Organosilicon compounds as adult T-cell leukemia cell proliferation inhibitors

Article abstract of DOI:10.1248/cpb.c12-00839

Aggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemotherapy, and new lead compounds are required for the development of drugs to treat this fatal disease. Recently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene (TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives. Among them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate. This result, as well as computational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these inhibitors.

Full text of DOI:10.1248/cpb.c12-00839

February 2013
Note
Chem. Pharm. Bull. 61(2) 237–241 (2013)
237
Organosilicon Compounds as Adult T-Cell Leukemia Cell Proliferation
Inhibitors
Masaharu Nakamura,a Yotaro Matsumoto,a Masaaki Toyama,b Masanori Baba,b and
,a
Yuichi Hashimoto*
a Institute of Molecular and Cellular Biosciences, The University of Tokyo; 1–1–1 Yayoi, Bunkyo-ku, Tokyo 113–0032,
b
Japan: and Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and
Dental Sciences, Kagoshima University; 8–35–1 Sakuragaoka, Kagoshima 890–8544, Japan.
Received September 23, 2012; accepted November 2, 2012
Aggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemo-
therapy, and new lead compounds are required for the development of drugs to treat this fatal disease. Re-
cently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene
(TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives. Among
them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though
its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate. This result, as well as compu-
tational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these
inhibitors.
Key words silicon; adult T-cell leukemia; tetrahydrotetramethylnaphthalene skeleton; T-lymphotropic virus
type 1; sila-substitution
Adult T-cell leukemia (ATL), an aggressive neoplasm of the carba-control compound 10. Silanediol has been reported
mature helper T cells, is caused by human T-lymphotropic to exist predominantly in diol form, while its carba-analog ex-
virus type 1 (HTLV-1) infection.1,2) Epidemiological studies ists predominantly in carbonyl form11) (Fig. 2).
indicate that approximately 15 to 20 million HTLV-1 carriers
First, we performed computational studies to examine the
exist throughout the world, with endemic areas in Japan, the similarities and differences between sila- and carba-analogs.
Caribbean, and Africa.3) In Japan, the number of HTLV-1 car- Generally, silicon has a longer bond distance than carbon,
riers is estimated to be 1.2 million, and more than 700 cases of and its electronegativity is small. Next, we focused on the
ATL are diagnosed every year.4) Since conventional anticancer designed compounds 8 and 10 (Figs. 4, 5). Structure optimi-
chemotherapy active against other lymphoid malignancies has zations were performed at the M06/6-31+G* level of theory
proved to be ineffective for treating aggressive types of ATL, with the Gaussian 09 program package.12) As shown in Fig. 4,
it is important to find or design superior lead compounds for due to the different covalent radii of carbon and silicon, the
the development of drugs to treat this fatal disease.5–7)
silicon compound 8 differs in size and shape from the carbon
Recently, we have succeeded in the development of ATL analogue 10, though the electrostatic potentials of 8 and 10 are
cell-selective proliferation inhibitors with a tetrahydrotet- very similar (Fig. 5). Therefore, we examined the ATL cell-
ramethylnaphthalene (TMN) skeleton. Among them, sev- inhibitory activity of various sila- and carba-analogs.
eral ketone compounds, including 2-acetyl-5,6,7,8-tetrahydro-
Chemistry Compounds 1–13 were prepared by usual or-
5,5,8,8-tetramethylnaphthalene (1) (Fig. 1), exhibited ATL ganic synthetic methods as illustrated in Chart 1. Compound 1
cell-selective growth-inhibitory activity.8,9) Furthermore, sila- was prepared according to the reported method.8) The silandi-
substitution (C/Si exchange) of existing drugs is an established ol derivatives 5 and 6 were synthesized as follows. Compound
approach to find new drug candidates that have beneficial 2, which was prepared as reported,13) was converted by means
biological properties and a clear intellectual property position.
Several organosilicon agents have advanced to clinical stud-
ies.10)
In the present paper, we report the synthesis and structure–
activity relationships of silanediol, which is an isostere of
ketone11) (Fig. 2), and silanol derivatives of our TMN-based
inhibitors (Fig. 3). We also describe the results of a computa-
tional study of these compounds.
Fig. 1. Structure of 2-Acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaph-
thalene (1)
Results and Discussion
Molecular Design and Computational Studies Our
previous structure–activity relationship studies of 2-acetyl-
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (1) for ATL
cell-selective proliferation-inhibiting activity suggested that
the enol form of 1 is the active form.8) Therefore, we designed
a number of silanol and silanediol derivatives 5–9, as well as
Fig. 2. Comparison of the Hydration Equilibrium for Ketone and Sila-
The authors declare no conflict of interest.
none (Silanediol) Moieties
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: hashimot@iam.u-tokyo.ac.jp

