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Synthesis structure and muscarinic agonist activity of substituted N-(silatran-1-ylmethyl)acetamides.

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Full Paper
Received: 25 March 2009
Revised: 1 July 2009
Accepted: 2 July 2009
Published online in Wiley Interscience: 21 August 2009
(www.interscience.com) DOI 10.1002/aoc.1539
Synthesis, structure and muscarinic
agonist activity of substituted
N-(silatran-1-ylmethyl)acetamides
Vera G. Pukhalskayaa , Eugeniya P. Kramarovaa, Larisa P. Kozaevab,
Alexander A. Korlyukovc , Alexander G. Shipova , Sergey Yu. Bylikina∗ ,
Vadim V. Negrebetskya, Gennady V. Poryadina and Yuri I. Baukova
Substituted N-(silatran-1-ylmethyl)acetamides, N-methyl-N-[1-(3 ,7 ,10 -trimethylsilatran-1-yl)methyl]acetamide (2a) and
N-(2-hydroxyethyl)-N-[1-(3 ,7 ,10 -trimethylsilatran-1-yl)methyl]acetamide (2b) were prepared by the reactions of triisopropanolamine with N-methyl-N-(trimethoxysilylmethyl)acetamide (1a) and 2,2-dimethoxy-4-acetyl-1-oxa-4-aza-2silacyclohexane (1b), respectively. According to X-ray data, the structures of the silatrane moieties are superpositions of
unsymmetrical and symmetrical stereoisomers. The O → Si coordination between the central atom and exocyclic substituent
is absent in both compounds. Silatranes 2a and 2b are partial muscarinic agonists which demonstrate submaximal effect and
c 2009 John
mimic the effect of acetylcholine by binding directly to cholinoreceptors of the ileal smooth muscle. Copyright Wiley & Sons, Ltd.
Keywords: silatranes; X-ray diffraction study; muscarinic agonist activity; guinea pig ileum contraction
Introduction
In recent years, the chemistry[1] and diverse biological activity[2 – 4]
of silatranes have attracted considerable interest. It was found
that carbofunctional aliphatic derivatives of silatranes intensify the biosynthesis of proteins, contribute to the growth and
regeneration of connective and epithelial tissue, prevent the development of atherosclerosis and stomach ulcers in animals, and
demonstrate neurotropism and antitumor effects[3,4] . Silatranylnucleosides and related compounds were reported as transition-state
analogs for phosphoryl transfer reactions[5] and RNA hydrolysis.[6]
The potential antiviral and anticancer activity of unsubstituted
and 3,7,10-trimethyl substituted silatranylnucleosides was also
discussed.[5 – 7] However, muscarinomimetic activity of silatranes
has not been observed.
In the present paper the synthesis, structural study and
partial muscarinic agonist activity of two new derivatives of
3,7,10-trimethylsilatrane with N-methyl-N-(acetamido)methyl and
N-(2-hydroxyethyl)-N-(acetamido)methyl substituents at silicon
are reported.
Experimental
General Notes
162
IR spectra of all compounds were recorded in KBr cells using a
Specord IR-75 instrument. The 1 H, 13 C and 29 Si NMR spectra in
CDCl3 were recorded on a Varian VXR-400 instrument (400.1, 100.6
and 79.5 MHz, respectively). 1 H, 13 C and 29 Si chemical shifts were
measured using tetramethylsilane as internal reference.
The starting chemicals and solvents were obtained from
commercial sources (Acros and Sigma-Aldrich). Initial N-methyl-
Appl. Organometal. Chem. 2010, 24, 162–168
N-(trimethoxysilylmethyl)acetamide (1a)[8] and 2,2-dimethoxy4-acetyl-1-oxa-4-aza-2-silacyclohexane (1b)[9] were prepared by
common synthetic methods; their yields and physico-chemical
properties were similar to those reported in literature.
