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Article Cite This: ACS Omega 2019, 4, 6106−6113
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Synthesis and Preliminary Biophysical and Cellular Evaluation of Some Ring-Enlarged Analogues of the Anti-Tumor Plant Alkaloid Acronycine Jeet Banerjee,† Indranil Kundu,† Shengyi Zhang,‡ Shijun Wen,‡ and Shital K. Chattopadhyay*,† †
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
‡
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S Supporting Information *
ABSTRACT: Three oxepinoacridine analogues of the important anti-cancer pyranoacridine natural product acronycine have been synthesized using a combined Claisen rearrangement ring-closing metathesis sequence as key steps to install the oxacyclic ring. Preliminary biophysical studies of these proposed oxepino analogues revealed that they interact with ct-DNA in a manner similar to the pyranoacridones but not possibly as intercalators. Cellular evaluations of these analogues in two human leukemic cell lines have also been carried out. These studies indicate that the ring-enlarged analogues have somewhat lower activity than the naturally occurring ones in the cell lines studied.
1. INTRODUCTION
unreported compounds and their preliminary biological evaluations.
The pyranoacridone alkaloid Acronycine (1, Figure 1) was isolated1 from an Australian scrub, which exhibited broad spectrum antitumor activity with moderate to good potency.2 This alkaloid was in clinical trials3 for some time, but because of its poor aqueous solubility, physicochemical properties, and slight toxicity, the trial was discontinued. In quest for a drug with better properties, several analogues of this compound have been prepared and biologically evaluated.4 For example, the cis-1,2-dihydroxyacronycine derivative 5, its diacetate derivative 6, and the epoxy acronycine derivative 4 having a modified pyran ring were all shown to possess improved activity and better pharmacological properties.5 It has also been noticed that compounds lacking the pyran ring are devoid of any useful level of biological activity.6 Additionally, the linear- and angularly benzofused acronycines 2, 3, and 7 were synthesized and evaluated.7 It was observed that the benzoanalogue diacetate derivative 7 possesses remarkable activity and it is found to have comparable efficiency to some wellknown anti-cancer drugs. It is now undergoing clinical trials. On the other hand, ring-enlarged acronycine derivatives remain to be explored as possible analogues. We became interested to evaluate the oxepine derivatives 8−10 in this regard, wherein other parameters of the successful drugs, that is, a 1-methoxyacridone unit, an endocyclic-conjugated double bond, a gemdimethyl unit, a vicinal diol, or a diacetate unit in 1,2-relation all have been kept unaltered excepting replacement of the pyran ring by a seven-membered oxacyclic ring. Herein, we describe synthesis of these hitherto © 2019 American Chemical Society
2. RESULTS AND DISCUSSION 2.1. Synthesis. Medium-ring-sized oxacycle synthesis has greatly advanced with the advent of the powerful ring-closing metathesis reaction.8 We, 9 and others,10 have earlier demonstrated the efficacy of a combined Claisen rearrangement-ring closing metathesis sequence for the synthesis of benz-annulated oxepine derivatives. We adopted our methodology for the synthesis of the projected oxepinoacridine derivatives 8−10. Thus, the known 1,3-dihydroxyacridone derivative 11 (Scheme 1) was selectively allylated at the 3hydroxy group under mild conditions to provide the corresponding 3-allyloxy derivative 12 in a moderate yield of 64%. It was then N,O-dimethylated under conventional conditions to give the N,O,O-trialkylated compound 13 in good yield. The Claisen rearrangement of 13 was found to proceed better in refluxing N,N-diethylaniline within 6 h to provide the angularly rearranged product 14 (64%) together with some unreacted ether (15%). Prolonged heating results in complete conversion but formation of some unwanted linearly rearranged regio-isomer was noticed. Installation of the gemdimethylallyl unit in the phenolic oxygen in 14 was achieved using a two-step sequence involving alkylation with 3-chloro-3methyl-but-1-yne leading to the propargyl derivative 15 Received: December 30, 2018 Accepted: March 13, 2019 Published: April 1, 2019 6106
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Figure 1. Anti-cancer natural product acronycine and its analogues.
