Ultrasound mediated synthesis of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives and their pharmacological evaluation

Manam Sreenivasa Rao; Meda Haritha; N. Chandrasekhar; Mandava V. Basaveswara Rao; Manojit Pal

doi:10.1016/j.arabjc.2015.05.013

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Original article

12 (

); 2697-2703

doi:

10.1016/j.arabjc.2015.05.013

Ultrasound mediated synthesis of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives and their pharmacological evaluation

Manam Sreenivasa Rao^{^a}, Meda Haritha^{^b}, N. Chandrasekhar^{^b}, Mandava V. Basaveswara Rao^{^b,⁎}, Manojit Pal^{^c,⁎}

a C.R. College, Ganapavaram, Chilakaluripet 522616, Andhra Pradesh, India

b Department of Chemistry, Krishna University, Nuzvid 521201, Andhra Pradesh, India

c Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India

⁎Corresponding authors. Tel.: +91 40 6657 1500. vbrmandava@yahoo.com (Mandava V. Basaveswara Rao), manojitpal@rediffmail.com (Manojit Pal)

Received: 2015-2-2, Accepted: 2015-5-16, Published: 2015-12-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Designed as potential cytotoxic agents a series of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives were synthesized by using a Bischler type reaction. The methodology involved the cyclodehydration of 2-(3,4-dihydroquinolin-1(2H)-yl)-1-alkyl/aryl ethanones in the presence of p-TSA under ultrasound irradiation. A number of compounds were prepared using this methodology and tested for their in vitro anti-proliferative properties against cancer (leukemia) and non-cancerous cell lines. Some of the compounds showed promising and selective cytotoxic effects toward leukemia cells.

Keywords

Pyrrolo[3,2,1-ij]quinoline

Cyclodehydration

Ultrasound

Cytotoxicity

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1 Introduction

The pyrrolo[3,2,1-ij]quinoline framework has been found to be an integral part of several bioactive molecules and agents (Stanton and Ackerman, 1983; Al-awar et al., 2004). For example, compounds containing this framework were found to be useful for the potential treatment of asthma (Paris et al., 1995), epilepsy, obesity (Isaac et al., 2000) and rice blast diseases (Bass et al., 1981). This framework attracted our attention because of a recent report that disclosed anti-leukemic activity of a series of polycyclic isatin derivatives including pyrrolo[3,2,1-ij]quinoline-1,2-diones (Matesic et al., 2012). Indeed, the compound A (Fig. 1) that belongs to this class showed notable cytotoxicity (IC₅₀ = 8.36 ± 3.5 μM) when tested against U937 cells. This report and our interest (Layek et al., 2009a,b, 2011; Rao et al., 2014 ) in this class of compounds prompted us to evaluate a library of compounds based on 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline framework B (Fig. 1). The substituent “R” was introduced at C-6 position of the tricyclic ring not only for the creation of diversity but also for the fact that 3-substituted indoles were found to be antiproliferative agents (Rao et al., 2011).

The known pyrrolo[3,2,1-ij]quinoline-1,2-dione derivative A and the new framework B for the identification of potential cytotoxic agents.

While a number of methods have been reported for the construction of pyrrolo[3,2,1-ij]quinoline or related rings all of them involved in the use of expensive transition metals especially Pd/Cu catalysts (Layek et al., 2009a,b, 2011; Rao et al., 2014; Marchand et al., 2005; Blurton et al., 1997; Dorow et al., 2006 ). Moreover, all these methods are useful for accessing compounds having a substituent at C-5 position and not handy for the synthesis of compounds based on B. A literature search revealed that the Bischler (Bischler and Brion, 1892; Bischler and Fireman, 1893) type of reaction (Shikhaliev et al., 2003; Wijngaarden et al., 1993; Zhu et al., 2004; Adam-Worrall, 2005 ) has been explored to prepare tricyclic compounds possessing a substituent at C-6 similar to B. For example, N-phenacyl derivatives of hydroquinolines were cyclized to the corresponding pyrroloquinolines in the presence of an acid catalyst (Shikhaliev et al., 2003). We therefore decided to adopt a similar but faster strategy for accessing our target compounds based on B. The ultrasound mediated reactions have gained considerable interest in recent time. Compared to the traditional methods the ultrasound mediated reactions offer several advantages such as shorter reaction time, mild conditions, and good yields of products (Li et al., 2005; Ratoarinoro et al., 1992). Thus, the use of ultrasound radiation has emerged as a common strategy in present day organic synthesis. Herein we report an ultrasound mediated faster approach toward 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives (3) via a Bischler type reaction of 2-(3,4-dihydroquinolin-1(2H)-yl)-1-alkyl/aryl ethanone (2) prepared from 1,2,3,4-tetrahydroquinoline (1) (Scheme 1). To our knowledge the present strategy has not been explored for the preparation of compound 3 earlier. We also report the cytotoxicity of the synthesized compounds tested against human chronic myeloid leukemia cells i.e. K562 in vitro. Being a cancer of the blood-forming tissues, leukemia is characterized by a large increase in the numbers of white blood cells (leukocytes) in the circulation or bone marrow.