Synthesis
N-methyl-N-[1-(3 ,7 ,10 -trimethylsilatranyl)methyl]acetamide (2a)
A mixture of amide 1a (6.21 g, 0.03 mol), triisopropylamine (5.73 g,
0.03 mol), powdered KOH (0.1 g) and xylene (25 ml) was heated
in an oil bath at 130–140 ◦ C until all methanol was distilled off.
The reaction mixture was cooled down to 100 ◦ C and diluted
with heptane (30 ml) to produce crystals of 2a. Yield 5.4 g (60%),
m.p. 150–153 ◦ C (heptane–xylene, 2 : 1) (lit.[10] : m.p. 85–87 ◦ C). IR
spectrum (CHCl3 , ν, cm−1 ): 1605 (C O) (lit.[10] : 1613 cm−1 , KBr
press.). 1 H NMR spectrum (CHCl3 , δ, ppm): 1.03–1.16 m (3CH3 CH,
9H); 2.21 m, 2.28 m, 2.60–2.70 m, 2.80–3.01 m [N(CH2 )3 C, 6H];
2.03 s (CH3 CO, 3H); 2.48 s (NCH2 Si, 2H); 2.88 s (CH3 N, 3H); 3.81 m,
4.01 m (3OCH, 3H). The isomer ratio is approx. 1:4. 13 C NMR
spectrum (CHCl3 , δ, ppm): 20.12, 20.40 (CHCH3 ), 21.47, 23.11
∗
Correspondence to: Sergey Yu. Bylikin, Russian State Medical University,
1 Ostrovityanov Str., Moscow 117997, Russian Federation.
E-mail: bylikin@chemlet.com
a Russian State Medical University, 1 Ostrovityanov St, 117997 Moscow, Russian
Federation
b Lomonosov Moscow State University, Department of Medicine, Lomonosovski
Av. 31/5, 119192 Moscow, Russian Federation
c A. N. Nesmeyanov’s Institute of Organoelement Compounds, RAS, Vavilova St
28, 11991 Moscow, Russian Federation
c 2009 John Wiley & Sons, Ltd.
Copyright Substituted N-(silatran-1-ylmethyl)acetamides
[CH3 C(O)], 35.04 br. s (NCH2 Si), 41.84, 42.01 (NCH3 ), 58.53, 61.40
(CHCH3 ), 64.43, 64.91, 66.10 br. s (NCH2 , ring), 170.50 (C O). 29 Si
NMR spectrum (CDCl3 , δ, ppm): −76.7 and −79.2. Found (%): C
51.55; H 8.64, C13 H26 N2 O4 Si. Calcd (%): C 51.62; H 8.66.
N-(2-hydroxyethyl)-N-[1-(3 ,7 ,10 -trimethylsilatranyl)methyl]
acetamide (2b)
A mixture of 2-silacyclohexane 1b (3.6 g, 0.017 mol), triisopropylamine (3.25 g, 0.017 mol), powdered KOH (0.1 g) and xylene
(20 ml) was heated in an oil bath at 130–140 ◦ C until all methanol
was distilled out. The reaction mixture was cooled down to 100 ◦ C
and diluted with heptane (20 ml) to produce crystals of 2b. Yield
4.54 g (78%), m.p. 138–140 ◦ C (benzene–heptane, 2 : 1). IR spectrum (CHCl3 , ν, cm−1 ): 1600 (C O). 1 H NMR spectrum (CHCl3 ,
δ, ppm): 1.07–1.25 m (3CH3 CH, 9H); 3.51–3.61 m [N(CH2 )2 OH];
2.19 m, 2.26 m, 2.58–2.99 m [N(CH2 )3 C, 6H]; 2.09 s (CH3 CO, 3H);
2.49 s, 2.60–2.80 m (NCH2 Si, 2H); 4.87 br. s (OH, 1H); 3.85 m, 4.06 m
(3OCH, 3H). The isomer ratio is approx. 1 : 4. 13 C NMR spectrum (CHCl3 , δ, ppm): 22.03; 24.37 (CHCH3 ), 20.88–20.97 br. s,
[CH3 C(O)], 42.14 br. s. (NCH2 ), 52.69, 58.89 (NCH2 CH2 OH), 63.23,
64.54 (NCH2 CH2 OH), 61.60, 63.10, 63.60 (CHCH3 ), 64.56, 64.90,
66.17 (NCH2 , ring), 173.53 (C O). 29 Si NMR spectrum (CDCl3 , δ,
ppm): −77.8 and −80.2. Found (%): C 50.30, H 8.50. C14 H28 N2 O5 Si.