Scheme 1. (i) Allyl Bromide, K2CO3, DMF, rt, 6 h, 64%; (ii) NaH, Me2SO4, DMF, 0 °C to rt, 3 h, 86%; (iii) N,NDiethylaniline, Reflux, 1 h, 65%; (iv) 3-Chloro-3-methyl-1-butyne, KI, K2CO3, DMF, 65−130 °C, 22 h, 69%; (v) H2, Lindlar’s Catalyst, THF, rt, 6−8 h, 72%; (vi) Grubbs’ 2nd Generation Catalyst 17, Toluene, 80 °C, 74%; (vii) Ru(CO)HCl(PPh3)3, Toluene, 80 °C, 24 h, 79%; (viii) OsO4, NMMO, Acetone−Water, rt, 18 h, 74%; (ix) Ac2O, DMAP, DCM, rt, 18 h, 84%
Scheme 2. Preparation of Acronycine and Its Derivatives
the Grubbs second generation catalyst [(1,3-bis-(2,4,6trimethylphenyl)-2-imidazolidinylidene)dichloro (phenylmethylene) (trichlorohexylphosphne) ruthenium, 17]in toluene at elevated temperature and prolonged reaction time provided the desired ring-closed product 18 in an acceptable yield of 74%. The 3,4-double bond of the oxepine ring in 18 was brought to conjugation employing another ruthenium catalyst to obtain the desired ring-enlarged acronycine derivative 8 in good yield. Compound 8 could also be
followed by semi-hydrogenation of the triple bond in the latter to provide the desired dimethylallyl ether 16 in good yield. Although a great variety of pyran and furan rings have been constructed11 by RCM methodology using Grubbs’ 1st or 2nd generation catalysts, examples of formation of the higher ring with a gem-dimethyl unit,12 are indeed less documented. The RCM reaction of compound 16 was first attempted with the GI catalyst under a range of conditions. However, very little conversion was observed in all such attempts. Pleasingly, use of 6107
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Figure 2. Absorption spectra of 1 (50 μM) in presence of ct-DNA (0−373 μM) and absorption spectra of 8 (50 μM) in presence of ct-DNA (0− 373 μM).
obtained in a one-pot manner without isolation of 18 with similar overall yield. Osmium teroxide-catalyzed dihydrolyxation of the alkene 8 proceeded uneventfully to provide the diol 9 in good yield. Subsequent diacetylation of the later smoothly provided the proposed analogue 10. Acronycine (1), its diol 5 and the corresponding diacetate derivative 6 were prepared following literature13 as outlined in Scheme 2. These were used in subsequent biological studies for comparison under identical conditions. 2.2. Biophysical Studies. Dorr and Liddil studied14 the interaction of acronycine with DNA and concluded that acronycine may interact with DNA, either by intercalation or by some other noncovalent process. Subsequent studies revealed15 that 1,2-dioxygenated acronycine derivatives 4−6 behave as DNA-alkylating agent and interact with amino group of guanine N-2 in the minor groove. The diacetate derivative 6 exhibited comparable/better activity than taxol against human ovarian, lung, and colon cancers. The oxygenated pentacyclic compounds of the type 7 behave similarly or even better. We studied the interaction of the oxepino compounds 8−10 and compared their behavior with those of the pyran derivatives 1, 5, and 6 under an identical setup to understand if any subtlety is associated in the change from pyran to oxepine ring. The results are presented below. At first, we measured the absorption and emission spectra (in the absence and presence of ct-DNA) of the abovementioned compounds. Compound 1 showed absorption maxima at λ = 270 nm with a shoulder at 279 nm while compound 8 showed absorption maxima at λ = 272 nm. Now, with increasing the concentration of ct-DNA the peak intensity of both the compounds gradually decreased (Figure 2). At higher concentration of DNA, the peak at λ = 270 nm became blue-shifted at λ = 250 nm, while the overlapping one shifted at λ = 285 nm. Whereas, in the case of compound 8, at higher concentration of DNA, the peak at λ = 272 nm disappeared and two distinct peaks appeared at λ = 236 and 288 nm. Thus, at higher concentration of ct-DNA the visualization of two distinct peaks of compound 1 and compound 8 indicates strong perturbation of the electronic states of the compound in presence of DNA in a similar fashion. The diol pair 5 & 9 and the diacetate pair 6 & 10 behaved similarly (see Supporting Information for graphs) both showing similar trends in shifting of absorption maxima. The data are appended below (Table 1). We then studied16 the DNA interaction of the two sets of compounds with respect to emission behavior. In aqueous buffer medium emission maxima appears at λ = 450 nm for compound 1 and λ = 467 nm for compound 8 (Figure 3).
