Diorganotin(IV) derivatives of dipeptides containing at least one essential amino acid residue: Synthesis, characteristic spectral data, cardiovascular, and anti-inflammatory activities

Article abstract of DOI:10.1081/SIM-200030161

New diphenyltin(IV) derivatives of the formula Ph₂SnL, where L is the dianion of glycyltryptophan (Gly-Trp), glycylphenylalanine (Gly-Phe), valylvaline (Val-Val), alanylvaline (Ala-Val), and leucylalanine (Leu-Ala), have been synthesized by the reaction of Ph₂SnCl₂ and the disodium salt of the respective dipeptides. The bonding and coordination behaviour in these derivatives are discussed on the basis of IR, multinuclear ¹H, ¹³C, and ¹¹⁹Sn NMR and ¹¹⁹Sn Moessbauer spectroscopic studies. These investigations suggest that all the dipeptides in Ph₂SnL act as dianionic tridentate ligands coordinating through the COO^-, NH₂, and N_peptide groups. The ¹¹⁹Sn Moessbauer studies, together with the NMR data, suggest a trigonal-bipyramidal geometry around tin in Ph₂SnL with the phenyl groups and N_peptide in the equatorial positions, whereas a carboxylic oxygen and the amino nitrogen atom occupy the axial positions. The anti-inflammatory and cardiovascular activities, and toxicity of all the synthesized diphenyltin(IV) derivatives of dipeptides and of n-dibutyltin(IV) derivatives of dipeptides (synthesized and characterized earlier) viz. Gly-Trp, Val-Val, Ala-Val, glycyltyrosine (Gly-Tyr), leucyltyrosine (Leu-Tyr), and leucylleucine (Leu-Leu) are discussed. The n-dibutyltin(IV) derivatives exhibit better cardiovascular and anti-inflammatory activities than the diphenyltin(IV) analogues.

