Next Article in Journal
Biological Activities of Hydrazone Derivatives
Previous Article in Journal
Synthesis of Novel Steroid-Peptoid Hybrid Macrocycles by Multiple Multicomponent Macrocyclizations Including Bifunctional Building Blocks (MiBs)
Article Menu

Export Article

Molecules 2007, 12(8), 1900-1909; https://doi.org/10.3390/12081900

Full Paper
Synthesis and In-vitro Antitumor Activity of 1-[3-(Indol-1-yl)-prop-1-yn-1-yl]phthalazines and Related Compounds
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Austria
*
Author to whom correspondence should be addressed.
Received: 2 August 2007; in revised form: 14 August 2007 / Accepted: 14 August 2007 / Published: 17 August 2007

Abstract

:
A series of novel 3-(indol-1-yl)prop-1-yn-1-yl-substituted phthalazines and related azines was prepared via a concise pathway by palladium-catalyzed cross-coupling of appropriate halo-azines and N-propargylindoles. Some of the compounds exhibited significant antitumor activity in an in-vitro assay.
Keywords:
1-[3-(indol-1-yl)prop-1-yn-1-yl]phthalazines; N-propargylindoles; palladium-catalyzed cross-coupling; Sonogashira reaction; antitumor activity

Introduction

During the course of a research program at our department, focusing on the synthesis and antitumor activity of polycyclic hetarenes, especially condensed carbazoles of the ellipticine/olivacine type [1,2,3,4,5] (cf. Figure 1) and polycyclic quinones [6,7,8], we recently described the preparation of novel pentacyclic ellipticine analogs via a route featuring an intramolecular inverse-electron-demand Diels-Alder reaction of indolylpropyl-substituted 1,2-diazines as the key step (Scheme 1) [9]. In a routine in-vitro screening for cytotoxic activity, not only the target compounds, but also one of the intermediates, namely 1-[3-(indol-1-yl)prop-1-yn-1-yl]phthalazine, showed significant tumor cell-growth inhibition. Therefore, this compound with a 1,3-disubstituted propyne unit as the central element was selected as a new lead structure for further exploratory investigations. Here, we report on the synthesis and the results of preliminary in-vitro antitumor tests of a focused compound library featuring the same propyne motif with one electron-rich and one electron-deficient hetarene attached at the terminal carbon atoms.
Figure 1. Structures of the alkaloids, ellipticine and olivacine.
Figure 1. Structures of the alkaloids, ellipticine and olivacine.
Molecules 12 01900 g001
Scheme 1. Synthesis of bridged ellipticine/olivacine analogs [9].
Scheme 1. Synthesis of bridged ellipticine/olivacine analogs [9].
Molecules 12 01900 g002

Results and Discussion

Syntheses

Following the first step of the pathway above (Scheme 1), the target compounds were prepared essentially by a Sonogashira cross-coupling reaction of an appropriate propargyl-substituted indole or indoline synthon with an iodohetarene or bromohetarene, respectively. Two series of compounds were synthesized, keeping always one of the two heterocyclic subunits constant (either the indole or the azine) and varying the other one. The propynyl-substituted educts were obtained in good yields by treatment of the N-unsubstituted precursors with propargyl bromide in toluene/50% sodium hydroxide, using tetrabutylammonium bromide as a phase-transfer catalyst [10].

An improved synthesis of 1-iodophthalazine

During the preparation of the requisite starting materials, it turned out that the transformation of 1-chlorophthalazine into 1-iodophthalazine by treatment of the former with potassium iodide and hydroiodic acid in acetone, as described by Hirsch and Orphanos [11], gives very unreliable results if the original work-up procedure is applied (dissolving the initially formed hydroiodide salt of 1-iodo-phthalazine in water, followed by neutralization and filtration of the free base). In several runs, the compound underwent complete decomposition within a very short time. We found that this crude material is highly acid-sensitive and is prone to an autocatalytic decomposition process if exposed to traces of acid. Therefore, it is essential to keep the pH after liberation of the free base strictly alkaline. Instead of collecting the product by filtration, it is extracted quickly into dichloromethane and the organic extract is immediately basified by addition of triethylamine (see Experimental section). Evaporation of this solution gives a pure product which can be stored under refrigeration for several weeks.

