Synthesis, antitumor activity, and SAR of N-substituted γ-aminopropylsilatrane derivatives

Article abstract of DOI:10.1080/10426507.2013.829835

γ-Aminopropylsilatrane has been reported to possess biological activity against tumor cancer cells with low cytotoxicity in many kinds of silatranes. So some N-substituted γ-aminopropylsilatrane derivatives were synthesized and assayed by a primary antica

Full text of DOI:10.1080/10426507.2013.829835

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Synthesis, Antitumor Activity, and SAR
of N-Substituted γ-Aminopropylsilatrane
Derivatives
Guo Ping a , Wang Yue-Wu a , Luo Xin-Tong a , Qi Xiao-Lu a , Hou Le-
Ping a , Xie Zi-Xin a & Ye Fa-Qing a
a School of Pharmacy, Wenzhou Medical College , Wenzhou ,
Zhejiang , 325035 , P. R. China
Accepted author version posted online: 23 Sep 2013.Published
online: 12 Mar 2014.
To cite this article: Guo Ping , Wang Yue-Wu , Luo Xin-Tong , Qi Xiao-Lu , Hou Le-Ping , Xie Zi-Xin &
Ye Fa-Qing (2014) Synthesis, Antitumor Activity, and SAR of N-Substituted γ-Aminopropylsilatrane
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:4, 511-518, DOI:
10.1080/10426507.2013.829835
To link to this article: http://dx.doi.org/10.1080/10426507.2013.829835
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Phosphorus, Sulfur, and Silicon, 189:511–518, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.829835
THE SYNTHESIS, ANTITUMOR ACTIVITY, AND SAR OF
N-SUBSTITUTED γ -AMINOPROPYLSILATRANE
DERIVATIVES
Guo Ping, Wang Yue-Wu, Luo Xin-Tong, Qi Xiao-Lu, Hou
Le-Ping, Xie Zi-Xin, and Ye Fa-Qing
School of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang 325035,
P. R. China
GRAPHICAL ABSTRACT
Abstract γ -Aminopropylsilatrane has been reported to possess biological activity against
tumor cancer cells with low cytotoxicity in many kinds of silatranes. So some N-substituted
γ -aminopropylsilatrane derivatives were synthesized and assayed by a primary anticancer
screening against HT-29, Hela, and MDAMB435 cells by the use of the 3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The structures of these derivatives were
confirmed by 1H NMR, electrospray ionization-mass spectrometry, and elemental analysis. The
structure–activity relationship showed that the N-substituted derivatives exhibit better activity
in which the γ -amino group of the silatrane is connected with stronger electron-withdrawing
groups.
Keywords γ -Aminopropylsilatrane derivatives; structure–activity relationship (SAR); physi-
ological activity
Received 13 May 2013; accepted 1 July 2013.
Address correspondence to Dr Guo Ping, School of Pharmacy, Wenzhou Medical College; Wenzhou,
Zhejiang 325035, P. R. China. E-mail: gp 0713@163.com
511