Full text of DOI:10.1081/SIM-200030161

SYNTHESIS AND REACTIVITY IN INORGANIC AND METAL-ORGANIC CHEMISTRY
Vol. 34, No. 10, pp. 1689–1708, 2004
Diorganotin(IV) Derivatives of Dipeptides
Containing at Least One Essential Amino
Acid Residue: Synthesis, Characteristic
Spectral Data, Cardiovascular, and
Anti-inflammatory Activities
1
2
Mala Nath,1, Sandeep Pokharia, George Eng,
*
Xueqing Song,2 and Ashok Kumar3
1Department of Chemistry, Indian Institute of Technology Roorkee,
Roorkee, India
2Departments of Chemistry and Physics, University of the District
of Columbia, Washington, District of Columbia, USA
3Department of Pharmacology, L.L.R.M. Medical College, Meerut, India
ABSTRACT
New diphenyltin(IV) derivatives of the formula Ph2SnL, where L is the
dianion of glycyltryptophan (Gly-Trp), glycylphenylalanine (Gly-Phe),
valylvaline (Val-Val), alanylvaline (Ala-Val), and leucylalanine (Leu-
Ala), have been synthesized by the reaction of Ph2SnCl2 and the
disodium salt of the respective dipeptides. The bonding and coordination
behaviour in these derivatives are discussed on the basis of IR, multi-
119
nuclear 1H, 13C, and 119Sn NMR and
Sn Mossbauer spectroscopic
¨
*
Correspondence: Mala Nath, Department of Chemistry, Indian Institute of
Technology Roorkee, Roorkee 247 667, India; E-mail: malanfcy@iitr.ernet.in.
1689
DOI: 10.1081/SIM-200030161
0094-5714 (Print); 1532-2440 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Nath et al.
studies. These investigations suggest that all the dipeptides in Ph2SnL act
as dianionic tridentate ligands coordinating through the COO2, NH2, and
119
¨
Sn Mossbauer studies, together with the NMR
Npeptide groups. The
data, suggest a trigonal-bipyramidal geometry around tin in Ph2SnL
with the phenyl groups and Npeptide in the equatorial positions, whereas
a carboxylic oxygen and the amino nitrogen atom occupy the axial
positions. The anti-inflammatory and cardiovascular activities, and tox-
icity of all the synthesized diphenyltin(IV) derivatives of dipeptides
and of n-dibutyltin(IV) derivatives of dipeptides (synthesized and charac-
terized earlier) viz. Gly-Trp, Val-Val, Ala-Val, glycyltyrosine (Gly-Tyr),
leucyltyrosine (Leu-Tyr), and leucylleucine (Leu-Leu) are discussed. The
n-dibutyltin(IV) derivatives exhibit better cardiovascular and
anti-inflammatory activities than the diphenyltin(IV) analogues.
Key Words: Spectral studies; Diphenyltin(IV) derivative; Dipeptides;
Anti-inflammatory activity.
INTRODUCTION
Among the class of organotins, diorganotins have attracted a great deal
of attention not only because of their wide range of industrial and biological appli-
cations,[1] but more because of their place among non-platinum chemotherapeutic
compounds exhibiting anti-tumour activity.[2–14] Furthermore, the speciation
(possibilities of the formation of new organotin species during the course of
action in a biological fluid) of the organotins in the biological systems has
revealed that the diorganotins, R2SnX2, may act by inhibiting mitochondrial oxi-
dative phosphorylation;[3] this effect is brought about by inhibition of a-keto acid
oxidation, probably by combining with enzymes or coenzymes which possess
vicinal dithiol groups. Moreover, it has been proposed that the nature of the X
group in diorganotin(IV) complexes as well as the carbon chain length may
also affect their toxicity.[3] The spectrum of the biological activity of diorganotins
has grown as they also have been proposed as potential antifungal,[15,16] anti-
microbial,[15–19] anti-inflammatory,[19,20] and cardiovascular[20] agents.
Owing to the potential biological activity of diorganotins, recently,
considerable efforts have been directed at studies of the interaction of
diorganotins with amino acids[6,8,9,13,16,20,21] and peptides.[6,8,9,12,18,20–23] In
view of this, the study of the interaction of the diorganotin(IV) moiety with
dipeptides containing at least one essential amino acid residue is important.
Further, diorganotin(IV) derivatives of dipeptides[18,20] have been found to
exhibit anti-inflammatory activity, thus such complexes may hold the potential
to be placed in the class of non-steroidal anti-inflammatory drugs (NSAIDs).
Here, we report the synthesis and structural studies of some diphenyl-
tin(IV) derivatives of dipeptides containing at least one essential amino acid

Diorganotin(IV) Derivatives of Dipeptides
1691
residue, viz. glycyltryptophan (Gly-Trp), glycylphenylalanine (Gly-Phe),
valylvaline (Val-Val), alanylvaline (Ala-Val), and leucylalanine (Leu-Ala).
The cardiovascular and anti-inflammatory activities of all of the complexes
are reported herein. The cardiovascular and anti-inflammatory activities of
the n-dibutyltin(IV) derivatives of Gly-Trp, Val-Val, Ala-Val, glycyltyrosine
(Gly-Tyr), leucyltyrosine (Leu-Tyr), and leucylleucine (Leu-Leu), the syn-
thesis and structural characterization of which were reported earlier,[12]
have also been included and discussed.
RESULTS AND DISCUSSION
The disodium salt of the dipeptides is formed according to Eq. (1).
The reaction of Ph2SnCl2 with the salt at pH ꢀ7.0 in 1 : 1 molar ratio led to the
formation of the complexes according to Eq. (2). Details of the synthesis of
the corresponding n-dibutyltin(IV) derivatives of Gly-Trp (6), Val-Val (7),
Ala-Val (8), Gly-Tyr (9), Leu-Tyr (10), and Leu-Leu (11) have been described
previously.[12]
H2L þ 2NaOMe ꢀ! Na2L þ 2MeOH
Na2L þ Ph2SnCl2 ꢀ! Ph2SnL þ 2NaCl
ð1Þ
ð2Þ
where, H2L ¼

