- Research Article
- Open Access
Synthesis and biological evaluation of a new series of ortho-carboranyl biphenyloxime derivatives
© The Author(s) 2018
Received: 22 May 2018
Accepted: 22 June 2018
Published: 29 June 2018
All manipulations were performed under a dry nitrogen atmosphere using standard Schlenk techniques. Tetrahydrofuran (THF) was purchased from Aladdin Pure Chemical Company and dried over sodium metal distillation prior use. The reactions were monitored on Merck F-254 pre-coated TLC plastic sheets using hexane as the mobile phase. All yields refer to the isolated yields of the products after column chromatography using silica gel (200–230 mesh). All glassware, syringes, magnetic stirring bars, and needles were dried overnight in a convection oven. Ortho-carborane (C2H2B10H10) was purchased from HENAN WANXIANG Fine Chemical Company and used after sublimation. The NMR spectra were recorded on a Bruker 300 spectrometer operated and the chemical shifts were measured relative to the internal residual peaks from the lock solvent (99.9% CDCl3 and CD3COCD3), and then referenced to Si(CH3)4 (0.00 ppm). The Fourier transform infrared (FTIR) spectra of the samples were recorded on an Agilent Cary 600 Series FT-IR spectrometer using KBr disks. Elemental analyses were performed using a Carlo Erba Instruments CHNS–O EA1108 analyzer (Additional file 1).
Synthetic routes and experimental data
Synthesis of bis(3-methoxybenzyl)-ortho-carborane (1). A 2.5 M n-BuLi (4.0 mL, 10 mmol) solution was added via a syringe to a solution of o-carborane (1.44 g, 10 mmol) in 50 mL of THF at − 78 °C. A solution of 1-(bromomethyl)-3-methoxybenzene (4.22 g, 21 mmol) in THF 10 mL was added slowly to the reaction flask at − 78 °C, and the reaction temperature was maintained at − 78 °C for 1 h. The reaction mixture was then warmed slowly to room temperature, stirred for an additional 12 h, and quenched with distilled H2O (30 mL). The crude product was then extracted with methylene chloride (30 mL × 3). The organic layer was washed with H2O, dried with anhydrous Na2SO4, and filtered then concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:10) to give compound 1 as a colorless oil: yield: 3.6 g (93%). IR(KBr pellet), cm−1, ν: (B-Ho-carborane) 2593. 1HNMR (CDCl3), δ, ppm: 3.2–0.8 (br, B-Ho-carborane, 10H), 3.61 (s, –CH2, 4H), 3.83 (s, –OCH3, 6H), 6.77 (s, 1-Hbenzene, 2H), 6.84–6.82 (d, J = 6.9 Hz, 2-Hbenzene, 2H), 6.90–6.88 (d, J = 6.9 Hz, 3-Hbenzene, 2H), 7.32–7.29 (m, 4-Hbenzene, 2H). Found, %: C 56.31; H 7.65. C18H28B10O2. Calculated, %: C 56.23; H 7.34.
Synthesis of 1,1′-(4-caboranyldimethyl)-bis(2-methoxy-4,1-phenylene-ethan-1-one) (2). Acetyl chloride (1.4 mL, 20 mmol) was added via a syringe to a solution of aluminum chloride (2.6 g, 20 mmol) in 50 mL of methylene chloride at 0 °C and stirred for 30 min. A solution of compound 1 (3.5 g, 10 mmol) in methylene chloride 10 mL was added slowly to the reaction flask at 0 °C, and the reaction temperature was maintained at 0 °C for 30 min. The reaction mixture was then warmed slowly to room temperature, stirred for an additional 3 h, and quenched with a saturated NaHCO3 (30 mL) solution. The crude product was then extracted, and the organic layer was washed with H2O, dried with anhydrous Na2SO4, and filtered then concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:8) to give compound 2 as a colorless oil: yield: 4.1 g (97%). IR (KBr pellet), cm−1, ν: (B-Ho-carborane) 2602. 1HNMR(CDCl3), δ, ppm: 3.2–0.8 (br, B-Ho-carborane, 10H), 3.64 (s, –CH3, 6H), 3.66 (s, –CH2, 4H), 3.95 (s, –OCH3, 6H), 6.82 (s, 1-Hbenzene, 2H), 6.89–6.86 (d, J = 7.8 Hz, 2-Hbenzene, 2H), 7.77–7.74 (d, J = 7.8 Hz, 3-Hbenzene, 2H). Found, %: C 56.42; H 6.67. C22H32B10O4. Calculated, %: C 56.39; H 6.88.