512
G. PING ET AL.
INTRODUCTION
Silatranes, heterotricyclic compounds exhibiting an intramolecular transannular da-
tive Si←N bond, are challenging targets for scientists from the point of view of their
structural features and applications. The strength of the dative bond depends not only on
the substituent on the silicon but also on the skeletal structure of the parent ring. The
length of this bond is also influenced by the position, axial or equatorial, occupied by the
substituent on the silicon as well as by cage effects.1–4 The analysis of the electron density
distribution in the silatrane led to the conclusion that obviously the interaction between
nitrogen and silicon is rather electrostatic and less covalent. Therefore, they are relatively
stable to moisture, and more difficult to hydrolyze compared with their analogs (trialkoxysi-
lanes) and can be used in various reactions, e.g., additions and nucleophilic substitutions.5–8
Optimization of the 1-substituted groups is important since the toxicity and bioactivity of
silatranes is correlated with these groups.
Many derivatives of silatrane could even stimulate the biosynthesis of nucleic acids
and proteins and the growth of some cells, especially regenerating cells of connective tissue
and liver.9–11 But some 1-arylsilatranes were almost twice as toxic as well-known poisons
as strychnine and hydrocyanic acid. Meanwhile, 1-alkyl- or 1-alkoxysilatranes did not
influence the growth of normal cells even in a higher concentration. In 1-alkyl derivatives, γ -
aminopropylsilatranes (Figure 1, R=CH3) has captured high interest due to their bioactivity,
safety, and potential for the preparation of new silatranes by derivatization of the amino
group. They are also an important group of biologically active compounds as a result of
their diverse pharmacological applications, such as antitumor,12 antiviral,13,14 and regulating
plant growth.8 At the same time, it was found that γ -aminopropylsilatrane is capable of
enhancing the carcinostatic effect of the well-known antitumor drug cyclophosphamide.13,15
Recently, silatranes were shown to exhibit pronounced antitumor activity by reducing the
ability of tumor cells to undergo invasion and by inhibiting tumor growth. Inaddition,
silatranes adorned with methyl groups (Figure 1, R=CH3) have the advantage of being more
stable toward hydrolysis, whereas those without (Figure 1, R=H) may have an advantage
in terms of inhibiting an enzyme because the active site should better accommodate the
less bulky ligands.12
To get a better understanding of the structure–activity relationship (SAR) in this
type of compounds by modifications in the γ -amino groups of silatrane, we report here
Figure 1 Structure of γ -aminopropylsilatrane.

SYNTHESIS, ANTITUMOR ACTIVITY, AND SAR OF N-SUBSTITUTED
513
the synthesis and biological activity of compounds derived from γ -aminopropylsilatrane
and γ -aminopropyl-3,7,10-trimethylsilatrane. By use of various aroyl chlorides, aldehy-
des, and isocyanates for reactions with the γ -amino group, numerous N-substituted γ -
aminopropylsilatranes were synthesized and their action in vitro against HT-29, Hela, and
MDAMB435 was investigated. Because γ -aminopropylsilatrane could improve the effect
of antitumor drugs, its mutual prodrugs were designed and synthesized. A clinical antitu-
mor drug 5-fluorouracil (5-FU), but not cyclophosphamide, was selected to introduce into
the mutual prodrugs due to better reactive properties and lesser molecular weight. Finally,
some N-substituted γ -aminopropylsilatrane derivatives containing the structure of 5-FU
were synthesized and assayed to check their synergism.
RESULTS AND DISCUSSION
Our strategy for the synthesis of derivatives with different structures was based on
a nucleophilic addition reaction between silatrane and aromatic acid chlorides, aromatic
aldehydes, aromatic isocyanates, and 5-FU. Thirty-two compounds (2a–j, 3a–i, 4a–i, 5a–b,
Figure 2 Synthesis of diverse N-substituted γ -aminopropylsilatranes. Regents and conditions: (i) CHCl3, dif-
ferent alkyl chlorides, NEt3, rt., 2 h; (ii) benzene, aromatic aldehydes, reflux, 2 h; (iii) toluene, NEt3, aromatic
isocyanate, reflux, 2 h; (iv) N2, CHCl3, NEt3, 2–3 h; (v) DMF, DCC, rt., 2–3 h.

