Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives
- Maralinganadoddi Panchegowda Sadashiva†1,
- Basappa†2, 3,
- Shivananju NanjundaSwamy4,
- Feng Li4,
- Kanjoormana Aryan Manu4,
- Murugan Sengottuvelan2,
- Doddakunche Shivaramu Prasanna1,
- Nirvanappa Chikkagundagal Anilkumar3,
- Gautam Sethi4,
- Kazuyuki Sugahara2 and
- Kanchugarakoppal Subbegowda Rangappa1Email author
© Sadashiva et al.; licensee BioMed Central Ltd. 2012
Received: 6 February 2012
Accepted: 3 September 2012
Published: 3 October 2012
Dibenzoazepine (DB) derivatives are important and valuable compounds in medicinal chemistry. The synthesis and chemotherapeutic properties of naturally occurring DBs and different heterocyclic moiety tethered DBs are reported. Herein, we report the DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules.
Results and Conclusion
The synthesis and characterization of novel ring DB tethered isoxazoline derivatives (DBIs) were carried out. After the detailed structural characterization using 2D-NMR experiments, the compounds were identified as 5-substituted isoxazolines. The effect of newly synthesized DBIs against the invasion of murine osteosarcoma (LM8G7) cells was studied. Among the tested molecules, compound 4g (5-[−3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H- dibenzo[b,f]azepine), was found to inhibit the invasion of LM8G7 cells strongly, when compared to other structurally related compounds. Cumulatively, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 μM. In addition to anti-invasion property the compound 4g also inhibited the migration of LM8G7 and human ovarian cancer cells (OVSAHO) dose-dependently. Compound 4g inhibited the proliferation of LM8G7, OVSAHO, human breast cancer cells (MCF-7) and human melphalan-resistant multiple myeloma (RPMI8226-LR5) cells that are comparable to cisplatin and suramin.
Nucleosides are the building blocks of DNA and become a key molecule in the field of medicinal chemistry for the discovery of new natural nucleoside derivatives. So, extensive modifications have been performed on both the heterocyclic base as well as on the sugar moiety. Mainly, the replacement of the ribose ring with an isoxazolidine nucleus has emerged as an interesting class of dideoxynucleoside analogues[14–16]. These analogues undergo phosphorylation by cellular kinases and metabolized by enzymatic systems instead of natural nucleosides, inserted in the DNA growing chain, and finally acting as chain terminators[17, 18].
In continuation of our effort to synthesise novel DBs and isoxazoli(di)ne derivatives[19–21] herein we report the synthesis of DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules.
Results and Discussion
The dipolarophile 2 was prepared by the reaction of commercially available iminostilbene 1 with allylbromide. The N-allyl pendant arrangement of the intermediate 2 showed a major role in the formation of product. It means that, product will be obtained on the basis of either allyl pendant bent towards the tricyclic ring or disposed outside the ring. The X-ray crystallographic studies revealed that the pendant is disposed outside from the tricyclic aromatic ring.
Progress of the reaction was monitored using TLC. After completion of the reaction, the compounds 4(a-h) were purified using column chromatography. The structures of the final products as well as intermediate were confirmed by NMR, mass and elemental analysis.
1 H and 13 C NMR (HMQC and HMBC) data of the compound, 5-[-3-(4-Chlorophenyl)-4,5-dihydroisoxazol-5-ylmethyl]-5 H dibenzo[b,f]azepine
2D-NMR data (COSY) of the compound, 5-[-3-(4-chlorophenyl)-4, 5-dihydroisoxazol-5-yl methyl]-5 H dibenzo [b,f]azepine
Chemical Shifts in ppm
H 4ax (C-4)
H 4eq (C-4)
H 6a (C-6)
H 6b (C-6)
H 5 (C-5)
DBIs inhibited the invasion of murine osteosarcoma and human breast cancer cells
Compound 4g inhibited the migration of tumor cells
Compound 4g inhibited the proliferation of tumor cells
Inhibition of the proliferation of tumor and endothelial cells by compound 4g
Anti-proliferative activity (IC50inμ M)
30 ± 24
15 ± 0.6
12 ± 0.4
12 ± 2.8
14 ± 24
34 ± 1.4
Compound 4g can induce apoptosis in tumor cells
Absorption–distribution–metabolism–excretion–toxicity (ADMET) properties of DBIs
ADMET-properties of the sugar mimetic isoxazoline molecules by use of Discovery Studio 2.5 version
In conclusion, we herein report the incorporation of isoxazoline ring tethered to dibenzo[b,f]azepine for the first time. After the detailed structural characterization using 2D-NMR experiments, the products were confirmed as 5-substituted isoxazolines. Among the tested compounds, compound 4g was found to inhibit the invasion of LM8G7 cells, when compared to other structurally related DBIs. Also, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 μM. Evident to invasion, the compound 4g also inhibited the migration of LM8G7 and OVSAHO cells dose dependently. As a result, inhibitory activity of compound 4g on proliferation of LM8G7, OVSAHO, MCF-7 and RPMI8226/LR5 cells and was comparable to that of cisplatin and suramin.