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Nath et al.
All of the diphenyltin(IV) derivatives are stable towards air and moisture,
soluble in DMSO, but sparingly soluble in methanol, chloroform, and other
organic solvents. The analytical data of these derivatives are presented
in Table 1. From the data, it can be inferred that the resulting derivatives crys-
tallized with 1 : 1 stoichiometry regardless of the proportions of the organotin
moiety and dipeptide used. The molar conductance of 1023 M solutions of
the derivatives in methanol lies in the low range, 0.0–0.1 V21 cm2 mol21
,
indicating their non-electrolytic nature.
Infrared Spectral Studies
Characteristic IR frequencies (cm21) and their assignments for the dipep-
tides and their diphenyltin(IV) derivatives are presented in Table 2. In all of the
studied diphenyltin(IV) derivatives of dipeptides, the n(NH2) frequency under-
goes a bathochromic shift of ꢀ50 cm21 (Table 2), indicating the coordination
of the amino group to the tin atom, as reported in earlier papers.[8,18,20,24]
Further, the n(NH2) absorption bands are broad, suggesting the presence of
inter- and/or intra-molecular hydrogen bonding.[8] The IR spectra indicate
that the nas(O–C55O) values shown by these amino-coordinated derivatives
are shifted substantially to higher frequencies (1636–1589 cm21), whereas
the corresponding ns(O–C55O) absorption frequencies (1404–1389 cm21
)
shift slightly either to higher or lower frequencies in comparison with the
non-coordinated dipeptides (Table 2). The magnitude of the (nas–ns)

Diorganotin(IV) Derivatives of Dipeptides
1693

1694
Nath et al.

Diorganotin(IV) Derivatives of Dipeptides
1695

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Nath et al.
(O–C55O) (Dn) separation is larger in the amino coordinated diphenyltin(IV)
derivatives (Dn ¼ 216 + 16 cm21) than in the dipeptides (168 + 18 cm21).
Furthermore, the observed values of Dn of all these derivatives are comparable
with those obtained for R2SnL (R ¼ n-Bu and Ph, H2L ¼ L-carnosine; R ¼ n-
Bu, H2L ¼ Gly-Tyr, Gly-Trp, Leu-Tyr, Leu-Leu, Val-Val, and Ala-Val),[12,20]
indicating that the carboxylate groups act as monodentate ligands. However,
the magnitude of Dn in Ph2Sn(Val-Val) is ,200 cm21, indicating that the car-
boxylate group is bidentate. Similar results have also been reported for
R2Sn(Gly-Gly) (R ¼ Me and n-Bu), n-Bu2Sn(Gly-Gly)H2O and Me2Sn(Gly-
Ala).[24] The appearance of a new band of medium intensity in the spectra of
all the derivatives in the region 545 + 27 cm21, which may be assigned to
n(Sn–O), further supports the bonding of the O–C55O group to the tin
atom.[8,15–20] In addition to the carboxylate oxygen and amino nitrogen, the
amide (or peptide) group may also coordinate to the organotin(IV) moiety.
An intense band of the n(C55O)amide at 1667 + 17 cm21 in the non-coordi-
nated dipeptides undergoes a bathochromic shift of ꢀ35 cm21 (Table 2) in
the IR spectra of the diphenyltin(IV) derivatives upon complexation. This is
probably due to the involvement of the peptide nitrogen (because of the depro-
tonation that has taken place) in bonding with tin, which lowers the bond order
of the C55O (amide) group due to resonance stabilization.[18,20] However, the
possibility of the involvement of the C55O (amide) group in the intermolecular
hydrogen bonding cannot be excluded. The appearance of a pair of bands of
medium intensity in the region 450 + 30 cm21, which may be assigned to
n(Sn–N) and n(Sn N), further confirms the coordination of the amino nitro-
gen as well as of the peptide nitrogen to the diphenyltin(IV) moiety.[8,12,18,20]
The nas(Sn–C) and ns(Sn–C) bands in all the studied diphenyltin(IV) deriva-
tives were observed at 280 + 8 and 227 + 5 cm21, respectively, which suggest
the existence of a bent C–Sn–C moiety in all of these derivatives.[15,18,20]
1H NMR Spectral Studies
The 1H NMR chemical shifts of all of the diphenyltin(IV) derivatives are
presented in Table 3. In the 1H NMR spectra of all studied derivatives
(Table 3), the CO(OH) resonance (d 12.0–13.0 ppm) is absent, which suggests
the replacement of the carboxylic proton by the organotin(IV) moiety.
The NH2 resonances observed either as a broad signal or in conjugation
with phenyl protons attached to tin are shifted downfield in the range of
d 7.26–7.31 ppm, suggesting the coordination of the amino group to the orga-
notin(IV) moiety. The resonances due to the magnetically non-equivalent
alkyl protons of the ligands and the tin-phenyl protons in the studied
derivatives have been identified and assigned.[12,15,18,20]