Synthesis of (Z,Z′)-1,1′-(4-caboranyldimethyl)-bis(2-methoxyphenylethan-1-oxime) (3). A solution of compound 2 (3.8 g, 8.1 mmol) and hydroxylamine (1.2 g, 17.8 mmol) in 40 mL of methanol was heated under reflux for 2 h. The reaction mixture was then cooled to room temperature, and the crude product was concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:4) to give compound 3 as a colorless oil: Yield: 3.7 g (92%). IR (KBr pellet), cm−1, ν: (B-Ho-carborane) 2586. 1H NMR (CD3COCD3), δ, ppm: 3.16 (s, –CH3, 6H), 3.2–0.8 (br, B-Ho-carborane, 10H), 3.88 (s, –OCH3, 6H), 3.93 (s, –CH2, 4H), 6.97–6.95 (d, J = 7.5 Hz, 2-Hbenzene, 2H), 7.05 (s, 1-Hbenzene, 2H), 7.30–7.28 (d, J = 7.5 Hz, 3-Hbenzene, 2H). Found, %: C 52.68; H 6.81; N 5.69. C22H34B10N2O4. Calculated, %: C 52.99; H 6.87; N 5.62.
Synthesis of (1Z,1′Z)-1,1′-(carboranyldimethyl)-bis(2-methoxy-4,1-phenylene-ethan-1-one)-O,O-dipyridin-2-ylmethyldioxime (4). A solution of compound 3 (0.7 g, 1.4 mmol) and potassium carbonate (0.4 g, 3.0 mmol) in 10 mL of acetonitrile was stirred at room temperature for 30 min. Subsequently, (2-bromomethyl)pyridine (0.5 g, 3.0 mmol) was added at room temperature, and then heated under reflux for 5 h. The crude product was then concentrated, and the residue was purified by flash column chromatography (ethyl acetate/hexane 1:4) to give compound 4 as a yellow oil: Yield: 0.8 g (88%). IR (KBr pellet), cm−1, ν: (B-Ho-carborane) 2607. 1HNMR (CD3Cl), δ, ppm: 2.31 (s, –CH2, 6H), 3.2–0.8 (br, B-Ho-carborane, 10H), 3.63 (s, –CH3, 4H), 3.84 (s, –OCH3, 6H), 5.37 (s, –CH2, 2H), 6.73 (s, 1-Hbenzene, 2H), 6.80–6.77 (d, J = 7.8 Hz, 2-Hbenzene, 2H), 7.29–7.24 (m, 3-Hbenzene and pyridine, 4H), 7.47–7.44 (d, J = 7.8 Hz, 3-Hpyridine, 2H), 7.76–7.70 (t, J = 7.8 Hz, 2-Hpyridine, 2H), 8.61–8.59 (d, J = 4.8 Hz, 1-Hpyridine, 2H). Found, %: C 59.36; H 6.63; N 8.35. C34H44B10N4O4. Calculated, %: C 59.98; H 6.51; N 8.23.