Table 1. UV Data for Compounds 5, 6, 9, and 10 compound
λmax (nm)
pyranodiol 5 oxepinodiol 9 pyranodiacetate 6 oxepinodiacetate 10
274 265, 270 (shoulder) 273 269
new peak values (nm) 243 238 241 245
and and and and
279 283 282 276
Here, again with increasing concentration of ct-DNA the emission intensity drops down. The fluorescence quenching by DNA indicated that the compounds had binding with DNA. The binding constant was found to be Ka = 0.146 × 104 M−1 for compound 1, while Ka = 1.026 × 104 M−1 for compound 8. Similar behavior of the diol pair 5 & 9 and the diacetate pair 6 & 10 were observed. A tabular comparison of the photophysical behavior of all the compounds are presented in Table 2. To predict the possible mode of binding, we performed the thermal denaturation study of our synthesized compound with ct-DNA. Significant stabilization of the double helix is commonly observed for intercalating ligands, whereas groove binders may lead to stabilization or destabilization or negligible change in the melting temperature (Tm) of double-stranded DNA.17 For ct-DNA, in 1 mM sodium cacodylate buffer the melting temperature (Tm) was measured to be 56 °C. Melting temperatures of all the compounds are listed in Table 3 (see the Supporting Information for the graphs). These studies indicate that the mode of binding is other than intercalation. 2.3. Cell Viability Analysis. Most of the earlier studies on acronycine derivatives and their benz-annulated analogues have been carried out on murine leukemia cell line L1210 and human epidermoid carcinoma cell line KB 3-1. The present study was carried out on two human leukemic cell lines MV411(acute myeloid leukemia) and ML-1(acute myeloblastic leukemia). Drug-related effects on cell viability were assessed by the MTS cell proliferation assay (Promega, Madison, WI). Cancer cells were seeded in 96-well plates at a density of 3.0 × 103 cells/well for drug treatment. After the treatment for 3 days, the cells were then incubated with MTS (3-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) for 3−4 h at 37 °C. The spectrophotometric absorbance in each well at 490 nm to record the relevant cell viability was measured using a microplate reader (SpectraMax M5, Molecular Devices). The cell viability data is presented in the Table 4. It is observed that the data for the pyran derivatives are somewhat better than those for the oxepine derivatives, and the acetates are the best among the three in each series. The 6108
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Figure 3. (A) Emission spectra of compound 1 in the presence of ct-DNA (0−42.6 μM) with excitation at λmax = 270 nm. (B) Emission spectra of compound 8 in presence of ct-DNA (0−82.7 μM) with excitation at λmax = 272 nm.
Table 2. Summary of Photophysical Data of the Projected Compounds compound
absorption (nm) 270 272 274 265 273 269
1 8 5 9 6 10
emission (nm)
ε (M−1 L−1)
450 467 453 463 445 453
× × × × × ×
2.5 3.2 4.7 3.7 3.6 3.8
Tm (°C)
ΔTm (°C)
1 8 5 9 6 10
59.8 54.7 50 53 50.5 45.4
3.8 −1.3 −6 −3 −5.5 −10.6
0.146 1.026 1.98 0.64 1.37 1.44
10 104 104 104 104 104
× × × × × ×
quantum yield (φ)
104 104 104 104 104 104
0.40 0.32 0.55 0.62 0.54 0.56
further studies are required to fully explore the potential of the prepared oxepinoacridine derivatives in other cell lines.