Diorganotin(IV) Derivatives of Dipeptides
1697
b
g
d
a

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Nath et al.
a
b
g
d

Diorganotin(IV) Derivatives of Dipeptides
13C NMR Spectral Studies
1699
The characteristic resonance peaks in the 13C NMR spectra of all the
diphenyltin(IV) derivatives are presented in Table 4. The assignment of the
13C resonances is in accordance with literature values for the amino
acids.[25] The resonances of the carboxylic carbon atom (i.e., C-1) in the
studied derivatives are deshielded indicating the coordination of the dipeptides
through the carboxylic oxygen to the organotin(IV) moiety. The observed
downfield shifts of the magnetically non-equivalent alkyl carbons of the
dipeptides are due to: (i) the coordination of COO2, Namino, and Np2eptide to
the diphenyltin(IV) moiety, (ii) the resonances in the –CONH– group,
and (iii) inter-/intra-molecular hydrogen bonding. Further, in compounds
Ph2Sn(Val-Val) and Ph2Sn(Ala-Val), doublets of some signals have been
observed, which may be due to the presence of diastereoisomers.
119Sn NMR Spectral Studies
119Sn chemical shifts increase markedly with increase in coordina-
tion number, ca. d 250 to 2100 ppm for four-coordinate tin; d 2200 to
2300 ppm for five-coordinate tin; d . 330 ppm for six-coordinate dialkyltin
compounds.[26] Tin shifts are normally higher for aryl compared with alkyl
substituents.[26] The 117Sn and 119Sn chemical shifts of Ph2Sn(Ala-Val) are
observed at d 2175.7 ppm (CD3OD) and d 2259.2 ppm (CDCl3), respec-
tively, which are characteristic of five-coordinate tin in the diphenyltin(IV)
derivatives.[26]
119
¨
Sn Mossbauer data (80 K) of the diphenyltin(IV) derivatives of
Table 5.
dipeptides.a
Q.S.
(mm sec21
I.S.
(mm sec21
Complex no.b
)
)
r
t1 (L)
t2 (R)
(1)
(2)
(3)
(4)
(5)
1.54
1.51
1.64
1.46
1.56
0.72
0.70
0.69
0.69
0.67
2.14
2.16
2.38
2.12
2.33
1.20
1.39
1.24
1.40
1.42
2.08
2.00
2.00
1.88
1.65
aQ.S., quadrupole splitting; I.S., isomeric shift relative to BaSnO3 and tin foil (splitting:
2.52 mm sec21); t1 (L): half line-width left doublet component; t2 (R): half line-width
right doublet component.
bComplex no. as in Table 1.

1700
Nath et al.
119
¨
Sn Mossbauer Spectral Studies
The 119Sn Mossbauer spectral data are presented in Table 5. The Mossbauer
¨
¨
spectra of all of the Ph2Sn(IV) derivatives exhibit a doublet centered in the
region 0.67 2 0.72mm sec21. The presence of quadrupole splitting (Q.S.) in
the region 1.46–1.64mmsec21 shows that the electric field gradient around
the tin nucleus is produced by the inequalities in the tin-peptide s
bonds.[12,18,20] Isomeric shift (I.S.) and Q.S. values of the Ph2Sn(IV) deriva-
tives reported herein are slightly lower than those of other R2SnL derivatives
(R ¼ n-Bu and Ph, H2L ¼ L-carnosine; R ¼ n-Bu, H2L ¼ Gly-Tyr, Gly-Trp,
Leu-Tyr, Leu-Leu, Val-Val, and Ala-Val).[12,20] A distorted trigonal-
bipyramidal configuration of R2SnL had been reported, where the carbon
atoms of the organotin(IV) moiety and the peptide nitrogen are in an equatorial
position, and the amino nitrogen and carboxylic oxygen atoms are
axial.[8,12,18,20,24,27,28] Thus, the tin atom configuration shown in Fig. 1 can be
again proposed for the studied diphenyltin(IV) derivatives of dipeptides.
The slightly lower values of I.S. and Q.S. in all the diphenyltin(IV)
derivatives of dipeptides when compared with those of the n-dibutyltin(IV)
analogues,[12] may be due to the almost symmetrical distribution of charge
in the plane containing the O,N,N donor atoms, even though considerable
s-character in the Sn–Npeptide bond makes N2peptide similar to phenyl groups
in equatorial position of trigonal-bipyramidal geometry. This suggests that
considerable electron-withdrawal from an equatorial plane occurs, due to
Figure 1. Suggested structure of the diphenyltin(IV) derivatives of dipeptides.