Calcd (%): C 50.57, H 8.48.
Table 1. Crystallographic and experimental parameters of compounds 2a and 2b
Molecular formula
Formula weight
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å 3 )
dcalc (g cm−3 )
Space group, Z
2θmax (deg)
F(000)
Scan type
Reflections collected
Independent reflections (Rint )
Reflections with I > 2σ (I)
Parameters
Absorption coefficient (cm−1 )
R1 [I > 2σ (I)]
wR2 (all reflections)
Largest difference peak/hole (e Å −3 )
2a
2b
C13 H26 N2 O4 Si
302.45
18.7629(9)
10.4633(5)
17.9938(9)
90
115.0870(10)
90
3199.3(3)
1.256
P21 /c, 8
56.0
1312
ω
35559
7723
4456
374
1.61
0.0554
0.1375
0.622/−0.392
C14 H28 N2 O5 Si
332.47
8.0240(9)
10.8997(12)
11.3194(13)
116.228(2)
99.759(3)
94.269(3)
862.63(17)
1.280
P 1, 2
55.96
1448
ω
4387
4387(0.0904)
2851
235
1.60
0.0493
0.0944
0.522/−0.503
X-ray Diffraction Study
Single crystals of 2a and 2b suitable for X-ray study were
obtained from xylene–heptane (1 : 2) and benzene–heptane
(2 : 1), respectively. X-ray diffraction measurements of 2a and
2b were carried out on a Bruker Smart Apex II at 100 K. The
details of crystallographic data and experimental conditions are
given in Table 1. Important structural parameters of 2a and 2b are
summarized in Table 2.
The structures were solved by direct method and refined by full-matrix least-squares technique against F 2 in
the anisotropic–isotropic approximation. Positions of hydrogen
atoms were calculated geometrically and refined using the rigid
body model. All calculations were performed in SHELXTL PLUS 5.10
program package.[11] Atomic coordinates, bond lengths, bond
angles and displacement parameters of 2a and 2b have been deposited at the Cambridge Crystallographic Data Base (deposition
numbers 722558 and 722559, respectively).
Table 2. Selected experimental bond lengthsa , interatomic distances
and bond angles in molecules 2a and 2b (Å and deg)
Si1–N(1)
Si(1)–O(1)
Si(1)–O(2)
Si(1)–O(3)
Si(1)–C(10)
N(2)–C(10)
N(2)–C(13)
N(2)–C(11)
N(1)–Si(1)–C(10)
Si b
a
b
2a
2b
2.139(2)
1.664(1)
1.654(2)
1.668(1)
1.900(2)
1.487(3)
1.350(3)
1.500(3)
175.16(7)
0.1828(6)
2.137(2)
1.665(1)
1.660(1)
1.666(1)
1.906(2)
1.484(3)
1.459(3)
1.251(3)
176.27(6)
0.1779(5)
For the silatrane fragment, average bond lengths are given.
Si(1) in 2a and 2b deviates from the equatorial plane towards C(10).
Quantum Chemical Calculations
All calculations were carried out using Priroda program.[12] The
PBE[13] exchange-correlation functional and all-electron triplezeta basis set were applied for all elements. The stability of each
calculated structure was verified by the calculation of hessian
matrix.