Palladium-catalyzed cross-coupling reactions

As the educts for the Sonogashira cross-coupling reaction (see Scheme 2), the following azines were chosen besides 1-iodophthalazine (2a): 1-iodo-4-methylphthalazine (2b) [12], 1-iodo-4-phenyl-phthalazine (2c) [13], 1-iodoisoquinoline (2d) [14], and 4-bromoisoquinoline (2e) [15]. As the acetylenic building blocks, N-propargyl-substituted 5-methoxyindole (1a) [9], 5-bromoindole (1b), methyl indole-5-carboxylate (1c) [16], and indoline (1d) [17] were employed.
Scheme 2. Synthesis of the target compounds (3) by Sonogashira cross-coupling.
Scheme 2. Synthesis of the target compounds (3) by Sonogashira cross-coupling.
Molecules 12 01900 g003
In all cases, bis(triphenylphosphine)palladium(II)dichloride and copper(I)iodide were used as catalysts, and the reactions were run in tetrahydrofuran/triethylamine under an argon atmosphere at room temperature (except for 3-bromoisoquinoline: reflux temperature) with TLC monitoring. Extended reaction times were found to result in a substantial drop of yields, mainly because of increased decomposition and/or a base-promoted alkyne/allene rearrangement of the products [18] (the latter process was particularly problematic in the case of the 5-bromoindole derivative 3f). Whereas conversion rates were generally good, yields in some cases were only moderate owing to substantial losses during the purification process. Product structures, reaction conditions and yields of isolated material as well as the results of in-vitro antitumor screening (see below), including the values for the previously prepared analogs 3h-j [9] are summarized in Table 1.
Table 1. Structures, reaction conditions, yields, and biological activities for the title compounds.
Table 1. Structures, reaction conditions, yields, and biological activities for the title compounds.
ProductReaction conditions or referenceYield (%)Tumor cell growth inhibition (%) a)
KBSK OV-3SF-268NCI H460RKOP27
Molecules 12 01900 i0013ar.t., 20 h479113938596
Molecules 12 01900 i0023br.t., 6 h5599619995100
Molecules 12 01900 i0033creflux, 7 d3419681828
Molecules 12 01900 i0043dr.t., 48 h75n.d.n.d.n.d.2731
Molecules 12 01900 i0053er.t., 5 h801928267445
Molecules 12 01900 i0063fr.t., 4 h305450636864
Molecules 12 01900 i0073gr.t., 5 h152341416454
Molecules 12 01900 i0083hlit. [9]-9758819790
Molecules 12 01900 i0093ilit. [9]-2813113628
Molecules 12 01900 i0103jlit. [9]-8653889378
a) Tumor cell lines used: KB: cervical carcinoma; SF-268: CNS cancer; RKOP27: colon adenocarcinoma; SK OV-3: ovarial carcinoma; NCI H-460: non-small-cell lung cancer.

Biological Activity

All compounds were subjected to a preliminary screening for antitumor activity at a fixed sample concentration of 3.16 µg/mL, using the XTT in-vitro assay [19]. As can be concluded from the results (see Table 1), replacement of the phthalazine unit by a monocyclic 1,2-diazine (3i) or by an isoquinoline (3c, 3d) leads to a marked drop in activity, whereas substitution of the phthalazine at position 4 [methyl (3a) or phenyl (3b)] is well tolerated. In the indole part of the molecule, the 5-methoxy substituent appears to be most favorable among the variations studied. Replacement of an indole by an indoline structure (3e) results in lower activity.