Synthesis of (1Z,1′Z)-1,1′-(carboranyldimethyl)-bis(2-methoxy-4,1-phenylene-ethan-1-one)-O,O-di(2-phenoxyethyl)dioxime (5). A procedure analogous to the preparation of 4 was used and a colorless oil was obtained. Yield: 0.9 g (89%). IR (KBr pellet), cm−1, ν: (B-Ho-carborane) 2577. 1H NMR (CD3Cl) δ, ppm: 2.22 (s, –CH3, 6H), 3.2–0.8 (br, B-Ho-carborane, 10H), 3.64 (s, –CH2, 4H), 3.85 (s, –OCH3, 6H), 4.31–4.28 (t, J = 4.8 Hz, –CH2 alkyl-1, 4H), 4.56–4.52 (t, J = 5.1 Hz, –CH2 alkyl-2 4H), 6.75 (s, 1-Hbenzene-1 2H), 6.83–6.80 (d, J = 7.5 Hz, 2-Hbenzene-1, 2H), 7.00–6.95 (m, 1-Hbenzene-2, 6H), 7.34–7.29 (m, 2-Hbenzene-1 and 2, 6H). Found, %: C 61.47; H 6.92; N 3.84. C38H50B10N2O6. Calculated, %: C 61.77; H 6.82; N 3.79.
Synthesis of (1Z,1′Z)-1,1′-(carboranyldimethyl)-bis(2-methoxy-4,1-phenylene-ethan-1-one)-O,O-di(3-phenoxypropyl)dioxime (6). A procedure analogous to the preparation of 4 was used and a colorless oil was obtained. Yield: 0.9 g (86%). IR (KBr pellet), cm−1, ν: (B–H) 2589. 1H NMR(CD3Cl), δ, ppm: 2.25–2.17 (m, –CH3 and -CH2 alkyl-1, 10H), 3.2–0.8 (br, B-Ho-carborane, 10H), 3.64 (s, –CH2, 4H), 3.85 (s, –OCH3, 6H), 4.16–4.12 (t, J = 6.0 Hz, –CH2 alkyl-2, 4H), 4.40–4.36 (t, J = 6.0 Hz, –CH2 alkyl-3, 4H), 6.74 (s, 1-Hbenzene-1, 2H), 6.82–6.79 (d, J = 7.8 Hz, 2-Hbenzene-1, 2H), 6.96–6.93 (m, 1-Hbenzene-2, 6H), 7.33–7.30 (m, 2-Hbenzene-1 and 2, 6H). Found, %: C 62.52; H 7.12; N 3.77. C40H54B10N2O6. Calculated, %: C 62.64; H 7.10; N 3.65.
Synthesis of (1Z,1′Z)-1,1′-(carboranyldimethyl)-bis(2-methoxy-4,1-phenylene-ethan-1-one)-O,O-di(2-piperidin-1-ylethyl)dioxime (7). A procedure analogous to the preparation of 4 was used and a colorless oil was obtained. Yield: 0.8 g (82%) colorless oil. IR (KBr pellet), cm−1, ν: (B-Ho-carborane) 2591. 1H NMR (CD3Cl), δ, ppm: 1.47–1.45 (m, 1-Hpiperidine, 4H), 1.64–1.60 (m, 2-Hpiperidine, 4H), 1.88–1.86 (m, 3-Hpiperidine, 4H), 2.19 (s, –CH3, 6H), 2.53–2.51 (m, 8H), 2.76–2.72 (t, J = 6.0 Hz, –CH2 alkyl-1, 4H), 3.2–0.8 (br, B-Ho-carborane, 10H), 3.63 (s, –CH2, 4H), 3.85 (s, –OCH3, 6H), 4.36–4.32 (t, J = 6.0 Hz, –CH2 alkyl-2, 4H), 6.74 (s, 1-Hbenzene, 2H), 6.82–6.79 (d, J = 7.8 Hz, 2-Hbenzene, 2H), 7.31–7.29 (d, J = 7.8 Hz, 3-Hbenzene, 2H). Found, %: C 59.65; H 8.34; N 7.68. C36H60B10N4O4. C 59.97; H 8.39; N 7.77.
