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M.P. Chelopo et al. / European Journal of Medicinal Chemistry 66 (2013) 407e414
4. Conclusions
3.59 (q, J ¼ 7.0 Hz, 1H), 3.62 (dd, J ¼ 5.0, 11.5 Hz, 1H), 4.22 (s, 2H);
6.49 (d, J ¼ 13.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) ꢃ4.05, 18.37,
25.96, 29.61, 31.64, 41.27, 45.01, 46.88, 50.22, 52.09, 55.40e55.95,
112.15, 115.36, 118.22, 121.13, 124.40e129.00, 145.25, 162.83, 173.56;
HRMS m/z ¼ 452.2714 [M þ H]þ for C23H41NO4Si2.
Novel organometallic Ru(II) complexes bearing amino alcohol TIQ
ligands were successfully prepared and tested for anticancer activity.
These complexes exhibited moderate activity against MCF-7 cancer
cells with IC50 values ranging from 34 to 218 mM. Complex C5 gave the
lowest activity and C4 the highest. This was surprising as the com-
pounds differ byonlyone diastereomeric centre. The complexes were
inactive against the A549 and MDA-MB-231 cell lines. The most
interesting result observed was the remarkable selectivity displayed
for MCF-7 cells in comparison to normal MDBK cells. Our results
indicate that ruthenium N,O-complexes are capable of effective ac-
tivity and are more selective than reported platinum based drugs.
5.1.2. (S)-Methyl 6-(tert-butyldimethylsilyloxy)-7-hydroxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate 8
Compound 8 was obtained in 27% yield; Rf ¼ 0.4 (8:2 tolue-
ne:ethanol)); 1H NMR (400 MHz, CDCl3) 0.15 (d, J ¼ 1.75 Hz, 6H),
0.91 (s, 9), 2.72 (d, J ¼ 10.2 Hz, 1H), 2.84-2.89 (m, 2H), 3.59 (dd,
J ¼ 4.64, 10.2 Hz, 1H), 3.67 (s, 3H), 3.89 (d, J ¼ 8.2 Hz, 2H); 6.45 (q,
J ¼ 19.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) ꢃ4.48, 18.12, 25.86,
30.95, 47.04, 51.93, 56.00, 112.00, 115.06, 118.11, 124.42, 126.58,
128.89, 145.60, HRMS m/z ¼ 338.1787 [M þ H]þ for: C17H27NO4Si.
5. Experimental
All reagents and solvents were purchased from SigmaeAldrich,
Merck and Fluka, except if stated otherwise. 1H and 13C NMR
spectra were recorded on a Bruker AVANCE III 400 MHz instrument,
the 1H NMR spectrum was recorded at 400.222 MHz and the 13C
NMR spectrum was recorded at 100.635 MHz. Chemical shifts are
reported in ppm, referenced to the solvent used, CDCl3, MeOD, D2O
and D6-DMSO [42]. Coupling constants are expressed in Hz. NMR
spectra were obtained at room temperature. Infrared (IR) spectra
were obtained on a Perkin Elmer Spectrum 100 instrument with an
ATR attachment. Optical rotations were carried out on a Perkin
Elmer 341 polarimeter. Liquid chromatography mass spectroscopic
LC-MS data were obtained from a Shimadzu LC-MS 2020 with
solvent A [0.1% FA in H2O] and solvent B (0.1% FA in acetonitrile).
HRMS were determined using a Bruker ESI-QTOF mass spectrom-
eter in positive mode. Microwave reactions were performed with a
Discovery CEM Liberty automated microwave synthesizer. Some of
the diamine ligands were purified using a C-18 reverse phase semi-
preparative HPLC on LC-8A Shimadzu with 0.1% FA in H2O as sol-
vent A and 0.1% FA in methanol as solvent B as eluents. Thin layer
chromatography (TLC) was carried out using Merck Kieselgel 60
F254 and all crude compounds were purified via column chroma-
tography using silica gel 60e200 mesh. Solvents were dried using
standard procedures from Vogel [43].
5.2. General procedure for the preparation of 15aee
The experimental procedure was adapted from litera-
ture [45,46]. A solution of TIQ ester 4aee (2.0 g) was added drop-
wise to a stirred suspension of LiAlH4 (4 mol equiv) in cooled (0 ꢁC
in ice) dry THF (80 mL) under argon gas flow. The reaction mixture
was stirred at 0 ꢁC for 1.5 h and then at room temperature for 2 h.
The reaction was monitored with TLC (7:3 hexane:ethyl acetate) to
confirm the completion of the reaction. After that, THF (20 mL) was
added to dilute the reaction mixture and excess LiAlH4 was
decomposed by the dropwise addition of saturated Na2SO4 at 0 ꢁC.
The inorganic salts were filtered and washed with portions of EtOAc
(3 ꢀ 20 mL). The organic filtrate was dried over MgSO4 and
concentrated in vacuo to give product as a yellow solid.