Conclusions

Sonogashira reaction of 1-iodophthalazines and related haloazines with the terminal acetylene unit of N-propargylindoles provides a convenient access to the title compounds, which are of pharmaceutical interest due to their activity in an in-vitro antitumor screen. Further investigations will be required for a more detailed evaluation of these agents.

Experimental

General

Melting points (uncorrected) were determined on a Kofler hot-stage microscope (Reichert). 1H-NMR spectra were recorded on a Bruker Avance DPX 200 (200 MHz) or on a Varian UnityPlus 300 (300 MHz) spectrometer. IR spectra were taken on a Perkin-Elmer 1605 FT-IR instrument. Mass spectra were obtained on a Shimadzu QP5050A DI 50 instrument, high-resolution mass spectra were recorded on a Finnigan MAT 8230 spectrometer at the Institute of Organic Chemistry, University of Vienna. Column chromato­graphy was carried out on Merck Kieselgel 60, 0.063–0.200 mm, thin layer chromatography was done on Merck aluminium sheets pre-coated with Kieselgel F254. Microanalyses were performed at the Microanalytical Laboratory, Faculty of Chemistry, University of Vienna.
5-Bromo-1-prop-2-yn-1-yl-1H-indole (1c). To a solution of 5-bromoindole (1.96 g, 10 mmol) and propargyl bromide (2.23 g of a 80% solution in toluene; 15 mmol) in toluene (30 mL) were added tetrabutylammonium bromide (0.161 g, 0.5 mmol) and 50% aqueous NaOH (6 mL). The two-phase system was stirred vigorously for 3 h at room temperature, then it was diluted with toluene (10 mL) and the phases were separated. The organic layer was washed several times with water and then with brine. It was dried over Na2SO4 and the solvent was removed under reduced pressure to give the product (2.179 g, 93%) as an almost colorless oil which darkened slowly on storage. IR (KBr): 3290, 2125, 1564, 1507, 1465, 1189, 1053, 898, 752 cm–1; MS (EI, 70 eV) m/z: 235 (M+, 46%), 233 (M+, 49), 196 (12), 194 (10), 154 (100), 127 (18), 115 (33), 88 (22), 62 (19); 1H-NMR (CDCl3) δ: 7.77 (d, J4–6 = 1.8 Hz, 1H, 4-H), 7.36–7.26 (m, 2H, 6-H, 7-H), 7.21 (d, J2–3 = 3.3 Hz, 2-H), 6.48 (d, J2–3 = 3.3 Hz, 1H, 3-H), 4.86 (d, J = 2.6 Hz, 2H, CH2), 2.42 (t, J = 2.6 Hz, 1H, C≡CH). HRMS (EI, 70 eV) m/z calcd. for C11H8BrN (M+): 232.9840. Found: 232.9844.