Chemical synthesis and reagents
Melting points were determined in capillaries on a Tottoli apparatus and are uncorrected. The NMR experiments 1 H, 13C, HMBC, HMQC were carried out at 500 (125) MHz and the reported chemical shifts (δ) are given in ppm and the coupling constants (J) in Hertz (Hz). Multiplicities of NMR signals are designed as s (singlet), d (doublet), m (multiplet, for unresolved lines). Mass spectra were recorded on a Trio 1000 Thermo Quest spectrometer in the electron impact mode or a Platform Micromass spectrometer in the electro spray mode. TLC was performed on silica gel Alugram SilG/UV254 (Macherey-Nagel). The murine osteosarcoma cell line LM8G7, a highly metastatic murine osteosarcoma cell line with the potential to form tumor nodules in the liver, was cloned from LM8G5 cells as described[26, 27] and cultured in DMEM supplemented with 10% FBS, streptomycin (100 μg/ml), penicillin (100 units/ml), 100X non-essential amino acids, β-mercaptoethanol (50 μM), 100X sodiumpyruvate, and L-glutamine (2 mM) at 37°C in a humidified 5% CO2 atmosphere. Human ovarian cancer cells (OVSAHO) were procured from ATCC and cultured in RPMI media supplemented with 10% FBS, L-glutamine (2 mM), and NaHCO3 (10%). The cells were grown to 80 % confluency before passage, and experiments were restricted to passages 5–20. The human multiple myeloma (MM) cell line RPMI-8226-LR-5 cells were cultured in RPMI 1640 medium containing 1x antibiotic-antimycotic with 10% FBS. RPMI-8226-LR-5 and MCF-7 cells were cultured in RPMI 1640 medium with 10% FBS supplemented with 100 U/mL penicillin and 100 μg/mL streptomycin. MCF-10A cells were cultured in MEGM® mammary epithelial cell complete medium obtained from Lonza, USA.
Synthesis of allyl-5 H dibenzo[b,f]azepine 2
The compound 2 was synthesized using the reported method .
The product is yellow solid. mp: 40–42°C. 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 4.4 (d, 2 H J = 14 Hz), 5.12 (dd, 2 H), 5.28 (dd, 2 H), 5.8 (m, 1 H), 6.76 (s, 2 H), 7.08 (d, 2 H J = 5 Hz), 6.98–7.12 (q, 4 H), 7.2–7.3 (t, 2 H).IR KBr (cm-1): 1315, 1642, 3040, 3072. Anal. Calcd for C17H15N: C, 87.6; H, 6.49; N, 6.0. Found: C, 87.63; H, 6.43; N, 6.0.
General procedure for the DBIs
The weighed amount of aldoxime 3 (2 eq) was dissolved in 10 mL of methylene dichloride taken in a round bottom flask. The solution was made basic using triethylamine (0.05 eq). 2 equivalents of sodiumhypochlorite, followed by tricyclicamine (1 equiv) 2, were added slowly at 0°C to the stirring solution. After complete addition of the reactants stirring was continued until the reaction is completed. The crude residue was purified by silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate with successive increasing the quantity of ethyl acetate, affording the corresponding product 4(a-h).