Diorganotin(IV) Derivatives of Dipeptides
1701
the involvement of the axial groups in the hydrogen bonding with the neigh-
bouring molecules, thereby, resulting in an associated structure which is
consistent with the poor solubility of these complexes in common organic
¨
solvents. The Mossbauer data in Table 5 also indicate a pronounced line
intensity asymmetry (the Goldanskii-Karyagin effect), in all the studied
Ph2Sn(IV) derivatives, which reflects a lattice dynamic anisotropy in the
recoil-free fraction arising in the organotin(IV) derivatives possessing
intermolecular association.[29]
Biological Studies
Anti-inflammatory Activity
The anti-inflammatory activity data (% inhibition) of the diorganotin(IV)
derivatives of dipeptides are presented in Table 6. The activity of the
standard drug, phenylbutazone, is used for comparison. The results
obtained indicate the order of the anti-inflammatory activity of Ph2Sn(IV)
derivatives as: Ph2Sn(Gly-Phe) . Ph2Sn(Val-Val) . Ph2Sn(Gly-Trp) .
Ph2Sn(Ala-Val) . Ph2Sn(Leu-Ala), and that of n-Bu2Sn(IV) derivatives
as: n-Bu2Sn(Val-Val) . n-Bu2Sn(Leu-Leu) . n-Bu2Sn(Leu-Tyr) . n-Bu2Sn
(Gly-Trp) . n-Bu2Sn(Ala-Val) . n-Bu2Sn(Gly-Tyr). The data analysis of
the results obtained indicates that the anti-inflammatory activity is influenced
by the nature of the ligand environment of the metal. Further, among the
diorganotin(IV) derivatives studied, Ph2Sn(Gly-Phe) and n-Bu2Sn(Val-Val)
exhibited potent anti-inflammatory activity (% inhibition is 35.3 and 33.2,
respectively) comparable with that of phenylbutazone (% inhibition: 38.4).
On the basis of the structure–activity correlation of the studied diorgano-
tin(IV) derivatives, the following factors may be responsible for the transport
of the R2Sn(IV)2þ (R ¼ Ph or n-Bu) moiety across the cellular membrane
either as a single entity or as a dipeptide derivative as a whole, in order to
show any activity.
i. The presence of the substituents in the side chain at the methylene
carbon (adjacent to either O–C55O or NH2 group).
ii. The steric factor, and conformation which the peptidic anion
(attached to R2Sn(IV)2þ moiety) may adopt in the cellular fluid.
iii. The stability of Sn–O/N bonds.
Further, for a given dipeptide, the replacement of the phenyl group with a
n-butyl group, as in the n-dibutyltin(IV) derivatives, led to an increase in the

