (ca. 5%). 1H NMR (D2O): d
2.17 [m, 1H, CH2{(CHSH)(CO2H)}2], 2.56 [m, 1H, CH2{(CHSH)(CO2
(d6-acetone): Meso-isomer:
d
2.05 [m, 1H, CH2{(CHSAc)
(CO2CH3)}2], 2.39 [s, 6H, CH2{(CHSAc)(CO2CH3)}2], 2.66 [m, 1H,
CH2{(CHSAc)(CO2CH3)}2], 3.69 (overlap with rac-isomer) [s, 6H,
CH2{(CHSAc)(CO2CH3)}2], 4.28 (overlap with rac-isomer) [m, 2H,
CH2{(CHSAc)(CO2CH3)}2]; rac-isomer: d 2.35 [s, 6H, CH2{(CHSAc)
(CO2CH3)}2], 2.83 [s, 2H, CH2{(CHSAc)(CO2CH3)}2], 3.69 (overlap
with meso-isomer) [s, 6H, CH2{(CHSAc)(CO2CH3)}2], 4.28 (overlap
with meso-isomer) [m, 2H, CH2{(CHSAc)(CO2CH3)}2].
3
H)}2], 3.69 [t, JH–H = 7 Hz, 2H, CH2{(CHSH)(CO2H)}2].
4.3.6. Chelation studies
4.3.3. Rac- and meso-1,2-dithiolane-3,5-dicarboxylic acids
Male Wistar rats, weighing 150–175 g, were obtained from Har-
lan (Indianapolis, IN). Rats were injected intravenously as de-
scribed previously [37]. Briefly, rats were anesthetized using
isoflurane and a small incision was made to expose the femoral
vein and artery. A non-toxic dose of HgCl2 containing radioactive
Rac- and meso-1,2-dithiolane-3,5-dicarboxylic acids have been
previously reported [17], but an alternative route was used here.
Dimethyl-2,4-bis(acetylthio)glutarate (3.05 g, 9.89 mmol) was
added to a solution of KHCO3 (10.0 g, 99.90 mmol) in H2O (ca.
100 mL) and the biphasic mixture was refluxed for 6 hours in air,
thereby resulting in the formation of a single yellow aqueous
phase. The solution was allowed to cool to room temperature
and then placed in an ice bath. HCl (1 M) was added to adjust
the pH to a value of 1 (caution: stench!) and the solution was
extracted into ethyl acetate. The extract was dried with MgSO4
and then concentrated in vacuo to give a mixture of rac- and
meso-1,2-dithiolane-3,5-dicarboxylic acids as a ca.1:1 ratio, to-
gether with other impurities. The solution was placed at ꢁ15 °C,
thereby depositing crystals of rac-1,2-dithiolane-3,5-dicarboxylic
acid (270 mg, 14%). The mother liquor contained both rac and meso
isomers, and repeated crystallizations deposited more rac-1,2-
dithiolane-3,5-dicarboxylic acid, thereby enriching the mother
liquor in meso-1,2-dithiolane-3,5-dicarboxylic acid. Although nei-
ther compound was obtained isomerically pure, the purity (rac
mercury ([203Hg]) in normal saline (0.5
l
mol in 2 mL, i.e.
0.25 mM) was administered into the vein at a dose of 2 mL per
kg body weight, corresponding to approximately 1 Ci per rat.
203Hg] was generated by irradiation of mercuric oxide at the Uni-
l
[
versity of Missouri Research Reactor (MURR) as described previ-
ously [41]. Twenty-four hours after injection with HgCl2, rats
were injected intraperitoneally with either saline or a dose of
H3DMPS, H4DMSA, rac-H4DMGA, or H3DMCP (see Figs. 14–16).
Animals were sacrificed 24 h later and blood and organs were
harvested for estimation of mercury content. Urine and feces were
collected after each 24 h period.
4.3.7. Data analyses
Data from animal experiments were analyzed with the
Kolmogorov–Smirnov test for normality and Levene’s test for

278
W. Sattler et al. / Polyhedron 64 (2013) 268–279
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