Table 3. DNA Melting Temperature Data for the Three Pairs of Targeted Compounds Compound with ct-DNA
binding constant (M−1)
4
4. EXPERIMENTAL SECTION 4.1. General. Infrared spectra were recorded with a PerkinElmer Infrared Spectrometer model No L120−000A. 1 H and 13C NMR spectra were recorded with a Bruker400 MHz Ultrashield NMR spectrometer purchased through a DST-PURSE grant. Mass spectra were recorded with a Water Xevo QTOF mass spectrometer purchased through the DSTFIST grant. Elemental analysis was performed with a PerkinElmer 2400 series II Instrument. All solvents obtained from commercial sources were dried with appropriate drying agents and were immediately distilled before use. Column chromatography was performed with silica gel (230−400) purchased from Spectrochem India Pvt. Ltd. Thin-layer chromatography was performed with precoated silica plates and was visualized under a UV lamp or with an iodine spray. Melting points were determined in open capillaries and are uncorrected. 4.1.1. 3-Allyloxy-1-hydroxy-10H-acridin-9-one (12). To a stirring solution of 1,3-dihydroxy-10H-acridin-9-one (5 g, 22 mmol) (1) in dry DMF (35 mL), potassium carbonate (6.1 g, 44 mmol) was added in a single portion. The reaction mixture was allowed to stir for 15−20 min at room temperature under nitrogen atmosphere. Allyl bromide (3.45 mL, 40 mmol) was added slowly to the reaction mixture over twenty minutes and stirring continued for 3 h. It was then poured in a beaker over ice with constant stirring and then extracted with chloroform (2 × 50 mL). The combined organic layer was washed with
inhibitory rates of MV411 and ML1 by the pyran derivative 6 are best, being 63.1 and 57.03% at 30 μM.
3. CONCLUSIONS Oxepinoacridone analogues of the important anti-cancer pyranoacridone alkaloid acronycine have been prepared for the first time, involving our previously developed domino Claisen rearrangement-RCM sequence as key steps. Preliminary biophysical evaluation of three such analogues involving the interaction with ct-DNA by UV and fluorescence studies has been carried out in a comparative basis with the corresponding pyranoacridine natural product and two of its derivatives. The studies further corroborate that the apparently flat molecules perhaps are not DNA intercalators. Cellular evaluation of the two series of compounds with two human leukemic cell lines MV411 and ML1 have also been carried out. Cellular data indicate that the activities of the pyran compounds are better than those of the oxepine compounds in the particular cell lines studied. However,
Table 4. Cell Viability Data of the Three Pairs of Targeted Compounds against Cell Lines MV4-11 and ML-1 1
5
6
8
9
10
cell line
10 μm
30 μm
10 μm
30 μm
10 μm
30 μm
10 μm
30 μm
10 μm
30 μm
10 μm
30 μm
MV4-11 ML-1
0.9089 0.7355
0.7757 0.8618
1.1889 1.1526
1.2379 1.1048
0.8471 0.7150
0.6032 0.4807
1.2829 1.1095
0.7908 0.7363
1.3389 1.1086
1.0058 1.0304
1.1893 1.0550
0.7045 0.6982