514
G. PING ET AL.
Table 1 The inhibitory activities of the tested compounds
IC50 (μg/mL)
Compound
MDAMB435
Hela
HT29
5-FU
1a
1b
2a
2b
2c
2d
2e
2f
9.66
>100
77.4
69.3
33.1
36.3
57.5
61.4
35.6
77.3
96.2
>100
40.6
25.3
32.7
29.0
24.6
19.2
15.7
14.9
14.9
12.5
87.7
85.8
35.4
76.6
69.5
90.0
>100
>100
>100
20.6
17.1
22.5
15.7
10.1
6.22
89.3
86.8
77.4
29.0
30.4
44.3
50.8
28.9
50.1
84.9
80.0
62.5
27.3
32.8
25.1
28.3
20.0
15.2
15.9
15.8
12.3
70.6
63.1
32.3
47.5
45.9
57.7
95.6
87.7
80.6
25.2
11.6
14.9
18.2
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
22.4
30.0
30.9
27.1
24.9
18.3
11.1
14.15
11.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
18.7
2g
2h
2i
2j
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
6a
6b
13.3
31.2
35.6
6a–b) exhibiting the framework of γ -aminopropylsilatrane (1a and 1b) were designed
and synthesized. Their chemical structures are shown in Figure 2. Initially, 2a–j were
synthesized by the reaction of 1a–b with various aroyl chlorides, 3a–i were synthesized by
the reaction of 1a–b with aldehydes, 4a–i were synthesized by the reaction of 1a–b with
isocyanates, and 5a–b and 6a–b were synthesized by linking 1a–b with 5-FU via different
chemical bridges.
For the primary assay, the percentage inhibitions of compounds at 0.4, 2, 10, 50,
and 100 μg/mL were measured against HT-29, Hela, MDAMB435 respectively in vitro in
comparison with 5-FU. Then we determined their IC50 values by SPSS.
From the results listed in Table 1, one can see that all target compounds are weaker
than 5-FU in the inhibition of tumor cell growth. In contrast, the performance of compounds
5a–b and 6a–b is quite good, and is very close to 5-FU. Next, 3a–i is better than 4a–i.

SYNTHESIS, ANTITUMOR ACTIVITY, AND SAR OF N-SUBSTITUTED
515
CONCLUSIONS
Thirty-two N-substituted γ -aminopropylsilatranes were synthesized and tested for
their activities on HT-29, Hela, and MDAMB435.
Different types of products exhibit their own selectivity. For example, 1a–b, 2d–j, and
4a–i had no activity to Hela cells. The 3,7,10-trimethyl derivatives derived from 1b were
more active than those without methyl substituents (derived from 1a). 2a and 2f showed a
higher antitumor activity than 2i and 2j respectively.
Since 3a–i exhibited good performance to three types of cancer cells, obviously,
the C=N double bond plays a critical role. On the other hand, a two-fold increase in the
inhibitory activity of both MDAMB435 and HT-29 assays was observed when the N atom
was substituted by a strong electron-withdrawing group, e.g., 2b and 4c showed more
preferable bioactivity than 2e and 4f respectively.
To check the synergism between the γ -aminopropylsilatrane and 5-FU, we linked
these moieties together. However, the activity of 5a–b and 6a–b was still slightly lower
compared with 5-FU. This could be due to the amide linkage, which can rarely be cleaved
in culture cells that block their synergism.
The SAR analysis indicates that the N-substituted γ -aminopropylsilatranes were well
optimized for bioactivity via appropriate chemical modification.
EXPERIMENTAL
Instruments and Reagents
Uncorrected melting points (m.p.) were determined using an XRC-1 micro-melting
point apparatus. Thin layer chromatography (TLC, Rf values) was performed on F254 or
1
silica gel plates F254 (0.2-mm thick) and visualization was effected with UV light. H
NMR spectra were recorded on a Bruker Avance-3600 spectrometer (600 MHz). Samples
were dissolved in CDCl3, while tetramethylsilane (TMS) was used as an internal standard.
Chemical shifts δ were recorded in ppm relative to TMS, and J-values are expressed in Hz.
Mass spectra (MS) were recorded using an Agilent-1100 LC mass spectrometer.
General Procedure for the Preparation of 1a–b
The γ -aminopropylsilatranes 1a and 1b were synthesized by condensation of triiso-
propanolamine or triethylolamine with γ -aminopropyltriethoxysilane. The products were
obtained by vacuum distillation. For the data of 1a and 1b see Dumitriu et al.6
General Procedure for the Preparation of 2a–j
Different chlorides (0.012 mol) were added drop-wise to a solution of 1a/1b
(0.01 mol) in CHCl3 (10 mL) containing triethylamine (2 mL). The solution was stirred at
room temperature for 2 h. The filtrate was washed twice with NaHCO3 (0.6 mol/L). The
organic layer was dried with Na2SO4 and then dumped into petroleum ether. The products
2a–j precipitated as white solids. They were purified by further recrystallization. 2e, 2f,
2h, and 2j have not been reported before. For the data of 2a–d, see Hu et al.16
[γ -(4-Methylbenzoylamino]propyl-3,7,10-trimethylsilatrane (2e). M.p.:
139–140◦C; 1H NMR: 0.22–0.49 (m, 2H, H-α), 1.05–1.50 (m, 9H, CH3–3,7,10), 1.51–1.82
(m, 2H, H-β), 2.02–2.33 (m, 2H, H-γ ), 2.35 (s, 3H, Ph-CH3), 2.62–3.28 (m, 6H, H-4,6,11),