1-Iodophthalazine (2a) [11]. Modified Procedure. A mixture of 1-chlorophthalazine (2.75 g, 17 mmol), potassium iodide (5.0 g, 30 mmol), 57% hydroiodic acid (3.4 mL) and acetone (50 mL) was stirred in the dark at room temperature for 96 h. The yellow precipitate (2a·HI) was collected by filtration, washed with diethyl ether, and dried in vacuo. The material was then suspended in ice-water and the mixture was stirred for 15 min and made alkaline with dilute ammonium hydroxide. It was extracted several times with CH2Cl2 and the combined extracts were repeatedly washed with a solution of sodium thiosulfate (0.5 g) in 1% ammonium hydroxide, then with brine. Triethylamine (2 mL) was added to the CH2Cl2 extract, then it was dried over Na2SO4. Evaporation of the volatile components gave 2a (3.153 g, 74%) as yellow crystals, mp 87–96 °C (lit. [11]: 78 °C), which were stored in a deep freezer and which were used for the subsequent steps without further purification.
Synthesis of Compounds 3 by Pd-Catalyzed Cross-Coupling Reaction. General Procedure. To a solution of the aryl halide 2a, 2b, 2c, 2d, or 2e (2.6 mmol), respectively, and the appropriate alkyne 1a, 1b, 1c, or 1d (3.25 mmol), respectively, in dry THF (6 mL) were added triethylamine (1.0 mL, 7.2 mmol), CuI (0.015 g, 3 mol%) and Pd(PPh3)2Cl2 (0.055 g, 3 mol%), and the mixture was flushed with argon. It was then stirred under an argon atmosphere under the conditions (room temperature or reflux) and for the time listed in Table 1. The insoluble material was filtered off and washed carefully with THF. The combined filtrates were evaporated under reduced pressure and the residue was purified by column chromatography (eluent: ethyl acetate or ethyl acetate/light petroleum).
1-[3-(5-Methoxy-1H-indol-1-yl)prop-1-yn-1-yl]-4-methylphthalazine (3a). Prepared from 5-methoxy-1-prop-2-yn-1-yl-1H-indole (1a) and 1-iodo-4-methylphthalazine (2b); yield: 0.408 g (47%), recrystallization from ethyl acetate/light petroleum gave almost colorless crystals, mp 166–168 °C. IR (KBr): 2921, 2231, 1620, 1484, 1383, 1239, 1153, 1029, 848, 799, 771, 619 cm–1; MS (EI, 70 eV) m/z: 327 (M+, 19%), 312 (10), 296 (2), 284 (6), 164 (6), 152 (15), 142 (9), 127 (7), 103 (4), 77 (7), 70 (13), 61 (14), 45 (24), 43 (100); 1H-NMR (CDCl3) δ: 8.09 (d, J = 8.7 Hz, 1H, phthalazine 8-H), 8.06 (d, J = 9.3 Hz, 1H, phthalazine 5-H, shows positive NOE on irradiation at 3.02 ppm), 7.92–7.80 (m, 2H, phthalazine 6-H, 7-H), 7.47 (d, J6–7 = 9.0 Hz, 1H, indole 7-H), 7.31 (d, J2–3 = 3.0 Hz, 1H, indole 2-H), 7.15 (d, J4–6 = 2.1 Hz, 1H, indole 4-H), 6.96 (dd, J6–7 = 9.0 Hz, J4–6 = 2.4 Hz, 1H, indole 6-H), 6.52 (d, J2–3 = 3.0 Hz, 1H, indole 3-H), 5.28 (s, 2H, CH2), 3.88 (s, 3H, OCH3), 3.02 (s, 3H, 4-CH3). Anal. calcd. for C21H17N3 O · 0.25 H2O: C, 76.00; H, 5.31; N, 12.60. Found: C, 76.04; H, 5.22; N, 12.45.