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Vol. 61, No. 2
Fig. 3. Chemical Structures of Compounds 5–13
Fig. 4. Superpositions of the Calculated Structures of Compounds 8
and 10 Obtained by Geometry Optimizations
Fig. 5. Electrostatic Potential Field Maps of Compounds 8 and 10
Hydrogen atoms are omitted for clarity.
Fig. 6. Electrostatic Potential Field Maps of the Compounds 12 and 13

February 2013
239
a) NaNO3, HBr aq, CuBr (b) i-PrMgBr–LiCl, tetrahydrofuran (THF), RSiCl3 (R= Me, Ph) (c) LAH, THF (d) Pd–C, 1,4-dioxane (e) n-BuLi–hexane, THF, MeSiCl3 (f)
n-BuLi–hexane, THF, Me2SiCl2 (R=Me, Et) (g) NaOH aq (h) MeMgBr, THF.
Chart 1
Table 1. Anti-proliferative Activity of Compounds 1 and 5–13 against
S1T and MOLT-4 Cells
of the Sandmeyer reaction to the bromo derivative 3. This was
treated with n-butyllithium (n-BuLi), and then reacted with
methyltrichlorosilane or phenyltrichlorosilane. The reaction
IC50 (µm)
Compounds
SIa)
product was reduced with lithium aluminium hydride (LAH),
and oxidized with Pd/C to give silanediol derivatives 5 and 6.
The silanol derivatives 8, 9, 11 and 13 were synthesized in an
analogous manner. Tertiary alcohol 10 was prepared by the
reaction of methylmagnesium bromide (MeMgBr) with 1.
Cell Biological Assays For screening of ATL cell-selec-
tive inhibitors, two cell lines were adopted: S1T established
from acute-type ATL6,14) and MOLT-4 established from
HTLV-1- negative T-cell leukemia. Chemicals that inhibit pro-
liferation of S1T cells, but not MOLT-4 cells, might be suitable
lead compound(s) for the development of drugs to treat ATL.
The effects of compounds 5–13 on the growth and viability of
S1T and MOLT-4 cells were examined. S1T and MOLT-4 cells
were incubated in the absence or presence of various concen-
trations of test compounds for 4d, then the viable cell num-
S1T
MOLT-4
1b)
5
6
7
8
9
10
11
12
13
6.9
5.63
23.2
66.0
63.1
40.4
9.6
1.1
1.7
—
1.2
1.3
2.1
—
>100
>100
48.0
38.7
28.2
35.7
37.7
73.8
>100
>100
6.3
>100
>100
12.8
—
2.0
a) SI=selectivity index (IC50 value for MOLT-4 cells/IC50 value for S1T cells). b)
Values taken from the literature.8)
ber was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5- comparable to that of silanediol 5. The substitution of a meth-
diphenyltetrazolium bromide (MTT) method, and IC50 values yl group for the ethyl group, that is, compound 9, resulted in
were calculated. The results are shown in Table 1.
a very slight enhancement of the growth-inhibitory activity.
Structure–Activity Relationships Compound 1 showed The corresponding carbon compound of 8, that is, tertiary
S1T cell-selective proliferation-inhibitory activity with a se- alcohol 10, showed about the same activity as 8 toward S1T
lectivity index (SI: IC50 value for MOLT-4 cells/IC50 value for cells. This result suggests that silanol can be used as a bioiso-
S1T cells) value of 9.6. Silanediol 5 showed weaker activity to- stere of tertiary alcohol. Like compound 7, compound 11 was
ward S1T cells, but with retention of activity toward MOLT-4 inactive (IC50 >100). The tetramethylcyclohexane moiety of
cells, resulting in loss of cell type selectivity (SI value of the above-mentioned compounds seems to be essential for the
1.1). The substitution of a methyl group for the phenyl group, activity. Compound 13 showed the highest growth-inhibitory
that is, compound 6, increased the growth-inhibitory activity activity towards both S1T and MOLT-4 cells and the high-
towards both S1T and MOLT-4 cells, and the SI value was est S1T selectivity (SI value of 2.0) among the silicon com-
higher than that of 5 (SI value of 1.7). Compound 7, in which pounds in this study. Deletion of the hydroxyl group of 13,
the TMN skeleton was replaced with a benzene ring, was in- that is, compound 12, resulted in loss of activity (IC50 >100).
active (IC50 >100). Silanol 8 showed activity and selectivity Thus, it appears that the hydroxyl moiety is important for the