Acute Toxicity in Mice
Appl. Organometal. Chem. 2010, 24, 162–168
The direct effects of compounds 2a and 2b on intestinal
contractions were determined in vitro using isolated segments
of guinea pig ileum.[14] The natural full muscarinic agonist,
acetylcholine (Sigma–Aldrich Chemie, Germany), was used as
reference. Male guinea pigs (300–400 g) were sacrificed by cervical
dislocation. The segments of the ileum were dissected out and
placed under an initial load of 1 g in an organ bath containing
Krebs solution of the following composition (mm): NaCl 118.1, KCl
4.7; CaCl2 2.5; KH2 PO4 1.2; NaHCO3 25, MgSO4 1.6 and glucose
5.5. The bath (10 ml) was continuously aerated. The isometric
contractions were recorded through a physiograph ‘Rikadenki’
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
163
The experiments in vivo were carried out on white male mice
(18–20 g). Aqueous solutions of tested substances in increasing
amounts were administered in mice by oral and intraperitoneal
routes. Surviving animals were observed for 14 days following the
test. The evaluation of 50% lethal dose (LD50 ) values in mice was
performed according to the method.[13]
Testing of Muscarinic Agonist Activity on Isolated Ileum
V. G. Pukhalskaya et al.
Scheme 1. Synthesis of silatranes 2a and 2b.
(‘Hugo Sachs Elektronik KG’, Germany) using a K30 transducer (the
same company).
After a 60-min period of equilibration, experiments were initiated. Concentration-response curves for the muscarinic agonist
acetylcholine (3 × 10−8 to 1 × 10−4 M) and 2a (3 × 10−5 to 1 × 10−2
M) were measured in a non-cumulative manner. Ligands were left
in contact with the tissue for the periods of 2 min at intervals of
15 min. The data obtained were used for calculating the mean
Emax (maximal contractor response, in grams) and mean EC50 (concentration of agonist eliciting half-maximal contractor effect, in
M) for each substance. The tension was ultimately expressed as a
percentage of the maximal response measured for acetylcholine
treatment.
At the end of each experiment, atropine (Sigma–Aldrich, Germany) was used as standard competitive muscarinic antagonist.
Results were analyzed by Student’s t-test.
Scheme 2. Conformations of N-methyl-N-(silatranylmethyl)acetamide (3).
Results and Discussion
Syntheses and Characterization
164
The compounds were prepared through well-known synthetic
route – trans-esterification of N-(trimethoxysilylmethyl)acetamide
(1a) or 2,2-dimethoxy-4-acetyl-1-oxa-4-aza-2-silacyclohexane (1b)
with stereorandom triisopropanolamine (Scheme 1). The reaction
conditions (refluxing in xylene in the presence of catalytic
quantities of KOH) were similar to those reported by us earlier.[9]
Silatranes 2a and 2b were obtained with good yields (60 and
78% respectively) as white crystals, readily soluble in water.
Compound 2a has been prepared earlier by M. G. Voronkov
et al.[10] from a substituted N-(triethoxysilylmethyl)amide and
triisopropanolamine, which is a common route for C-methyl
substituted silatranes.[15] However, neither experimental details
nor NMR spectra for 2a were reported at that time. It should be
noted that melting points of 2a samples prepared by Voronkov
et al.[10] and isolated by us are significantly different (85–87 and
150–153 ◦ C, respectively), which could be a result of different
ratios of stereoisomers in these samples (see below).
According to Voronkov et al.,[10] N-methyl-N-(silatran-1ylmethyl)amides in solutions exist as mixtures of Z- and Econformers (Scheme 2; see also: N. F. Lazareva, ‘New amino
derivatives of alkylalcoxysilanes, alkylfluorosilanes, and silatranes’,
Abstract of PhD thesis, Irkutsk, 1994, in Russian). The ratio between these forms depends on the sterical and electronic effects
of substituents in the amide group but not on the temperature
(within the studied temperature range). For example, in the 1 H
www.interscience.wiley.com/journal/aoc
Scheme 3. Stereoisomers of 3,7,10-substituted atranes.