1-[3-(5-Methoxy-1H-indol-1-yl)prop-1-yn-1-yl]-4-phenylphthalazine (3b). Prepared from 5-methoxy-1-prop-2-yn-1-yl-1H-indole (1a) and 1-iodo-4-phenylphthalazine (2c); yield: 0.552 g (55%), recrystallization from ethyl acetate gave almost colorless crystals, mp 150–152 °C. IR (KBr): 3057, 2939, 2236, 1619, 1576, 1485, 1386, 1239, 1151, 1028, 702, 653 cm–1; MS (EI, 70 eV) m/z: 389 (M+, 100%), 374 (24), 358 (10), 346 (22), 244 (20), 213 (50), 194 (56), 187 (42), 173 (33), 165 (12), 147 (27), 132 (34), 104 (19), 77 (18), 51 (17), 43 (20); 1H-NMR (CDCl3) δ: 8.19–8.16 (m, 1H, phthalazine 8-H), 8.09–8.05 (m, 1H, phthalazine 5-H, shows positive NOE on irradiation at 7.75 ppm), 7.88–7.83 (m, 2H, phthalazine 6-H, 7-H), 7.77–7.74 (m, 2H, phenyl 2-H, 6-H), 7.60–7.56 (m, 3H, phenyl 3-H, 4-H, 5-H, shows positive NOE on irradiation at 7.75 ppm), 7.49 (d, J6–7 = 8.9 Hz, 1H, indole 7-H), 7.33 (d, J2–3 = 3.3 Hz, 1H, indole 2-H), 7.16 (d, J4–6 = 2.4 Hz, 1H, indole 4-H), 6.97 (dd, J6–7 = 8.9 Hz, J4–6 = 2.4 Hz, 1H, indole 6-H), 6.54 (d, J2–3 = 3.3 Hz, 1H, indole 3-H), 5.31 (s, 2H, CH2), 3.88 (s, 3H, OCH3). Anal. calcd. for C26H19N3 O: C, 80.19; H, 4.92; N, 10.79. Found: C, 79.98; H, 4.99; N, 10.55.
4-[3-(5-Methoxy-1H-indol-1-yl)prop-1-yn-1-yl]isoquinoline (3c). Prepared from 5-methoxy-1-prop-2-yn-1-yl-1H-indole (1a) and 4-bromoisoquinoline (2e); yield: 0.284 g (34%), recrystallization from ethyl acetate/light petroleum gave brownish crystals, mp 131–133 °C. IR (KBr): 2903, 2825, 2244, 1620, 1488, 1241, 1150, 794, 753, 715, 580 cm–1; MS (EI, 70 eV) m/z: 312 (M+, 60%), 296 (2), 281 (3), 201 (4), 166 (100), 156 (9), 139 (36), 103 (5), 89 (6), 76 (6), 43 (14); 1H NMR (CDCl3) δ: 9.28 (br s, 1H, isoquinoline 1-H), 8.75 (br s, 1H, isoquinoline 3-H), 8.11 (d, J7–8 = 8.4 Hz, 1H, isoquinoline 8-H), 7.98 (d, J5–6 = 7.8 Hz, 1H, isoquinoline 5-H), 7.74 (t, J = 7.7 Hz, 1H, isoquinoline 7-H, shows positive NOE on irradiation at 8.11 ppm), 7.65 (t, J = 7.3 Hz, 1H, isoquinoline 6-H), 7.46 (d, J6–7 = 8.9 Hz, 1H, indole 7-H, shows positive NOE on irradiation at 5.25 ppm), 7.32 (d, J2–3 = 3.3 Hz, 1H, indole 2-H, shows positive NOE on irradiation at 5.25 ppm), 7.15 (d, J4–6 = 2.4 Hz, 1H, indole 4-H), 6.96 (dd, J6–7 = 8.9 Hz, J4–6 = 2.4 Hz, 1H, indole 6-H), 6.52 (d, J2–3 = 3.3 Hz, 1H, indole 3-H), 5.25 (s, 2H, CH2), 3.88 (s, 3H, OCH3). Anal. calcd for C21H16N2O · 0.25 H2O: C, 79.60; H, 5.25; N, 8.84. Found: C, 79.66; H, 5.50; N, 8.46.