516
G. PING ET AL.
3.85–4.20 (m, 3H, H-3,7,10), 6.69 (br, 1H, NH), 7.32 (d, 2H, J = 8.4, Ph-H), 7.84 (d, 2H,
J = 8.4, Ph-H). ESI-MS: 393 [M+H]+. Calcd. for C20H32N2O4Si: C, 61.19; H, 8.22; N,
7.14; Si, 7.14%. Found: C, 61.08; H, 8.21; N, 7.15; Si, 7.21%.
[γ -(2-Fluorobenzoyl)Amino]Propyl-3,7,10-Trimethylsilatrane (2f). M.p.:
152–153◦C; 1H NMR: 0.20–0.55 (m, 2H, H-α), 1.00–1.55 (m, 9H, CH3–3,7,10), 1.60–1.87
(m, 2H, H-β), 2.23–2.55 (m, 2H, H-γ ), 2.75–3.45 (m, 6H, H-4,6,11), 3.85–4.19 (m, 3H,
H-3,7,10), 7.04 (br, 1H, NH), 7.47–7.86(m, 4H, Ph-H). ESI-MS: 397 [M+H]+. Calcd. for
C19H29FN2O4Si: C, 57.55; H, 7.37; N, 7.06; Si, 7.06%. Found: C, 56.99; H, 7.35; N, 7.01;
Si, 6.98%.
[γ -(4-Methylbenzoyl)amino]propylsilatrane (2h). M.p.: 168–169◦C; 1H
NMR: 0.23–0.45 (m, 2H, H-α), 1.65–1.85 (m, 2H, H-β), 2.47–2.69 (m, 2H, H-γ ), 2.52
(s, 3H, PhCH3), 2.65–3.40 (m, 6H, H-4,6,11), 3.75–4.13 (m, 6H, H-3,7,10), 6.71 (br, 1H,
NH), 7.70 (d, 2H, J = 8.4, Ph-H), 8.42 (d, 2H, J = 8.4, Ph-H). ESI-MS: 351 [M+H]+.
Calcd. for C17H26N2O4Si: C, 58.26; H, 7.48; N, 7.99; Si, 7.99%. Found: C, 58.11; H, 7.50;
N, 7.81; Si, 7.80%.
[γ -(2-Fluorobenzoyl)amino]propylsilatrane (2j). M.p.: 170–171◦C; 1H
NMR: 0.23–0.50 (m, 2H, H-α), 1.45–1.87 (m, 2H, H-β), 2.52–2.65 (m, 2H, H-γ ),
2.65–3.38 (m, 6H, H-4,6,11), 3.72–3.87 (m, 6H, H-3,7,10), 6.96 (br, 1H, NH), 7.30–7.76
(m, 4H, Ph-H). ESI-MS: 355 [M+H]+. Calcd. for C16H23FN2O4Si: C, 54.22; H, 6.54; N,
7.90; Si, 7.92, F, 5.36%. Found: C, 54.89; H, 6.77; N, 7.80; Si, 7.50, F, 5.44%.
General Procedure for the Preparation of 3a–j
0.01 Mol 1a or 1b was dissolved in 20 mL benzene. Then the aromatic aldehyde