NMR (CDCl3 ) spectra of MeC(O)N(Me)CH2 Si(OCH2 CH2 )3 N (3) the Zand E-forms appear as two sets of signals with integral intensities
of 17 : 83 both at 20 and 80 ◦ C. Thus, most molecules of compound
3 exist as E-conformers, in which the O → Si coordination is
sterically impossible.
The structures of silatranes 2a, b obtained by us in the solid
state and in solutions were confirmed by X-ray diffraction study, IR
and multinuclear (1 H, 13 C, 29 Si) NMR spectroscopy, and elemental
analysis. The common feature of the IR spectra of 2a, b is the lowfrequency (down to 1600–1605 cm−1 ) shift of the amide group
absorption.
and
Synthesis of 3,7,10-substituted silatranes[16 – 18]
germatranes[19,20] from stereorandom tris(2-hydroxyalkyl)amines
yields a mixture of four stereoisomers, which differ in the orientation of the substituents relative to the M–N axis (Scheme 3).
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2010, 24, 162–168
Substituted N-(silatran-1-ylmethyl)acetamides
Figure 1. Molecular structure of 2a in thermal ellipsoids at 50% probability.
Hydrogen atoms are not shown for clarity.
Figure 2. Molecular structure of 2b in thermal ellipsoids at 50% probability.
All hydrogen atoms except H(5) are omitted for clarity.
According to Tandura and co-workers,[16] the statistical A : B ratio
in such mixtures of stereoisomers is 1 : 3.
The signals of 29 Si nuclei in the NMR spectra of silatranes 2a,b appear as two sharp singlets in each case (−76.7 and −79.2 ppm for
2a; −77.8 and −80.2 ppm for 2b). Similar signals within the range
typical for silatranes[1] were observed for MeSi(OCHMeCH2 )3 N and
ICH2 Si(OCHMeCH2 )3 N (−64.2, −66.2 ppm and −78.0, −80.2 ppm,
respectively).[16] The chemical shifts in the 29 Si NMR spectra of silatranes 2a,b indicate the absence of additional O → Si coordination
in both compounds.
The exact ratio between symmetrical and unsymmetrical
stereoisomers A and B in silatranes 2a and 2b is difficult to
determine because of the complexity of their 1 H NMR spectra. In
particular, the signals of C-substituted silatrane rings appear as
two overlapping ABXM3 spin systems.[16] The spectra are further
complicated by the broadening of some signals, probably due to
the exchange between E- and Z-conformers of each stereoisomer
as a result of hindered rotation in the amide group.
Thus, the experimental data indicate that in solutions silatranes
2a and 2b exist as mixtures of symmetrical and unsymmetrical
stereoisomers with no additional coordination between the Si
atom and the amide group.
positions in five-membered NSiOCC rings, and the atrane cage has
approximately C3 symmetry (stereoisomers A). In unsymmetrical
isomers, the position of one of the substituents is changed to
pseudoequatorial (stereoisomers B).
To date, there is a lack of information about crystal structures
of silatranes with substituents at 3, 7 and 10 positions. Only three
Me-substituted species have been reported in the literature.[24,25]
Two crystallographically independent molecules in the crystal
structure of 1-phenyl-3,7,10-trimethylsilatrane[24] belong to symmetrical isomers. The structure of 1-bromo-1-[N,N,N-tris(propyl2-oxy)ammonio]silatranylethanol[25] contains uncertainties and
systematic errors, which do not allow reliable determination of the
configuration of the atrane cage.