1702
Nath et al.

Diorganotin(IV) Derivatives of Dipeptides
1703
activity, which suggests that apart from the nature of the dipeptide, the nature
of the organic residue attached to tin may also affect the activity.
Toxicity Study (LD50)
The studied diorganotin(IV) derivatives of dipeptides were further evalu-
ated for their average LD50 (mg/kg) on albino mice (body weight 20–25 g) of
either sex. The results, as presented in Table 6, indicated that the diphenyl-
tin(IV) derivatives are more toxic than the n-dibutyltin(IV) derivatives,
which suggest that the latter have wider safety margins than the former.
Further, the toxicity of these derivatives is due to the R2Sn(IV)2þ (R ¼ Ph
or n-Bu) moiety, but their mode of action is non-selective. In the present
study, among the n-dibutyltin(IV) derivatives, n-Bu2Sn(Leu-Tyr) was
found to be least toxic (LD50 . 800 mg/kg), and n-Bu2Sn(Val-Val) and
n-Bu2Sn(Leu-Leu) to be moderately toxic (LD50 . 400 mg/kg), whereas
among the diphenyltin(IV) derivatives, Ph2Sn(Gly-Trp) is found to be the
least toxic (LD50 . 500 mg/kg) and Ph2Sn(Gly-Phe) and Ph2Sn(Leu-Ala)
to be the most toxic (LD50 . 200 mg/kg).
Cardiovascular Activity
The cardiovascular activity of the synthesized compounds was
determined on either adult dogs (body weight 10–20 kg) or cats (body
weight 3–4 kg) of either sex. The results are presented in Table 6. All of
the n-dibutyltin(IV) and diphenyltin(IV) derivatives [except Ph2Sn(Leu-
Ala)], exhibited mild and delayed hypotensive activity of varying degree
and duration without affecting the carotid occlusion and noradrenaline
response. These results suggest that these compounds may act as direct vaso-
dilators on the smooth muscles of blood vessels. Moreover, none of these
compounds has shown bradycardia and, hence, no change in the resting
heart rates. Furthermore, among the diphenyltin(IV) derivatives, Ph2Sn
(Val-Val) is found to be the most effective, whereas Ph2Sn(Gly-Trp),
Ph2Sn(Gly-Phe), and Ph2Sn(Ala-Val) have comparable, but lesser activity.
However, an immediate drop of 180 mmHg compared to control has been
observed in Ph2Sn(Leu-Ala). These observations indicate that the hypotensive
activity is influenced by the structural features of the side chain at the methyl-
ene carbon atom adjacent to either the O–C55O group and/or NH2 group in
the dipeptide molecule coordinated to the diorganotin(IV) moiety. In general,
the di-n-butyltin(IV) derivatives exhibited greater activity than the diphenyl-
tin(IV) analogues. Furthermore, among all the studied diorganotin(IV)
derivatives, n-Bu2Sn(Leu-Tyr) was found to be the most active and
n-Bu2Sn(Gly-Trp) to be the least.

1704
Nath et al.
An attempt was made to correlate the toxicity, anti-inflammatory activity,
and cardiovascular activity of the studied derivatives. The results suggest
that n-Bu2Sn(Leu-Tyr) can act as an effective anti-inflammatory agent
(30% inhibition) as it is least toxic (LD50 . 800 mg/kg), but at the same
time it exhibits potent hypotensive activity (drop of 50 mmHg compared to
control that lasted for 35 min), whereas n-Bu2Sn(Val-Val) has higher anti-
inflammatory activity (33.2% inhibition) and is less hypotensive (drop of
30 mmHg compared to control that lasted for 10 min), but its toxicity is
slightly higher (LD50 . 400 mg/kg). Further, n-Bu2Sn(Ala-Val) exhibits
good hypotensive activity (drop of 40 mmHg compared to control that
lasted for 20 min) and LD50 of . 500 mg/kg. In addition, the potency of
the diorganotin(IV) dipeptide derivatives can be modulated as demonstrated
by the greater activity of the n-dibutyltin(IV) derivatives compared with the
diphenyltin(IV) analogues. In addition, among all the studied derivatives,
Ph2Sn(Leu-Ala) can not be considered as an effective hypotensive agent as
it is very toxic (LD50 . 200 mg/kg) and caused an immediate drop in the
blood pressure (180 mmHg) compared to control.
EXPERIMENTAL
Materials
All reactions were carried out in an anhydrous nitrogen atmosphere.
Methanol (99.9%, s.d. fine chemicals) was dried by refluxing it with
Na metal and then distilled. Petroleum ether (b.p. 60–80 8C, E. Merck) was
dried over CaCl2 and distilled. di-n-Butyltin(IV) oxide (E. Merck) and dipep-
tides, viz. Gly-Trp, Gly-Phe, Val-Val, Ala-Val, Leu-Ala, Gly-Tyr, Leu-Tyr,
and Leu-Leu (Sigma) were used as received. The diphenyltin(IV) dichloride
was synthesized by the 1 : 1 molar reaction of tetraphenyltin and tin tetra-
chloride at 180 + 2 8C, followed by the extraction with petroleum ether
(b.p. 60–80 8C).
Synthesis of Diphenyltin(IV) Derivatives of Dipeptides
The dipeptide (3.0 mmol) was dissolved in the minimum amount
(ꢀ20 mL) of dry methanol. To this was added sodium methoxide, pre-
pared by dissolving sodium (0.1581 g, 6.6 mg atoms or 2.2 equiv.) in dry
methanol (ꢀ10 mL). The resulting mixture was refluxed with constant
stirring, giving a clear solution of Na2L within half an hour. Refluxing
was continued for another 4–5 hr with constant stirring. A hot methanolic