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94.0, 55.4, 44.6, 31.5. MS (QTOF ES+): found, 296.1274 [M+ + H]; calcd for C18H18NO3, 296.1287. 4.1.4. 4-Allyl-3-(1,1-dimethyl-prop-2-ynyloxy)-1-methoxy10-methyl-10H-acridin-9-one (15). A solution of compound 14 (0.50 g, 1.7 mmol) in dry DMF (10 mL) was stirred and heated at 65 °C under nitrogen atmosphere in presence of K2CO3 (0.47 g, 3.4 mmol) for 15 min. Then KI (0.56 g, 3.4 mmol) and 3-chloro-3-methyl-1-butyne (0.5 mL, 4.3 mmol) were sequentially added. The reaction mixture was stirred for 22 h before being cooled. It was diluted with water and extracted with CH2Cl2 (2 × 20 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), and then dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated under reduced pressure to leave a crude mass that was purified by column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether (1:4) to give the product as a yellowish solid (0.424 g, 69%). Melting point: 200−202 °C. IR (KBr): ν 3185, 2934, 2098, 1637, 1600, 1579, 1495 cm−1.1H NMR (400 MHz, CDCl3): δ 8.24 (1H, dd, J = 7.6, 1.2 Hz, −ArH), 7.53 (1H, dt, J = 1.2, 8.0 Hz, −ArH), 7.24 (1H, d, J = 8.4 Hz), 7.19 (1H, s, −ArH), 7.12 (1H, t, J = 7.6 Hz, −ArH), 6.02 (1H, m, CH), 5.03 (2H, m, CH2), 3.92 (3H, s, −OMe), 3.66 (3H, s, −NMe), 3.42 (2H, t, J = 2.8 Hz, −CH2), 2.65 (1H, s, acetylenic), 1.67 (6H, s, −C(Me)2). 13C NMR (100 MHz, CDCl3): δ 178.3, 160.2, 160.0, 149.9, 145.7, 137.3, 132.6, 126.9, 125.3, 121.4, 116.3, 115.2, 111.9, 109.8, 95.9, 85.8, 74.6, 72.3, 56.2, 45.1, 32.6, 29.7. MS (QTOF ES+): found, 362.1754 [M+ + H]; calcd for C23H24NO3, 362.1756. 4.1.5. 4-Allyl-3-(1,1-dimethyl-allyloxy)-1-methoxy-10methyl-10H-acridin-9-one (16). A heterogeneous mixture of the compound 15 (0.25 g,0.69 mmol) and 10 mol % Lindler’s catalyst (15 mg, 10 mol %) in dry tetrahydrofuran (THF) (10 mL) was vigorously stirred in a hydrogen atmosphere at room temperature for 6−8 h under balloon pressure. The reaction mixture was filtered through a bed of Celite, the filter cake was washed with THF (10 mL) and the combined filtrate was concentrated in vacuo to afford the product as a yellowish crude, which was purified by column chromatography over silica gel (100−200 mesh) (ethyl acetate:petroleum ether = 40:60) to give the product as an yellow gum (0.18 g, 72%). IR (KBr): 2921, 1623, 1602 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.23 (1H, dd, J = 8.0, 1.6 Hz, −ArH), 7.58 (1H, m, −ArH), 7.30 (1H, m, −ArH), 7.19 (1H, t, J = 7.2 Hz, −ArH), 6.69 (1H, s, −ArH), 6.24 (1H, dd, J = 10.8, 17.6 Hz, CH), 6.13 (1H, m, CH), 5.31−5.24 (2H, m, CH2), 5.13−5.08 (2H, m, CH2), 3.87 (3H, s, −OMe), 3.73 (3H, s, −NMe), 3.51 (2H, d, J = 5.2 Hz, −ArCH2), 1.57 (6H, s, −C(Me)2). 13C NMR (100 MHz, CDCl3): δ 178.2, 160.9, 160.0, 149.9, 145.7, 145.0, 137.5, 132.6, 126.9, 125.2, 121.3, 116.3, 115.0, 113.3, 111.4, 109.6, 96.1, 80.8, 56.1, 45.2, 32.8, 27.3. MS (QTOF ES+): found, 364.1929 [M+ + H]; calcd for C23H26NO3, 364.1913. 4.1.6. 7-Methoxy-4,4,13-trimethyl-1,13-dihydro-4H-5-oxa13-aza-cyclohept[a]anthracen-8-one (18). To a solution of the diene 16 (0.110 g, 0.30 mmol) in dry toluene (5 mL) catalyst 17 (8 mg, 3 mol %) was added under argon atmosphere and the resulting reaction mixture was stirred at 90 °C for 24 h. It was allowed to come to rt and then concentrated in vacuo to afford a brownish crude, which was purified by column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether (40:60) to give the product as yellow solid (0.073 g,74%). Melting point: 102