1-[3-(5-Methoxy-1H-indol-1-yl)prop-1-yn-1-yl]isoquinoline (3d). Prepared from 5-methoxy-1-prop-2-yn-1-yl-1H-indole (1a) and 1-iodoisoquinoline (2d); yield: 0.620 g (75%), recrystallization from ethyl acetate/light petroleum gave almost colorless crystals, mp 155–157 °C. IR (KBr): 3048, 2953, 2235, 1620, 1578, 1551, 1486, 1350, 1242, 1153, 1028, 830, 747, 723, 666 cm–1; MS (EI, 70 eV) m/z: 312 (M+, 34%), 297 (6), 281 (2), 269 (9), 184 (11), 166 (44), 146 (11), 139 (38), 134 (15), 103 (7), 89 (6), 76 (9), 61 (13), 45 (26), 43 (100); 1H-NMR (CDCl3) δ: 8.51 (d, J3–4 = 5.4 Hz, 1H, isoquinoline 3-H), 8.22 (dd, J7–8 = 8.4 Hz, J6–8 = 1.2 Hz, 1H, isoquinoline 8-H), 7.82 (d, J5–6 = 8.1 Hz, 1H, isoquinoline 5-H), 7.72–7.69 (m, 1H, isoquinoline 6-H, shows positive NOE on irradiation at 7.82 ppm), 7.67–7.63 (m, 1H, isoquinoline 4-H, shows positive NOE on irradiation at 8.51 ppm), 7.61–7.55 (m, 1H, isoquinoline 7-H, shows positive NOE on irradiation at 8.22 ppm), 7.47 (d, J6–7 = 8.9 Hz, 1H, indole 7-H), 7.32 (d, J2–3 = 3.3 Hz, 1H, indole 2-H), 7.14 (d, J4–6 = 2.4 Hz, 1H, indole 4-H), 6.96 (dd, J6–7 = 8.9 Hz, J4–6 = 2.4 Hz, 1H, indole 6-H), 6.51 (d, J2–3 = 3.3 Hz, 1H, indole 3-H), 5.26 (s, 2H, CH2), 3.88 (s, 3H, OCH3). Anal. calcd. for C21H16N2O · 0.2 H2O: C, 79.83; H, 5.23; N, 8.87. Found: C, 79.82; H, 5.22; N, 8.59.
1-[3-(2,3-Dihydro-1H-indol-1-yl)prop-1-yn-1-yl]phthalazine (3e). Preparation from 1-prop-2-yn-1-ylindoline (1d) and 1-iodophthalazine (2a); yield: 0.592 g (80%), recrystallization from ethyl acetate gave brownish crystals, mp 94–95 °C. IR (KBr): 3043, 2830, 2227, 1606, 1484, 1353, 1237, 1138, 757, 594 cm–1; MS (EI, 70 eV) m/z: 285 (M+, 2%), 168 (100), 141 (13), 114 (11), 91 (23), 77 (6), 65 (16), 51 (5); 1H-NMR (CDCl3) δ: 9.43 (s, 1H, phthalazine 4-H), 7.93–7.73 (m, 4H, phthalazine 5-H, 6-H, 7-H, 8-H), 7.21–7.16 (m, 2H, indoline 4-H, 6-H, shows positive NOE on irradiation at 3.05 ppm), 6.85–6.76 (m, 2H, indoline 5-H, indoline 7-H), 4.38 (s, 2H, C≡CCH2), 3.60 (t, J = 8.1 Hz, 2H, indoline 2-H, shows positive NOE on irradiation at 3.05 ppm), 3.05 (t, J = 8.1 Hz, 2H, indoline 3-H). Anal. calcd. for C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found: C, 79.93; H, 5.47; N, 14.68.