The number of 3,7,10-substituted germatranes is much
greater than that of their silatrane analogs.[19,20,26 – 28] However,
in the majority of structures the germatrane cage is disordered, so the observed structures comprise superpositions of
stereoisomers. Ordered germatrane cages in the structures of 1[9-(trimethylgermyl)-9-fluorenyl]-3,7,10-trimethylgermatrane and
1-[9-(trimethylstannyl)-9-fluorenyl]-3,7,10-trimethylgermatrane
belong to unsymmetrical stereoisomers.[26]
The atrane moieties of silatranes 2a and 2b are also disordered
in a 1 : 1 ratio, which makes it impossible to determine the ratio
of stereoisomers A and B. The structure of 2a is even more
complicated. In addition to disorder of the atrane cage in 2a, the
exocyclic N-methyl-N-(acetamido)methyl group is also disordered
in a 1 : 1 ratio in both independent molecules. All stereoisomers of
the latter compound are characterized by the absence of additional
O → Si coordination with N-methyl-N-(acetamido)methyl group.
In 2b, such coordination is also absent due to the interaction
between the N-(2-hydroxyethyl) moiety and the carbonyl group
of an adjacent molecule in the crystal.
X-ray Diffraction Study
Appl. Organometal. Chem. 2010, 24, 162–168
Quantum Chemical Studies of 2a and 2b
According to the Cambridge Structural Database,[29] hexacoordination of the Si atom in silatranes has not been reported. This
fact can be explained by the steric effect of atrane cage, which
does not allow the Si atom to participate in additional interactions.
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
165
The geometry of the Si(1) coordination centers in 2a and 2b (Figs 1
and 2, respectively) is typical for silatranes with weak acceptor
exocyclic substituents. The N· · ·Si interatomic distances [2.141(2)
and 2.137(2) Å, respectively] are very close to those in N-[1-(1silatranyl)ethyl]-2-pyrrolidone, N-(1-silatranylmethyl)succinimide
and -glutarimide (2.102–2.132 Å).[21,22] Thus, the induction of
methyl groups at 3, 7 and 10 positions does not significantly affect
the N· · ·Si interatomic distance. The silicon atoms in both 2a and
2b deviate by 0.18 Å from the plane of equatorial oxygens towards
the C(10) atom.
According to papers[16 – 18] and review by V. F. Sidorkin et al.,[23]
the atrane cage in 3,7,10-substituted silatranes can exist as two
pairs of symmetrical and unsymmetrical stereoisomers (see above).
In symmetrical isomers, the substituents occupy pseudoaxial
V. G. Pukhalskaya et al.
Figure 3. General view of isolated stereoisomers of molecule 2a (E-A-2a and E-B-2a).
Table 3. Calculated chemical shifts of 29 Si (ppm) in stereoisomers of
isolated molecules 2a and its solvated clusters
Isolated molecule
Solvate cluster with 4CHCl3
E-A-2a E-B-2a E-A-2a E-B-2a Z-A-2a Z-B-2a
−64.3
−63.4
−66.6
−68.0 −95.88 −92.3
Experimental data
2a
−76.7, −79.2
166
For example, the O → Si coordination bond is absent in N-[1-(1silatranyl)ethyl]-2-pyrrolidone,[21] which can be considered as an
analog of 2a. The only example of an N → Si coordination involving the nitrogen atom of an exocyclic substituent was described
by Corriu et al.[30] in the crystal structure of 8-(dimethylamino)l-naphthyl-silatrane, with the respective interatomic distance of
2.952 Å.
In case of 2a, there is a possibility of additional isomerism
related to mutual orientation of the exocyclic substituent and the
atrane cage. The structures of possible stereoisomers of 2a were
analyzed by quantum chemical calculations (see Experimental
section for details). First of all, the diastereomers observed in
the crystal state (E-A-2a and E-B-2a, Fig. 3) were studied. The
geometry optimization of isolated molecules gave significantly
elongated N· · ·Si distances (2.300 and 2.312 Å for E-A-2a and
E-B-2a, respectively) compared with the experimental values in
the crystal of 2a. Such differences could be the reason for major
disagreement between experimental and calculated 29 Si chemical
shifts (Table 3).