water (25 mL), brine (25 mL), and then dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated under reduced pressure to leave a crude mass that was purified by column chromatography over silica gel using a mixture of chloroform and methanol (5:1) to give the product as a yellow solid (3.56 g, 64%). Melting point: 250−252 °C. IR (KBr): ν 3150, 2957, 1655, 1609, 1587, 1479 1455, 1181 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 14.23 (1H, s, −OH), 11.95 (1H, s, −NH), 8.17 (1H, d, J = 8.0 Hz, −ArH), 7.75 (1H, s, −ArH), 7.50 (1H, d, J = 8.4 Hz, −ArH), 7.29 (1H, d, J = 7.2 Hz, −ArH), 6.40 (1H, s, −ArH), 6.19 (1H, s, −ArH), 6.18− 6.02 (1H, m, CH), 5.45 (1H, d, J = 17.2 Hz, CH2), 5.32 (1H, d, J = 10.8 Hz, CH2), 4.68 (2H, d, J = 4.4 Hz, −OCH3). 13C NMR (100 MHz, DMSO-d6): δ 180.2, 164.1, 163.4, 143.0, 140.7, 134.0, 133.0, 125.0, 121.4, 118.9, 118.0, 117.0, 104.0, 94.8, 90.9, 68.4. HRMS (QTOF ESMS+): found, 268.0966 [M+ + H]; calcd for C16H14NO3, 268.0974. 4.1.2. 3-Allyloxy-1-methoxy-10-methyl-10H-acridin-9-one (13). To a stirred suspension of NaH (60%, 1.55 g, 67.4 mmol) dry DMF (15 mL) under nitrogen atmosphere at 0 °C, compound 12 (4.0 g, 15.0 mmol) was added in a portion wise manner over 15 min. The resulting greenish mixture was allowed to stir for another 20−30 min at 0 °C followed by drop wise addition of dimethyl sulfate (2.8 mL, 29.5 mmol). The reaction mixture was allowed to come to room temperature and stirred for an additional 2 h. It was then quenched by adding cold saturated solution (10 mL) of ammonium chloride at 0 °C before being extracted with CHCl3 (2 × 50 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), and then dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated under reduced pressure to leave a crude mass that was purified by column chromatography over silica gel using a mixture of chloroform and methanol (97:3) to give the product as a yellow solid (3.81 g, 86%). Melting point: 170− 172 °C. IR (KBr): ν 2925, 2854, 1597, 1499 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.40 (1H, d, J = 8 Hz, −ArH), 7.53 (1H, m, −ArH), 7.28 (1H, d, J = 8.8 Hz), 7.14 (1H, t, J = 7.4 Hz, −ArH), 6.32 (1H, d, J = 2 Hz, −ArH), 6.22 (1H, d, J = 2 Hz, −ArH), 6.00 (1H, m, CH), 5.40 (1H, dd, J = 17.2, 1.2 Hz, CH), 5.29 (1H, dd, J = 10.4, 1.2 Hz, CH), 4.58 (2H, d, J = 5.6 Hz, −CH2), 3.90 (3H, s, −OMe), 3.67 (3H, s, −NMe). 13C NMR (100 MHz, CDCl3): δ 176.7, 163.2, 163.0, 146.7, 141.7, 132.6, 132.5, 127.6, 124.5, 121.2, 118.4, 114.1, 108.5, 92.6, 91.1, 69.0, 56.2, 34.7. HRMS (QTOF MSES+): found, 296.1276 [M+ + H]; calcd for C18H18NO3, 296.1287. 4.1.3. 4-Allyl-3-hydrooxy-1-methoxy-10-methyl-10H-acridin-9-one (14). A solution of the allyl ether 13 (1.0 g, 3.4 mmol in N,N diethyl aniline (8 mL)) was refluxed for 1 h under nitrogen atmosphere. It was then allowed to come to rt when the precipitated yellow product was filtered, washed with petroleum ether and the crude product was purified by column chromatography over silica gel using a mixture of chloroform− methanol (90:10) to give the product as a yellow solid (0.65 g, 65%). Melting point: 240−242 °C. IR (KBr): ν 3072, 1621, 1594, 1558, 1396 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 10.52 (1H, s, −OH), 8.02 (1H, dd, J = 8, 1.2 Hz, −ArH), 7.88 (1H, m, −ArH), 7.48 (1H, d, J = 8.4 Hz, −ArH), 7.19 (1H, t, J = 7.4 Hz, −ArH), 6.44 (1H, s, −ArH), 6.09 (1H, m, CH), 5.09−5.05 (2H, m, CH), 3.79 (3H, s, −OMe), 3.71 (3H, s, −NMe), 3.48 (2H, d, J = 5.2 Hz, −CH2). 