5-[−3-(2-nitrophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f] azepine 4a
The product is a thick liquid. Yield: 0.229 g (67.3%).1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.28 (dd, 1 H, H4a, J-14.4, 7.5 Hz); 3.37 (dd, 1 H, H4e, J-14.4, 5.2 Hz); 3.51 (dd, 1 H, H6a, J-12.1, 7.8 Hz); 4.33 (dd, 1 H, H6e, J-12.1, 4.1 Hz); 4.88 (m, 1 H, H5); 6.76 (d, 2 H, CH, J-2.1 Hz); 7.1-8.20 ( m, 12 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 38.2 (C-4), 55.6 (C-6), 77.5 (C-5), 124 (CH), 127–144.0 (Ar-C), 158.2 (C-C = N). MS (ESI + ion): m/z = 398.1 [M + H] +. Anal. calcd for C24 H19 N3O3: C, 72.53; H, 4.82; N, 10.57. Found : C, 72.45; H, 4.86; N, 10.48.
5-[−3-(3-nitrophenyl)-4, 5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine 4b
The product is a thick liquid. Yield: 0.224g (65.7 %). 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.24 (dd, 1 H, H4a, J-14.1, 7.2 Hz); 3.37 (dd, 1 H, H4e, J-14.1, 5.0 Hz); 3.45 (dd, 1 H, H6a, J-12.8, 6.8 Hz); 4.33 (dd, 1 H, H6e, J-12.8, 4.6 Hz); 4.77 (m, 1 H, H5); 6.70 (d, 2 H, CH, J-2.1 Hz); 7.4-8.26 (m, 12 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 38.6 (C-4), 54.3 (C-6), 76.4 (C-5), 125.2 (CH), 130–146.2 (Ar-C), 154.8 (C-C = N). MS (ESI + ion): m/z = 398.6 [M + H] +. Anal. calcd for C24 H19 N3O3: C, 72.53; H, 4.82; N, 10.57. Found : C, 72.48; H, 4.78; N, 10.41.
5-[−3-(3,4,5-trimethoxyphenyl)-4,5-dihydroisoxazol-5-yl-methyl]5 H-dibezo[b,f] azepine 4c
The product is a thick liquid. Yield: 0.260 g (68.6%). 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.21 (dd, 1 H, H4a, J-15.8, 9.6 Hz); 3.30 (dd, 1 H, H4e, J-15.8, 6.1 Hz); 3.48 (dd, 1 H, H6a, J-12.5, 8.1 Hz); 3.76 (s, 6 H, OCH3); 3.79(s, 3 H, OCH3); 4.28 (dd, 1 H, H6e, J-13.1, 4.4 Hz); 4.84 (m, 1 H, H5); 6.78 (d, 2 H, CH, J-2.2 Hz); 6.82-7.42 (m, 10 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 37.5 (C-4), 54.7 (C-6), 56.4 (OCH3), 76.9 (C-5), 126 (CH), 128–134.0 (Ar-C), 156.6 (C-C = N). MS (ESI + ion): m/z = 443.5 [M + H] +. Anal. calcd for C27 H26 N2O4: C, 73.2; H, 5.92; N, 6.33. Found : C, 73.15; H, 5.86; N, 6.28.
5-[−3-(4-methoxyphenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f] azepine 4d
The product is a thick liquid. Yield: 0.214g (65.3 %). 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.24 (dd, 1 H, H4a, J-16.8, 9.8 Hz); 3.36 (dd, 1 H, H4e, J-16.8, 6.8 Hz); 3.50 (dd, 1 H, H6a, J-14.8, 8.8 Hz); 3.72 (s, 3 H, OCH3); 4.30 (dd, 1 H, H6e, J-14.8, 4.5 Hz); 4.88 (m, 1 H, H5); 6.64 (d, 2 H, CH, J-2.8 Hz); 6.82-7.32 ( m, 12 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 36.2 (C-4), 53.8 (C-6), 56.8 (OCH3), 76.2 (C-5), 126.8 (CH), 128–136.0 (Ar-C), 158.1 (C-C\= N). MS (ESI + ion): m/z = 383.75 [M + H] +. Anal. calcd for C25 H22 N2O2: C, 78.51; H, 5.80; N, 7.32. Found : C, 78.58; H, 5.89; N, 5.68.