Therefore, the optimization of systems containing stereoisomers of 2a and several CHCl3 molecules (solvate clusters) was
carried out. The addition of the first two CHCl3 molecules decreased
the N· · ·Si distance significantly while further shortening of that
distance upon the addition of more solvent molecules was barely
noticeable. As a result, a solvate cluster with four CHCl3 molecules
was chosen as a good compromise between the reliability of the
model and computational time. Using this approach, four solvate
clusters containing symmetrical and unsymmetrical diastereomers
in non-coordinated E-forms (E-A-2a· 4CHCl3 and E-B-2a· 4CHCl3 )
as well as in coordinated Z-forms (Z-A-2a· 4CHCl3 and Z-B-2a·
4CHCl3 ) were studied (Fig. 4).
In all solvate clusters the Si· · ·N distances were found to be
0.05–0.08 Å longer than the experimental value (Table 2). In the
case of Si–O bonds the differences were 0.04–0.14 Å, which can
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be explained by the formation of C–H· · ·O bonds (with H· · ·O
distances of 2.09–2.38 Å) with CHCl3 molecules as well as the
expansion of the silicon coordination sphere in Z-A-2a· 4CHCl3
and Z-B-2a· 4CHCl3 . The agreement between the experimental
and calculated 29 Si NMR chemical shifts in E-A-2a· 4CHCl3 and
E-B-2a· 4CHCl3 had somewhat improved as compared to E-A-2a
and E-B-2a (Table 3).
Despite the Si(1)· · ·O(4) coordination, the Z-A-2a· 4CHCl3 and
Z-B-2a· 4CHCl3 are 4.07 and 3.84 kcal mol−1 less favorable than
E-A-2a· 4CHCl3 and E-B-2a· 4CHCl3 , respectively. A possible
reason for that is the sterical repulsion between the silatrane
and acetamide moieties. The absence of coordinated forms in
solutions of 2a is confirmed by the 29 Si NMR spectrum of this
compound, which contains no signals of hexacoordinate silicon in
the range −90 to −100 ppm.
Thus, the results of X-ray, NMR and quantum chemical studies
demonstrate that silicon atoms in compounds 2a and 2b are
pentacoordinated both in the solid state and in solution.
Acute Toxicity in Mice
The oral LD50 of compounds 2a and 2b were found to be more
than 3000 mg kg−1 body weight (no acute mortality was observed). Greater doses were not tested. The LD50 values of
intraperitoneal injections of 2a and 2b were estimated as 2000
and 3000 mg kg−1 of body weight, respectively.
After oral and intraperitoneal administration of a silatrane, the
toxic symptoms appeared after about 1–2 min of dosing and were
expressed in fluid stools. Higher doses led to bloody diarrhea.
Animals died about 10 min after lethal intraperitoneal injection.
The cause of death in mice in all cases was colon bleeding.
The diarrhea and mortality of animals could be prevented by
preliminary subcutaneous injection of atropine (0.2 mg kg−1 ).
Thus, the results of acute single dose toxicity studies in vivo
show that compounds 2a and 2b on oral and intraperitoneal
administration in mice exhibit a very low toxicity. Both compounds
were less toxic via oral ingestion than via intraperitoneal injection.
Compounds 2a and 2b have similar oral and intraperitoneal
toxicities. The toxicological profile in mice was characterized by
diarrhea regardless of the administration route. Effects of the
diarrhea increased in severity along with the doses.
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2010, 24, 162–168
Substituted N-(silatran-1-ylmethyl)acetamides
contraction, % of acetylcholine
maximum
Figure 4. Solvate clusters containing one (coordinated or non-coordinated) molecule of 2a and four molecules of CHCl3 (from left to right: E-A-2a, E-B-2a,
Z-A-2a and Z-B-2a).
100
acetylcholine
compound 2a
80
60
40
Scheme 4. Comparison of the structures of silatranes 2a,b (left) and
acetylcholine (right).