1-[3-(5-Bromo-1H-indol-1-yl)prop-1-yn-1-yl]phthalazine (3f). Preparation from 5-bromo-1-prop-2-yn-1-yl-1H-indole (1b) and 1-iodophthalazine (2a); yield: 0.281 g (30%), recrystallization from ethyl acetate gave almost colorless crystals, mp 154–158 °C. IR (KBr): 3097, 2955, 2239, 1465, 1394, 1353, 1282, 1185, 1051, 899, 758, 594 cm–1; MS (EI, 70 eV) m/z: 363 (M+, 13%), 361 (M+, 12), 282 (8), 195 (14), 167 (7), 141 (34), 127 (36), 114 (15), 97 (11), 84 (20), 69 (25), 58 (93), 57 (39), 43 (100); 1H NMR (CDCl3) δ: 9.48 (s, 1H, phthalazine 4-H), 8.06 (d, J7–8 = 8.1 Hz, 1H, phthalazine 8-H), 7.99–7.86 (m, 3H, phthalazine 5-H, 6-H, 7-H), 7.81 (d, J4–6 = 1.6 Hz, 1H, indole 4-H), 7.45 (d, J6–7 = 8.7 Hz, 1H, indole 7-H), 7.38 (dd, J6–7 = 8.7 Hz, J4–6 = 1.6 Hz, 1H, indole 6-H), 7.34 (d, J2–3 = 3.3 Hz, 1H, indole 2-H), 6.55 (d, J2–3 = 3.3 Hz, 1H, indole 3-H), 5.31 (s, 2H, CH2). Anal. calcd. for C19H12N3Br: C, 63.00; H, 3.34; N, 11.60. Found: C, 62.75; H, 3.34; N, 11.34.
Methyl 1-(3-Phthalazin-1-ylprop-2-yn-1-yl)-1H-indole-5-carboxylate (3g). Preparation from methyl 1-prop-2-yn-1-yl-1H-indole-5-carboxylate (1c) and 1-iodophthalazine (2a); modified work-up procedure: after completion of the reaction, the solid material (3g + triethylammonium iodide) was filtered off and washed with diethyl ether. It was then dissolved in CH2Cl2 and this solution was washed with 0.5 N HCl, then with water. The extract was dried over Na2SO4 and evaporated under reduced pressure to give the product (0.133 g, 15%) as brownish crystals, mp 97 °C (decomposition). IR (KBr): 2948, 2241, 1710, 1610, 1434, 1310, 1196, 1097, 754, 595 cm–1; MS (EI, 70 eV) m/z: 341 (M+, 23%), 282 (10), 175 (50), 165 (10), 144 (100), 141 (36), 116 (73), 89 (39), 72 (29), 58 (66), 44 (81); 1H-NMR (CDCl3) δ: 9.49 (s, 1H, phthalazine 4-H), 8.45 (d, J4–6 = 0.9 Hz, 1H, indole 4-H), 8.10–7.85 (m, 5H, indole 6-H, phthalazine 5-H, 6-H, 7-H, 8-H), 7.58 (d, J6–7 = 8.7 Hz, 1H, indole 7-H, shows positive NOE on irradiation at 5.35 ppm), 7.41 (d, J2–3 = 3.4 Hz, 1H, indole 2-H, shows positive NOE on irradiation at 5.35 ppm), 6.71 (d, J2–3 = 3.4 Hz, 1H, indole 3-H), 5.35 (s, 2H, CH2), 3.95 (s, 3H, OCH3). HRMS (EI, 70 eV) m/z calcd. for C21H15N3O2 (M+): 341.1164. Found: 341.1167.