Synthesis of 5-[−3-(pyridyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo [b,f] azepine 4e
The product is thick liquid. Yield: 0.22 g (72.6 %). 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 2.88 (dd, 1 H, H4a, J-16.7, 10.7 Hz); 3.28 (dd, 1 H, H4e, J-16.5, 6.0 Hz); 3.39 (dd, 1 H, H6a, J-13.0, 9.0 Hz); 4.27 (dd, 1 H, H6e, J-12.5, 4.5 Hz); 4.72 (m, 1 H, H5); 6.70 (d, 2 H, CH, J-2.5 Hz); 6.52-8.22 (m, 12 H, Ar-H). 13C NMR: δ 36.4 (C-4), 51.8 (C-6), 75.51 (C-5), 124.22 (CH), 124–152.9 (Ar-C), 158.21 (C-C = N). MS (ESI + ion): m/z =354.0 [M + H] +. Anal. calcd for C23 H19 N3O: C, 78.16; H, 5.42; N, 11.89. Found : C, 78.21; H, 5.34; N, 11.78.
5-[−3-(phenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine 4(f
The product is yellow thick liquid. Yield: 0.23 g (72.3 %). 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.11 (dd, 1 H, H4a, J-15.0, 10.2 Hz); 3.28 (dd, 1 H, H4e, J-15.0, 5.4 Hz); 3.48 (dd, 1 H, H6a, J-12.5, 8.5 Hz); 4.28 (dd, 1 H, H6e, J-12.3, 4.1 Hz); 4.84 (m, 1 H, H5); 6.73 (d, 2 H, CH, J-2.5 Hz); 7.00-7.33 (m, 13 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 36.10 (C-4), 51.25 (C-6), 75.81 (C-5), 121 (CH), 122–131.0 (Ar-C), 153.00 (C-C = N). MS (ESI + ion): m/z =353.1 [M + H] +. Anal. calcd for C24 H19 N2FO: C, 77.82; H, 5.17; N, 7.56. Found : C, 77.9; H, 5.21; N, 7.48.
5-[-3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f] azepine 4g
The product is yellow solid. Yield: 0.25 g (75 %). mp-156–158°C. 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.15 (dd, 1 H, H4a, J-16.7, 10.7 Hz); 3.20 (dd, 1 H, H4e, J-16.5, 6.0 Hz); 3.45 (dd, 1 H, H6a, J-13.0, 9.0 Hz); 4.30 (dd, 1 H, H6e, J-12.5, 4.5 Hz); 4.29 (m, 1 H, H5); 6.73 (d, 2 H, CH, J-2.5 Hz); 7.00-7.52 (m, 12 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 38.54 (C-4), 53.78 (C-6), 78.71 (C-5), 124 (CH), 127–135.9 (Ar-C), 155.56 (C-C = N). MS (ESI + ion): m/z =387.0 [M + H] +. Anal. calcd for C24 H19 N2ClO: C, 74.51; H, 4.95; N, 7.24. Found : C, 75.08; H, 5.14; N, 7.08.
5-[-3-(2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f] azepine 4h
The product is thick liquid. Yield: 0.209 g (69.2 %). 1 H NMR (δ ppm, CDCl3, 500 MHz): δ 3.11 (dd, 1 H, H4a, J-14.7, 9.8 Hz); 3.24 (dd, 1 H, H4e, J-14.7, 5.5 Hz); 3.48 (dd, 1 H, H6a, J-12.0, 7.0 Hz); 4.31 (dd, 1 H, H6e, J-12.0, 3.8 Hz); 4.71 (m, 1 H, H5); 6.68 (d, 2 H, CH, J-2.2 Hz); 6.8-7.62 (m, 11 H, Ar-H). 13C NMR (δ ppm, CDCl3, 125 MHz): δ 34.70 (C-4), 51.80 (C-6), 76.61 (C-5), 123.75 (CH), 128.8-165.9 (Ar-C), 158.80 (C-C = N). MS (ESI + ion): m/z =389.14 [M + H] +. Anal. calcd for C24 H18 N2F2O: C, 74.21; H, 4.67; N, 7.21. Found : C, 74.11; H, 4.54; N, 7.10.