13C NMR (100 MHz, 25 °C, DMSO-d6): δ 175.9, 161.8, 160.0, 149.7, 145.1, 137.4, 132.4, 125.5, 124.4, 121.0, 117.0, 114.8, 109.7, 105.1, 6110
DOI: 10.1021/acsomega.8b03673 ACS Omega 2019, 4, 6106−6113
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°C. IR (KBr): 2920, 1630, 1604 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.27 (1H, d, J = 8.0 Hz, −ArH), 7.54 (1H, m, −ArH), 7.26 (1H, d, J = 8.4 Hz, −ArH), 7.15 (1H, t, J = 7.6 Hz, −ArH), 6.40 (1H, s, −ArH), 5.93 (1H, m, CH), 5.43 (1H, d, J = 11.2 Hz, CH), 3.79 (3H, s, −OMe), 3.69 (3H, s, −NMe), 3.40 (2H, d, J = 6 Hz, −CH2), 1.38 (6H, s, CMe)2. 13 C NMR (100 MHz, CDCl3): δ 178.3, 161.5, 160.5, 147.7, 145.2, 137.3, 132.8, 127.2, 125.2, 122.7, 121.6, 117.8, 116.1, 113.1, 101.6, 81.1, 56.4, 44.9, 28.8, 26.4. MS (QTOF ES+): found, 335.1594 [M+ + H]; calcd for C21H22NO3, 336.1599. 4.1.7. 7-Methoxy-4,4,13-trimethyl-3,13-dihydro-4H-5-oxa13-aza-cyclohepta[a]anthracen-8-one (8). To a solution of the oxepine 18 (0.20 g, 0.60 mmol) in the dry toluene (5 mL) catalyst Ru(CO)HCl(PPh3)3 (40 mg, 7 mol %) was added and the reaction mixture was heated at 90 °C for 24 h under argon atmosphere. It was then allowed to come to rt and then concentrated in vacuo to afford a brownish crude which was purified by column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether (40:60) as eluent to give the product as a yellow solid. (0.156 g, 79%). Melting point: 107 °C. IR (KBr): ν 2976, 1629, 1575, 1492 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.31−8.29 (1H, m, −ArH), 7.57−7.53 (1H, m, −ArH), 7.30 (1H, d, J = 8.4, −ArH), 7.19− 7.15 (1H, m, −ArH), 6.35 (1H, d, J = 10.8 Hz, −ArH), 6.31 (1H, s, −ArH), 6.01−5.97 (1H, m, CH), 3.91 (3H, s, −OMe), 3.69 (3H, s, −NMe), 2.44 (2H, d, J = 5.6 Hz, −CH2), 1.42 (6H, s, > C(Me)2). 13C NMR (100 MHz, CDCl3): δ 177.9, 161.3, 161.0, 148.7, 145.2, 132.7, 128.0, 127.1, 125.6, 124.7, 121.9, 116.3, 112.6, 110.9, 99.9, 88.0, 56.3, 44.8, 41.5, 29.7, 28.0. HRMS (QTOF MSES+): found, 336.1596[M+ + H]; calcd for C21H22NO3, 335.1599. 4.1.8. 1,2-Dihydroxy-7-methoxy-4,4,13-trimethyl-1,3,4,13tetrahydro-2H-5-oxa-13-aza-cyclohepta[a]anthracen-8-one (9). To a solution of the olefin 8 (0.10 g (0.30 mmol) in a mixture of acetone and water (4:1, 1 mL), osmium tetroxide solution (1% in water, 0.1 mL), and N-methylmorpholine-Noxide (85 mg, 0.73 mmol) were sequentially added at room temperature. The reaction mixture was allowed to stir for 18 h before being quenched with aqueous saturated solution of sodium bisulfate (1 mL), and then extracted with dichloromethane (2 × 10 mL). The combined organic layer was washed successively with water (10 mL), brine (10 mL), and then dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated under reduced pressure