(0.01 mol) was added. A water separator was installed in order to remove the by-product
water and to accelerate the reaction. The mixture was stirred and refluxed for 2 h. Benzene
and water were removed under reduced pressure, and the residue was recrystallized from
benzene and ether. We have synthesized 3a–j previously.8
General Procedure for the Preparation of 4a–j
Compound 1a or 1b, 0.01 mol, was added to the stirred solution of toluene, and
dissolved. Then the aromatic isocyanate (0.01 mol) was added. The mixture was stirred
and refluxed for 0.5 h. Compounds 4a–j and 2a–j were isolated from the mixture. Com-
pounds 4e, 4f, 4h, and 4i have not been described before. For the data of 4a-d, see
Hu et al.16
Nꢁ-(3-Chlorophenyl)-γ -ureidopropyl-3,7,10-trimethylsilatrane (4e). M.p.:
151–152◦C. 1H NMR: 0.28–0.49 (m, 2H, H-α), 1.20–1.32(m, 9H, CH3–3,7,10), 1.65–1.76
(m, 2H, H-β), 2.20–2.35 (m, 2H, H-γ ), 2.85–3.30 (m, 6H, H-4,6,11), 3.82–4.15 (m, 3H,
H-3,7,10), 5.18 (br, 1H, NH), 6.16 (br, 1H, NH), 7.08–7.20 (m, 4H, Ph-H). ESI-MS: 428
[M+H]+. Calcd. for C19H30ClN3O4Si: C, 53.32; H, 7.06; N, 9.82; Si, 6.55%. Found: C,
53.08; H, 7.12; N, 9.87; Si, 6.75%.
Nꢁ-(4-Methylphenyl)-γ -ureidopropyl-3,7,10-trimethylsilatrane (4f). M.p.:
197–198◦C. 1H NMR: 0.25–0.45 (m, 2H, H-α), 1.19–1.33 (m, 9H, CH3–3,7,10), 1.56–1.87
(m, 2H, H-β), 2.10–2.30 (m, 2H, H-γ ), 2.41 (s, 3H, PhCH3), 2.60–3.31 (m, 6H, H-4,6,11),
3.76–4.19 (m, 3H, H-3,7,10), 5.23 (br, 1H, NH), 6.58 (br, 1H, NH), 7.21 (d, 2H, J = 8.4,
Ph-H), 7.28 (d, 2H, J = 8.4, Ph-H). ESI-MS: 408 [M+H]+. Calcd. for C20H33N3O4Si:

SYNTHESIS, ANTITUMOR ACTIVITY, AND SAR OF N-SUBSTITUTED
517
C, 58.94; H, 8.16; N, 10.31; Si, 6.88%. Found: C, 58.88; H, 8.20; N, 10.30; Si,
6.89%.
Nꢁ-(4-Methylphenyl)-γ -ureidopropylsilatrane (4h). M.p.: 196–197◦C. 1H
NMR: 0.26–0.47 (m, 2H, H-α), 1.15–1.35 (m, 2H, H-β), 2.15–2.60 (m, 2H, H-γ ),
2.65–3.40 (m, 6H, H-4,6,11), 3.57 (s, 3H, PhCH3), 3.70–3.83 (m, 6H, H-3,7,10), 5.25 (br,
1H, NH), 6.47 (br, 1H, NH), 7.88 (d, 2H, J = 8.4, Ph-H), 8.56 (d, 2H, J = 8.4, Ph-H).
ESI-MS: 366 [M+H]+. Calcd. for C17H27N3O4Si: C, 55.86; H, 7.45; N, 11.50; Si, 7.67%.
Found: C, 55.78; H, 7.49; N, 11.49; Si, 7.80%.
Nꢁ-(3-Methylphenyl)-γ -uureidopropylsilatrane (4i). M.p.: 148–149◦C. 1H
NMR: 0.26–0.44 (m, 2H, H-α), 1.17–1.37 (m, 2H, H-β), 2.49–2.79 (m, 2H, H-γ ),
2.64–3.39 (m, 6H, H-4,6,11), 3.76 (s, 3H, PhCH3), 3.70–3.83 (m, 6H, H-3,7,10), 5.18 (br,
1H, NH), 6.69 (br, 1H, NH), 7.51–8.50 (m, 4H, Ph-H). ESI-MS: 366 [M+H]+. Calcd.
for C17H27N3O4Si: C, 55.86; H, 7.45; N, 11.50; Si, 7.67%. Found: C, 55.67; H, 7.49; N,
11.44; Si, 7.59%.
General Procedure for the Preparation of 5a–6b
Triphosgene, 10 mmol, diluted with 10-mL CHCl3 was slowly added to 10-mmol
5-fluorouracil dissolved in 5-mL pyridine and the mixture was stirred at –5◦C for 5 ∼ 6 h
under nitrogen for protection. 10 mmol of 1a or 1b and 2-mL triethylamine were added
to the above solution, which reacted at room temperature for 2 ∼ 3 h. The progress of the
reaction was monitored by thin-layer chromatography (TLC). Compounds 6a and 6b have
been described previously.17
1
N-(5-Fluorouracil-1-yl)formyl-γ -aminopropylsilatrane (5a). H NMR:
0.25–0.45 (m, 2H, H-α), 1.35–1.65 (m, 2H, H-β), 2.11–2.43 (m, 2H, H-γ ), 2.71–2.79 (m,
6H, H-4,6,11), 3.85–4.20 (m, 6H, H-3,7,10), 5.48 (br, 1H,NH), 7.34 (br, 1H, FU-H), 7.92
(br, 1H, FU-H). ESI-MS: 389 [M+H]+. Calcd. for C14H21FN4O6Si: C, 43.29; H, 5.45; N,
14.42; Si, 7.23%. Found: C, 43.42; H, 5.65; N, 14.03; Si, 7.42%.
N-(5-Fluorouracil-1-yl)formyl-γ -aminopropyl-3,7,10-trimethylsilatrane
1
(5b). H NMR: 0.20–0.42 (m, 2H, H-α), 1.14–1.30 (m, 9H, CH3–3,7,10), 1.43–1.63 (m,
2H, H-β), 2.11–2.45 (m, 2H, H-γ ), 2.62–3.28 (m, 6H, H-4,6,11), 3.85–4.20 (m, 3H,
H-3,7,10), 5.48 (br, 1H,NH), 7.32 (br, 1H, FU-H), 7.89 (br, 1H, FU-H). ESI-MS: 431
[M+H]+. Calcd. for C17H27FN4O6Si: C, 47.43; H, 6.32; N, 13.01; Si, 6.52%. Found: C,
47.42; H, 6.45; N, 13.03; Si, 6.42%.
MTT Assay
The MTT assay was performed to evaluate the cytotoxic and anti-proliferative activ-
ities of all compounds. The cells were treated with various concentrations (0.4, 2, 10, 50,
and 100 μg/mL) of compound in 96-well culture plates for 24 h in final volumes of 100 μL
(5 × 103 cells/well). Then 20 μL of MTT solution (5 mg/mL) was added to each well, and
the cells were incubated for an additional 4 h. The medium was carefully removed, and the
residues were dissolved in 150 μL of dimethyl sulfoxide (DMSO), shaken mechanically
for 30 min, and absorbance values at a wavelength of 570 nm were collected on an ELX800
microplate reader. IC50 values were calculated using percentage of growth versus untreated
control by SPSS.

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G. PING ET AL.
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