The in vitro invasion assay was performed using bio-coat Matrigel invasion assay system (BD Biosciences, San Jose, CA, USA), according to the manufacturer’s instructions. MDA-MB-231 cells (2 × 105 cells) or LM8G7 cells (2.5 x 104) were suspended in serum-free RPMI 1640 medium or DMEM, respectively and seeded into the Matrigel transwell chambers consisting of polycarbonate membranes with 8-μm pores. After incubation with 1 or 10 μM concentrations of DBIs for 24 h, the upper surfaces of the transwell chambers were wiped with cotton swabs and the invading cells were fixed and stained with crystal violet solution. The invading cell numbers were counted in five randomly selected microscope fields. The % inhibition of the invaded cells was calculated.
In vitro migration assay
The efficacy of LM8G7 cell migration was assessed using the BD BioCoatTM chamber (8 μm PET pores) without Matrigel (BD Biosciences, 8 μm pore size, insert size: 6.4 μm) in vitro. Briefly, single cell suspensions of LM8G7 cells (2.5 x 104) were prepared by detaching and resuspending the cells in DMEM containing 0.1 % BSA. Before the cells were added, the chambers were rehydrated for 2 h in an incubator at 37°C. The lower chambers were filled with DMEM containing 5 % FBS. To the upper chamber, LM8G7 or OVSAHO cells and compound 4g in serum-free DMEM was added. After incubation for 24 h, cells that had passed through the BD BioCoatTM chamber and remained attached to the opposite surface of the membrane are stained with Diff-Quick solution and counted in five random microscopic fields per filter. The % inhibition of the migration of LM8G7 or OVSAHO cells by compound 4g was calculated.
Real-time cell proliferation assay
The cell proliferation assay was done using the RT-CESTM system (ACEA Biosciences, San Diego, CA). Briefly, LM8G7 cells (5x104 cells) were added to ACEA 96X microtiter plates (e-plateTM) in 100 μl of medium. In an experiment, cell monolayer was made and the various concentrations of compound 4g (2 to 75 μM), in 150 μL of DMEM were individually added. The effect of the compounds on the proliferation of LM8G7 or OVSAHO cells was continuously monitored up to 48 hours for every 10 min. The proliferation was monitored for a period of 70 h and expressed as a cell index (quantitative measurement of cell proliferation) as per the manufacturer’s instructions. A cell index was plotted against time (for duplicate experiments). The IC50 values were calculated from concentration-response curves by a non-linear regression analysis using the GraphPad Prism (GraphPad Prism Software Inc., San Diego).
The anti-proliferative effect of the compound 4g on MCF-7, melphalan-resistant multiple myeloma (RPMI8226/LR5) MCF-10A or UV♀2 cells was determined by MTT dye uptake method as described previously. Briefly, the cells were incubated in triplicate in a 96-well plate in the presence or absence of indicated concentration of compound 4g in a final volume of 0.2 ml for different time intervals at 37°C. Thereafter, 20 μL MTT solution (5 mg/ml in PBS) was added to each well. After a 2 h incubation at 37°C, 0.1 ml lysis buffer (20 % SDS, 50 % dimethylformamide) was added; incubation was continued overnight at 37°C; and then the optical density (OD) at 570 nm was measured by Tecan plate reader.
Annexin V Assay
One of the early indicators of apoptosis is the rapid translocation of the membrane phospholipid phosphatidylserine from the cell’s cytoplasmic interface to the extracellular surface and its accumulation there, producing a loss of membrane symmetry that can be detected using annexin V. Briefly, 1 x 106 MCF-7 cells were pretreated with compound 4g (30 μM) for various time points and then subjected to annexin V staining. Cells were washed, stained with FITC-conjugated anti-annexin V antibody, and then analyzed with a flow cytometer (BD FACS Calibur, BD Biosciences, US).
This work was supported in part by the INSA (Indian National Science Academy)-JSPS (Japan Society for the Promotion of Science) program between India (to K. S. R.) and Japan (to K. S.), Future Drug Discovery and Medical Care Innovation Program (K. S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), University Grants Commission (MPS-Grant-37-456-2009-SR, B-Grant 41-257-2012-SR), Vision Group Science and Technology, Government of Karnataka (B.), NUS Academic Research Fund (GS-Grant R-184-000-207-112), and a Grant-in-aid (19–07194) from JSPS. We thank Prof. M. Miyasaka for providing the LM8G7 cells.
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