to leave a crude mass, which was purified by column chromatography over silica gel using a mixture of methanol and chloroform (3:97) to give the product as a pale white solid (0.082g, 74%). Melting point: 180 °C. IR (KBr): ν 3419, 2922, 2852, 1626, 1601 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 8.21 (1H, d, J = 8 Hz, −ArH), 7.56−7.52 (1H, m, −ArH), 7.25 (1H, d, J = 8.4 Hz, −ArH), 7.19−7.14 (1H, m, −ArH), 6.25 (1H, s, −ArH), 5.06 (1H, d, J = 5.6 Hz, −CH), 3.89 (3H, s, −OMe), 3.79 (3H, s, −NMe), 2.90 (1H, d, J = 8 Hz, −CH), 2.46−2.39 (1H, m, −CH), 2.02−1.97 (1H, m, −CH), 1.54 (6H, s, > C(Me)2. 13C NMR (400 MHz, DMSO-d6): δ 177.9, 162.3, 161.8, 150.2, 145.3, 132.9, 126.8, 125.2, 121.9, 116.6, 114.0, 113.2, 102.1, 80.8, 74.1, 69.0, 56.3, 45.9, 44.1, 32.2, 29.6, 23.6. HRMS (QTOF MSES+): found, 392.1476 (M + Na); calcd for C21H23NaNO5, 392.1474. 4.1.9. 1,2-Diacetoxy-7-methoxy-4,4,13-trimethyl-1,3,4,13tetrahydro-2H-5-oxa-13-aza-cyclohepta[a]anthracen-8-one (10). To a solution of the diol 9 (0.05 g,0.135 mmol) in dry dichloromethane (2 mL) under nitrogen atmosphere,
dimethtylaminopyridine (5 mg, catalytic) and acetic anhydride (0.05 mL) were sequentially added, and the resulting reaction mixture was allowed to stir at room temperature for 18 h. It was then poured into ice-cold water (25 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic layer was washed successively with Fwater (10 mL), brine (10 mL), and then dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated under reduced pressure to leave a crude mass, which was purified by column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether (60:40) to give the product as a colourless solid (0.048 g, 84%). Melting point: 192 °C. IR (KBr): ν 2923, 2852, 1739, 1638, 1602, 1578 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.33−8.31 (1H, m, −ArH), 7.67−7.63 (1H, m, −ArH), 7.44 (1H, d, J = 8.4 Hz), 7.28−7.24 (1H, m, −ArH), 6.53 (1H, s, −ArH), 6.35 (1H, s, −CH), 5.68−5.64 (1H, m, −CH), 3.98 (3H, s, −OMe), 3.91 (3H, s, −NMe), 2.74 (1H, t, J = 12.8 Hz, −CH), 2.13 (3H, s, −Me), 2.00−1.99 (1H, m, −CH2), 1.97 (3H, s, −Me), 1.64 (6H, s, > C(Me)2), 1.28 (3H, s, −CH3). 13C NMR (100 MHz, CDCl3): δ 177.9, 170.5, 170.3, 163.4, 163.1, 151.2, 145.1, 133.0, 126.8, 125.5, 122.2, 117.0, 107.5, 100.9, 79.8, 71.6, 69.6, 56.3, 46.9, 40.5, 32.4, 29.7, 23.1, 21.2, 20.9. HRMS (QTOF MSES+): found, 454.1863 [M + H]; calcd for C25H28NO7, 454.1866.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b03673. 1 H NMR and 13C NMR data and spectra of all new compounds; characterization data for compounds leading to acronycine derivatives; and UV, fluorescence, and melting temperature graphs for compounds 1, 5, 6, 8, 9, and 10 (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shijun Wen: 0000-0002-9347-8243 Shital K. Chattopadhyay: 0000-0001-5972-6891 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are thankful to DST, New Delhi, for funds (EMR/2017/ 001336), and University of Kalyani for support under PURSE program, and also for a fellowship to one of us (J.B.).
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REFERENCES
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