240
Vol. 61, No. 2
growth-inhibitory activity.
13C-NMR (500MHz, CDCl3) δ: 146.60, 144.23, 135.54, 131.47,
The electrostatic potentials of 12m and 13m (model com- 130.20, 126.06, 35.19, 35.01, 34.32, 34.21, 31.90, 31.77, 0.00.
pounds of 12, 13, respectively) were calculated. As shown in HR-MS (FAB+) m/z: Calcd for C16H26OSi 262.1753, Found
Fig. 6, the hydroxyl group impacts significantly on the elec- 262.1749 (M+).
tron density pattern and electrostatic potential.
Diethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)silanol (9): Colorless oil. 1H-NMR (500MHz, CDCl3) δ:
7.51 (1H, s), 7.31 (2H, m), 1.68 (4H, s), 1.29 (6H, s), 1.28 (6H,
Conclusion
We designed silicon analogs of various TMN derivatives s), 1.03 (6H, t, J=7.9Hz), 0.85 (4H, q, J=7.9Hz). 13C-NMR
that we had previously found to show ATL cell-selective pro- (500MHz, CDCl3) δ: 146.32, 144.03, 133.64, 131.97, 130.55,
liferation-inhibitory activity, based on computational studies. 125.90, 35.15, 35.01, 34.26, 34.12, 31.88, 31.73, 6.67, 6.34.
Among the synthesized compounds, 13 showed the most po- HR-MS (FAB+) m/z: Calcd for C18H30OSi 290.2066, Found
tent growth-inhibitory activity towards S1T cells, though the 290.2061 (M+).
selectivity over non-ATL MOLT-4 cells was only moderate (SI
Dimethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
value of 2.0). These results suggest that sila-substitution (C–Si yl)silanol (10): Pale yellow solid. mp 89–90°C. 1H-NMR
exchange) is a useful approach for structure optimization of (500MHz, CDCl3) δ: 7.44 (1H, d, J=1.8Hz), 7.27 (1H, dd,
these inhibitors. The next requirement is to improve the selec- J=1.8, 7.9Hz), 7.21 (1H, d, J=7.9Hz), 1.68 (4H, s), 1.57 (6H,
tivity for ATL cells.
s), 1.29 (6H, s), 1.28 (6H, s). 13C-NMR (500MHz, CDCl3) δ:
145.97, 144.57, 143.23, 126.26, 122.27, 121.82, 72.46, 35.23,
35.08, 34.40, 33.98, 31.90, 31.84, 31.6. HR-MS (FAB+) m/z:
Experimental
General Comments 1H-NMR spectra were recorded on a Calcd for C17H26O 246.1984, Found 246.1972 (M+).
JEOL JNM-GX500 (500MHz) spectrometer. Chemical shifts
Methylbis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
are expressed in parts per million relative to tetramethylsilane. 2-yl)silane (12): White solid. mp 96–97°C. 1H-NMR
Mass spectra were recorded on a JEOL JMS-DX303 spec- (500MHz, CDCl3) δ: 7.51 (2H, s), 7.31 (2H, s), 7.30 (2H, s),
trometer. Melting points were determined on a MP-J3 melting 4.88 (1H, q, J=3.7Hz), 1.67 (8H, s), 1.27 (12H, s), 1.26 (12H,
point apparatus (Yanaco, Japan).
Dimethyl(phenyl)silanol 11 was purchased from Wako Pure 146.17, 144.15, 133.29, 131.94, 131.81, 126.02, 35.18, 35.04,
s), 0.59 (3H, d, J=3.7Hz). 13C-NMR (500MHz, CDCl3) δ:
Chemical Industries, Ltd. (Japan).
34.27, 34.17, 31.87, 31.76, −4.78. HR-MS (FAB+) m/z: Calcd