5.2.1. (S)-1,2,3,4-Tetrahydroisoquin-3-yl methanol 15a [47]
The compound 15a was prepared from 4a, according to general
procedure B, in 65% yield, mp 113e115 ꢁC (93e96 ꢁC) [47];
nmax (neat)/cmꢃ1 3280, 3245, 3047, 2801 1499, 1451, 1058, 1001 and
736 cmꢃ1, 1H NMR (400 MHz, CDCl3) 2.56 (dd, J ¼ 10.6, 26.7 Hz, 1H),
2.69 (dd, J ¼ 4.3, 21.3 Hz, 1H), 3.08 (m, 1H), 3.52 (dd, J ¼ 7.9, 10.9 Hz,
1H), 3.78 (dd, J ¼ 3.8, 10.9 Hz, 1H), 4.04 (s, 2H), 6.91-7.01 (m, 4H); 13
C
NMR (100 MHz, CDCl3) 31.95, 56.55, 66.32, 126.95, 127,29, 127.41,
130.23, 135.09, 135.91; HRMS m/z ¼ 164. [M þ H] þ for: C10H13NO.
5.1. Experimental procedures for preparation of TIQ amino esters
5.2.2. (S)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquin-3-yl methanol
15b [48]
Synthesis of the known intermediates (3e14) and TIQ ester
(4a,b,d,e) can be found in the Supplementary information section.
The compound 15b was prepared from 4b, according to general
procedure B, in 78% yield, mp 109e113 ꢁC (130e134 ꢁC) [48];
5.1.1. (S)-Methyl-6,7-bis(tert-butyldimethylsilyloxy)-1,2,3,4-tetra-
hydroisoquinoline 4c
[a
]
20 þ 21.85 (c ¼ 1.00, in CHCl3), nmax (neat)/cmꢃ1 3258, 3130, 2937,
D
2834, 1610, 1518, 1463, 1227, 1075 and 853 cmꢃ1
;
1H NMR
The experimental procedure was adapted from literature [44].
Dry DMF (21 mL) was added to dissolve 7 (3.0 g, 13.00 mmol) and
crystalline solid of TBDMS chloride (5.1 g, 33.40 mmol) under argon
atmosphere. Dry DIPEA (11.7 mL, 67.52 mmol) was added to the
stirred solution (in portions) over a period of 5 min, and the reac-
tion mixture was allowed to stir at room temperature for 4 h. The
reaction was monitored by TLC and it was quenched by adding H2O
(30 mL). The reaction mixture was extracted with portions of EtOAc
(3 ꢀ 30 mL). The organic phase was washed consecutively with 10%
NaHCO3 (20 mL) and H2O (20 mL). The organic phase was dried
over K2CO3 and the solvent was evaporated in vacuo to give mix-
tures of crude 4c and 8 mixtures. The product was purified by
column chromatography using 20% EtOH in toluene to give 4c as a
(400 MHz, CDCl3) 2.53 (dd, J ¼ 11.1 Hz, 1H), 2.65 (dd, J ¼ 4.1 Hz, 1H,
2.96-3.00 (m, 1H), 3.54 (dd, J ¼ 7.5, 10.9 Hz, 1H), 3.70 (dd, J ¼ 4.2,
10.9 Hz, 1H), 3.81 (d, J ¼ 2.2 Hz, 6H), 3.83 (d, J ¼ 2.2 Hz, 1H), 3.97 (d,
J ¼ 4.0 Hz, 2H), 6.61 (d, J ¼ 18.1 Hz, 2H); 13C NMR (100 MHz, CDCl3)
30.02, 46.90, 55.11e55.31, 64.86, 109.39, 112.12, 125.77, 126.48,
131.01, 147.41; HRMS m/z ¼ 224.1341 [M þ H]þ for C12H17NO3.
5.2.3. (S)-6,7-Bis(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydro-
isoquin-3-yl methanol 15c
The compound 15c was prepared from 4c, according to general
procedure B, in 78% yield, mp 111e115 ꢁC; [
a
]
20 ꢃ 43.85 (c ¼ 0.13, in
D
CHCl3) nmax (neat)/cmꢃ1 3394, 3184, 2929, 2856, 1513, 1317, 1249,
879, 833, 778; 1H NMR (400 MHz, CDCl3) 0.17 (s, 12H), 0.97 (s, 18H),
2.42e2.45 (m, 1H), 2.57 (dd, J ¼ 4.43, 7.01 Hz, 1H), 3.01e3.04 (m,
1H), 3.48 (q, J ¼ 7.8 Hz, 1H), 3.69 (q, J ¼ 3.4 Hz, 1H), 3.90 (s, 2H), 6.50
(d, J ¼ 22.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)ꢃ4.01, 18.48, 25.97,
30.30, 47.49, 55.20, 65.96, 118.19, 121.37, 126.25, 128.28, 145.23;
HRMS m/z ¼ 424.2574 [M þ H]þ for C22H41NO3Si2.
viscous brown material. Compound 4c was obtained in 65% yield;
20
Rf ¼ 0.51 (8:2 toluene:ethanol); [
a
]
D
ꢃ 29.50 (c ¼ 1.00, in CHCl3);
nmax (neat)/cmꢃ1 2929, 2857, 1740, 1512, 1252, 835 and 779 cmꢃ1
;
1H NMR (400 MHz, CDCl3) 0.19 (s, 12H), 0.97 (s, 18H), 2.85 (s, 1.5H),
2.98 (s, 3H), 3.20 (dd, J ¼ 5.0, 17.0 Hz, 1H), 3.29 (d, J ¼ 3.2 Hz, 1H),