Synthesis of (1Z,1′Z)-1,1′-(carboranyldimethyl)-bis(2-methoxy-4,1-phenylene-ethan-1-one)-O,O-di(2-morpholinoethyl)dioxime (8). A procedure analogous to the preparation of 4 was used and a colorless oil was obtained. Yield: 0.9 g (84%). IR (KBr pellet), cm−1, ν: (B-Ho-carborane) 2596. 1HNMR (CD3Cl), δ, ppm: 2.52 (s, –CH3, 6H), 2.55–2.54 (m, –CH2 alkyl-1, 4H), 2.77–2.72 (t, J = 6.9 Hz, –CH2 alkyl-2, 4H), 3.2–0.8 (br, B-Ho-carborane, 10H), 3.64–3.59 (m, 1-Hmorpholine, 8H), 3.76–3.73 (m, 2-Hmorpholine, 8H), 3.85 (s, –OCH3, 6H), 6.83–6.76 (m, 2-Hbenzene, 4H), 7.31 (s, 2-Hbenzene, 2H). Found, %: C 56.38; H 7.83; N 7.64. C34H56B10N4O6. C 56.33; H 7.79; N 7.73.
Cell viability assay (MTT assay)
HeLa cells in a 3 × 104/mL cell suspension per hole in 96 well plates were digested by adding 100 μL of a cell suspension and culturing for 24 h to absorb the original culture medium followed by the addition of 200 μL configured compounds-4, 5, 6, 7, 8 and BPA (l-boronphenylalanine). Each concentration was made from 4 compound holes, and the holes around the 96 well plates were sealed with PBS, the negative control. The blank control group lacked the compounds. After 24 h, 20 μL of a MTT solution was added to each hole, and cultured for 4 h. Subsequently, DMSO 150 μL was added to the medium through a suction hole and shaken for 10 min. The OD of each hole was determined at 490 nM, and the sample inhibition rate in different concentrations was calculated: inhibition rate = (Control OD value/Delivery OD value)/Control OD value × 100%. Finally, the IC50 value of the sample was calculated using the related software.
HeLa cells (5 × 103) were incubated for 48 h in the presence of various concentrations of compounds 4, 5, 6, 7, 8, and BPA. After washing three times, the cumulative boron concentration was determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) [15, 16]. (± is the average value).
Results and discussion
This paper reports the hydrophilic function of the ortho-carboranylbenzyloxime moiety, such as alkylmorpholine, alkylpiperidine, phenoxyalkyl and pyridine, on carbon–oxygen combined with chemical bonding. These compounds have higher solubility in polar solvents and increasing boron uptake in tumor cells within the organization for a drug evaluation.
Cytotoxicity (IC50) to HeLa cervical carcinoma cells
Cytotoxicity IC50 (μM)a
Boron uptake (ppm)
2.516 ± 0.022
0.127 ± 0.113
1.924 ± 0.014
0.106 ± 0.120
2.383 ± 0.301
0.114 ± 0.015
1.582 ± 0.027
0.481 ± 0.026
1.134 ± 0.035
0.520 ± 0.017
4.16 ± 0.021
0.226 ± 0.016
In conclusion, we reported the series of ortho-carborane substituted bipolar-function derivatives, such as alkyl pyridine, alkyl phenoxide, alkyl morpholine, and alkyl piperidine, were synthesized. The target compounds coupling of the aryl-oxime with chain functional group proceeded successfully for introduction of an ortho-carborane moiety in the molecules, which can easily be further four-step substituted to high yield final compound. The effects of synthesized compounds on biology activity were assay in HeLa cells. Both cyclic alkyl derivatives of ortho-carborane and oxime containing compounds, 7 and 8, respectively, were exhibit high boron uptake and higher cytotoxicity than BPA (l-boronphenylalanine). This resulted in carborane compounds with improved water solubility for the BNCT agent. The knowledge gained from modified bipolar groups could facilitate both drug selection and evaluations.
XFY designed and finalized the scheme; LRJ performed review work and JGF wrote the paper. All authors read and approved the final manuscript.
This study was supported financially by the scientific research foundation of Jiangsu University (Grant No. 5501290005).
The authors declare that they have no competing interests.
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