Acknowledgements

We are grateful to Æterna Zentaris GmbH, Frankfurt/Main (Germany) for the in-vitro evaluation of antitumor activity.

References and Notes

  1. Haider, N.; Jbara, R.; Khadami, F.; Wanko, R. Synthesis of Pyridazino[4,5-b]carbazoles as Potential Antineoplastic Agents. Heterocycles 1998, 48, 1609–1622. [Google Scholar] [CrossRef]
  2. Haider, N.; Käferböck, J.; Mátyus, P. Diels-Alder Reaction of Pyrano[3,4-b]indolones with an Electron-Deficient Pyridazinone: a New Pathway to Carbazole-Fused Pyridazines. Heterocycles 1999, 51, 2703–2710. [Google Scholar] [CrossRef]
  3. Fidesser, E.; Haider, N.; Jbara, R. Convenient Synthesis of New 3-Aminocarbazole and Pyrimido[5,4-b]carbazole Derivatives. ARKIVOC 2001, 2, 133–139. [Google Scholar]
  4. Haider, N. Pyridazine-Fused Carbazoles: Synthesis, Reactivity, and Antitumor Activity. J. Heterocycl. Chem. 2002, 39, 511–521. [Google Scholar]
  5. Haider, N.; Sotelo, E. 1,5-Dimethyl-6H-pyridazino[4,5-b]carbazole, a 3-Aza Bioisoster of the Antitumor Alkaloid Olivacine. Chem. Pharm. Bull. 2002, 50, 1479–1483. [Google Scholar] [CrossRef] [PubMed]
  6. Shanab, K.; Pongprom, N.; Wulz, E.; Holzer, W.; Spreitzer, H.; Schmidt, P.; Aicher, B.; Müller, G.; Günther, E. Synthesis and Biological Evaluation of Novel Cytotoxic Azanaphthoquinone Annelated Pyrrolo Oximes. Bioorg. Med. Chem. Lett. 2007, in press. [Google Scholar]
  7. Spreitzer, H.; Pichler, A.; Holzer, W.; Kratzel, M.; Slanz, R.; Koulouri, A.; Krenn, P.; Parrer, U.; Szieber, P. Synthesis of azanaphthoquinone annelated pyrroles. Heterocycles 2001, 54, 111–121. [Google Scholar]
  8. Spreitzer, H.; Puschmann, C. Synthesis of Anticancer Compounds, I, "Dual Function" Antitumor Agents Based on Bioreduction and DNA-Alkylation. Monatsh. Chem. 2007, 138, 517–522. [Google Scholar] [CrossRef]
  9. Haider, N.; Käferböck, J. Intramolecular [4+2] cycloaddition reactions of indolylalkylpyridazines: synthesis of annulated carbazoles. Tetrahedron 2004, 60, 6495–6507. [Google Scholar] [CrossRef]
  10. Broggini, G.; Bruché, L.; Zecchi, G.; Pilati, T. 1,3-Dipolar cycloadditions to nitrogen-substituted allenes. J. Chem. Soc., Perkin Trans. 1 1990, 533–539. [Google Scholar]
  11. Hirsch, A.; Orphanos, D. G. The synthesis of some iodophthalazines and phthalazinecarbonitriles. Can. J. Chem. 1966, 44, 1551–1554. [Google Scholar] [CrossRef]
  12. Gabriel, S.; Eschenbach, G. Über eine Darstellungsweise der Phthalazine. Chem. Ber. 1897, 30, 3022–3037. [Google Scholar] [CrossRef]
  13. Lieck, A. Über einige Phthalazine. Chem. Ber. 1905, 38, 3918–3924. [Google Scholar] [CrossRef]
  14. Hayashi, E.; Akahori, Y.; Yamamoto, Y. 1-Nitroisoquinoline. Yakugaku Zasshi 1967, 87, 1342–1345, [Chem. Abstr. 1968, 69, 2847]. [Google Scholar]
  15. Ukai, T. Mercuric derivatives of quinoline, methylquinoline and isoquinoline. VII. (Supplement). Yakugaku Zasshi 1931, 51, 542–576, [Chem. Abstr. 1931, 25, 48018]. [Google Scholar]
  16. Haider, N.; Kabicher, T. Methyl 1-prop-2-yn-1-yl-1H-indole-5-carboxylate. MolBank 2007. accepted. [Google Scholar]
  17. Torregrosa, J. L.; Baboulene, M.; Speziale, V.; Lattes, A. Hydroboration of unsaturated amines. V. New approach to aminoalkylidenecycloalkanes. J. Organomet. Chem. 1983, 244, 311–317. [Google Scholar]
  18. For recent examples of alkyne/allene rearrangements of N-propargylindoles, see: a) lit. [9]; b) Abbiati, G.; Canevari, V.; Caimi, S.; Rossi, E. Domino addition/annulation of delta-alkynyl-aldehydes and oxygen nucleophiles. A new entry to [1,4]oxazino[4,3-a]indoles. Tetrahedron Lett. 2005, 46, 7117–7120. [Google Scholar]
  19. Scudiero, D. A.; Shoemaker, R. H.; Paull, K. D.; Monks, A.; Tierney, S.; Nofziger, T. H.; Currens, M. J.; Seniff, D.; Boyd, M. R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res. 1988, 48, 4827–4833. [Google Scholar] [PubMed]
  • Sample Availability: available from the authors.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top