20
0
10-7 10-6 10-5 10-4 10-3
concentration of agonists (M)
10-2
Figure 5. Concentration–effect plots for contractile responses of ileal
smooth muscle to acetylcholine and silatrane 2a. Each point represents
mean ±S.E.M. (n = 10–14).
Contraction Effects on Isolated Guinea Pig Ileum
Appl. Organometal. Chem. 2010, 24, 162–168
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167
The ability of compounds 2a and 2b to increase peristaltic
activity in the gastrointestinal tract was found during testing
of their acute toxicity in mice. All animals suffered from diarrhea,
which developed within the first minutes after a single dose
of silatranes and prevented by the preliminary subcutaneous
injection of nonselective muscarinic antagonist atropine. Since
all muscarinic receptors had been blocked by atropine, these
observations indicated the presence of muscarinomimetic activity
in the synthesized silatranes.
In order to clarify the contractile activity mechanism of
compounds 2a and 2b, fragments of guinea pig ileum in vitro
were used for evaluating the action of pharmacological agents
with muscarinomimetic activity.
The activity of compound 2a tested on isolated guinea pig
ileum is summarized in Fig. 5. These data were compared with the
concentration–effect curve of acetylcholine. It was found that 2a
was active in the concentration range from 3 × 10−5 to 1 × 10−2
M, and in dose-dependent manner evoked increase in the ileum
tension. The activity of compound 2a was lower than the activity
of acetylcholine, whereas the EC50 of silatrane2a was calculated
as 7.7 × 10−4 M (− logEC50 = 6.48 ± 0.3), the EC50 value of
acetylcholine was 3.3 × 10−7 M (− logEC50 = 3.1 ± 0.05).
In addition, compound 2a demonstrated a somewhat lower
(2-fold, p < 0.001) maximal contractile response effect than
acetylcholine: the Emax for 2a was 0.6 ± 0.07 g while the Emax
for acetylcholine was 1.2 ± 0.11 g.
Compound 2b also produced weak contraction and was less
potent than acetylcholine. Data for 2b are not given as both EC50
and Emax were almost the same for both compounds. At the end
of the experiments we found that the contractile effects could be
completely abolished by small doses of atropine (1 × 10−7 M).
The protective effect of atropine strongly indicates that the
effects of compounds 2a and 2b are mediated by muscarinic
receptor, and both silatranes are partial muscarinic agonists
demonstrating submaximal effect.
The latest research indicates that muscarinic receptors in guinea
pig ileum are heterogeneous with a major M2 receptor population
(ca 80%) and a minor M3 population (ca 20%). Since both M2 and
M3 muscarinic receptors have a contractile role in smooth muscle
(see[31] for a review), it is impossible to suggest any selective
subtype activity. This problem will be studied in the future.
It is not surprising that both silatranes act as muscarinic agonists
because their molecules have all the attributes of typical muscarinomimetics. Specifically, they have ‘cation caput’ with a quaternary
ammonium group, and a carbonyl group bearing a partial negative
charge. These groups play an important role in agonist–receptor
interactions. Overall, their molecular frameworks are somewhat
similar to the framework of acetylcholine (Scheme 4).
The history of pharmacology shows that progress in understanding the function of different receptors greatly depends on
the synthesis of new ligands with agonist or antagonist activity.
The studied compounds might prove to be useful for studying the
pharmacology of muscarinic receptors.
Thus, for the first time, substances with muscarinic agonist
activity were found among silatranes, which can be of interest for
focused search of new biologically active agents, as well as for the
study of the structure and function of muscarinic receptors.
V. G. Pukhalskaya et al.
Acknowledgements
This work was financially supported by the Russian Foundation
for Basic Research (project nos 07-03-01067, 09-03-00669 and
07-03-01018).
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structure, synthesis, agonists, activity, muscarinic, substituted, acetamides, ylmethyl, silatran
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