Diorganotin(IV) Derivatives of Dipeptides
1705
solution (ꢀ20 mL) of diphenyltin(IV) dichloride (1.032 g, 3.0 mmol) was
added to the solution of the disodium salt of the dipeptide giving a
clear solution. The resulting mixture was further refluxed with constant
stirring for 7–8 hr, and then was centrifuged and filtered in order to
remove sodium chloride. The excess solvent was removed under reduced
pressure. The semi-solid mass obtained was solidified by trituration with
petroleum ether (b.p.: 40–60 8C) and recrystallized from methanol–
hexane (1 : 3, v/v).
Physical Measurements
The melting points of the synthesized complexes were determined with
a Toshniwal capillary melting point apparatus and are uncorrected. Carbon,
hydrogen, and nitrogen analyses of the synthesized complexes were carried
out on a Heraeus Carlo Erba 1108, CHN analyzer, at the Central Drug Research
Institute (CDRI), Lucknow, India. The tin content in the synthesized complexes
was determined gravimetrically as SnO2.[12,18,20] Molar conductance measure-
ments were carried out on the same instrument as reported previously.[12,18,20]
Infrared and far-infrared spectra were recorded on a Perkin–Elmer 1600
Series FTIR spectrophotometer in KBr discs in the range 4000–400 cm21 and
in CsI discs in the range 600–200 cm21. Nuclear magnetic resonance (1H and
13C) spectra were recorded on a Bruker DRX-300 (300MHz) FT NMR spec-
trometer using tetramethylsilane (TMS) as internal standard. Tin (119Sn) NMR
spectra were recorded on a Bruker DRX-300 (300MHz) FT NMR spectrometer
¨
using DMSO-d6 as solvent and tetramethyltin as internal standard. Mossbauer
119
¨
Sn) spectra were recorded on a Mossbauer spectrometer model MS-900
(
(Ranger Scientific Co., Burelson, TX) according to the procedure reported pre-
viously.[12,18,20] The anti-inflammatory activity (% inhibition), average LD50
(mg/kg), and cardiovascular activity were evaluated according to the procedures
reported recently.[18,20]
ACKNOWLEDGMENTS
This work was a part of a major research project sponsored by the
Department of Science and Technology (DST) (Grant No. SP/S1/F-07/
2000), New Delhi, India. M. Nath is thankful to the DST, New Delhi, India.
¨
Financial support for the Mossbauer work from the National Institute of
Health, Minority Biomedical Research Support Programs MBRS/SCORE,
GM08005, is gratefully acknowledged. Thanks are also due to the Head,
Regional Sophisticated Instrumentation Centre, Central Drug Research

1706
Nath et al.
Institute, Lucknow, India, for elemental analyses and NMR spectral mea-
surements, and to the Head, Department of Chemistry, Indian Institute of
Technology, Delhi, India, for 119Sn NMR spectral studies. One of the
authors (S. Pokharia) is thankful to the Council for Scientific and Industrial
Research, New Delhi, for a Senior Research fellowship during the period of
writing this manuscript.
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Received September 13, 2003
Accepted June 2, 2004