Spectral Data for Compounds 3–13 6-Bromo-1,1,4,4- for C29H41Si 417.2978, Found 417.2976 (M−H+). Calcd for
tetramethyl-1,2,3,4-tetrahydronaphthalene (3): Colorless oil. C29H42Si 418.3056, Found 418.3035 (M+).
1H-NMR (500MHz, CDCl3) δ: 7.40 (1H, d, J=1.9Hz), 7.22
Methylbis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
(1H, dd, J=1.9, 8.5Hz), 7.16 (1H, d, J=8.5Hz), 1.67 (4H, s), 2-yl)silanol (13): White solid. mp 131–132°C. 1H-NMR
1.26 (6H, s), 1.25 (6H, s). 13C-NMR (500MHz, CDCl3) δ: (500MHz, CDCl3) δ: 7.58 (2H, s), 7.36 (2H, d, J=7.9Hz), 7.31
147.41, 143.87, 129.43, 128.64, 128.46, 119.35, 34.87, 34.83, (2H, d, J=7.9Hz), 1.68 (8H, s), 1.28 (12H, s), 1.27 (12H, s),
34.48, 34.08, 31.87, 31.73. MS (FAB+) m/z: 268 (M+H+).
0.64 (3H, s). 13C-NMR (500MHz, CDCl3) δ: 146.61, 144.11,
Methyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- 133.74, 132.40, 131.03, 125.97, 35.18, 35.01, 34.31, 34.18,
1
yl)silanediol (5): White paste. H-NMR (500MHz, CDCl3) δ: 31.88, 31.74, −1.09. HR-MS (FAB+) m/z: calcd for C29H42OSi
7.60 (1H, s), 7.40 (1H, s), 7.32 (1H, s), 2.98 (2H, s), 1.68 (4H, 434.3005, Found 434.3001 (M+).
s), 1.29 (6H, s), 1.28 (6H, s), 0.39 (3H, s). 13C-NMR (500MHz,
Computational Methods All calculations were carried
CDCl3) δ: 147.31, 144.36, 132.66, 131.85, 130.51, 126.16, 35.11, with the Gaussian 09 program package. Geometry optimiza-
34.93, 34.34, 34.18, 31.84, 31.72. High resolution (HR)-MS tion and vibrational analysis were performed at the M06/6-31+
(FAB+) m/z: Calcd for C15H24O2SiLi 271.1706, Found 271.1693 G* level of theory. All stationary points were optimized with-
(M+Li+).
out any symmetry assumptions, and characterized by normal
Phenyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- coordinate analysis at the same level of the theory (number of
yl)silanediol (6): White solid. mp 98–100°C. 1H-NMR imaginary frequencies, NIMAG, 0 for minima).
(500MHz, CDCl3) δ: 7.70 (2H, d, J=6.7Hz), 7.66 (1H, s),
7.44–7.31 (4H, m), 7.30 (1H, d, J=8.0Hz), 1.68 (4H, s), 1.27
Acknowledgments The work described in this paper was
(6H, s), 1.26 (6H, s). 13C-NMR (500MHz, CDCl3) δ: 147.50, partially supported by Grant-in-Aid for Scientific Research
144.35, 134.54, 134.45, 134.35, 132.75, 131.34, 130.66, 130.36, from the Ministry of Education, Culture, Sports, Science and
127.90, 126.16, 35.10, 34.93, 34.36, 34.18, 31.83, 31.70. HR-MS Technology of Japan, and a Grant from the Japan Society for
(FAB+) m/z: Calcd for C20H26O2SiLi 333.1862, Found 333.1872 the Promotion of Science.
(M+Li+).
References
Methyl(phenyl)silanediol (7): White solid. mp 83–84°C
(lit. 85–86°C). 1H-NMR (500MHz, CDCl3) δ: 7.61 (2H, d,
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133.46, 130.29, 127.96, −1.80. HR-MS (FAB+) m/z: Calcd for
C7H10O2Si 154.0450, Found 154.0443 (M+).
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