Ultrasound mediated synthesis of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives (3) via a Bischler type reaction.

2 Material and methods

2.1

2.1 General methods

Unless stated otherwise, reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60 F₂₅₄), visualizing with ultraviolet light or iodine spray. Column chromatography was performed on silica gel (60–120 mesh) using distilled petroleum ether and ethyl acetate. ¹H and ¹³C NMR spectra were determined in CDCl₃ solution using a Varian 400 MHz spectrometer. Proton chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.0) as internal standard and expressed in parts per million. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), and m (multiplet) as well as b (broad). Coupling constants (J) are given in hertz. Infrared spectra were recorded on a FTIR spectrometer. Melting points were determined by using a Buchi melting point B-540 apparatus. MS spectra were obtained on a mass spectrometer.

2.2

2.2 Preparation of compound 2

To a solution of compound 1 (1 mmol) and α-bromo ketone (0.95 mmol) in 1,4-dioxane (5 mL) was added K₂CO₃ (1 mmol) and the mixture was stirred at 70–75 °C for 3–4 h under nitrogen. After completion of the reaction (indicated by TLC) the mixture was concentrated under reduced pressure and diluted with cold water (25 mL). The mixture was extracted with EtOAc (3 × 5 mL). The combined organic layer was collected, washed with water (2 × 5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under low vacuum. The product obtained was used for the next step.

2.3

2.3 General procedure for the preparation of compound 3

A solution of compound 2 (1 mmol) and p-TSA (0.5 mmol) in 1,4-dioxane (3 mL) was heated at 80 °C in the presence of nitrogen under ultrasound (using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz) for 2 h. The reaction mixture was then concentrated under vacuum, diluted with EtOAc (10 mL), and washed with 1 N K₂CO₃ solution (2 × 5 mL) followed by cold water. The EtOAc layer was collected, dried over anhydrous Na₂SO₄, filtered and concentrated under low vacuum. The crude product isolated was purified by column chromatography over silica gel using hexane–EtOAc as eluant.

2.4

2.4 1-Phenyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3a)

Light yellow solid; mp 61–63 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 7.9 Hz, 1H), 7.68–7.66 (m, 2H), 7.42–7.39 (m, 2H), 7.26–7.21 (m, 2H), 7.10–7.07 (m, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.27–2.22 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 136.1, 135.0, 128.7, 126.8, 125.4, 123.7, 123.6, 122.0, 120.3, 119.0, 117.5, 116.5, 44.1, 24.7, 22.6; MS (ESI) m/z: 233 (100), 232 (33), 204 (6), 154 (5), 88 (2); HRMS (ESI) for C₁₇H₁₆N (M+H)+: calcd 234.1277, found 234.1285.

2.5

2.5 1-(4-Fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3b)

Oily liquid; ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 7.14–7.04 (m, 3H), 6.95 (d, J = 7.0 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.30–2.19 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1 (d, J C – F = 242.5 Hz), 134.8, 132.1 (d, J C – F = 3.1 Hz), 128.1 (d, J C – F = 7.6 Hz), 123.6, 123.4, 122.0, 120.4, 119.0, 117.1, 115.6, 115.5 (d, J C – F = 21.1 Hz), 44.1, 24.6, 22.7; MS (ESI) m/z: 251 (100), 232 (9), 207 (5), 154 (11), 125 (11) 75 (4); HRMS (ESI) for C₁₇H₁₅FN (M+H)+: calcd 252.1183, found 252.1180.

2.6

2.6 1-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3c)

Light brown solid; mp 125–127 °C;¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 8.0 Hz, 1H), 7.59–7.56 (m, 2H), 7.37–7.34 (m, 2H), 7.23 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.16 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.26–2.21 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 135.0, 134.6, 131.0, 128.8, 128.0, 123.7, 123.5, 122.1, 120.5, 119.1, 117.2, 115.3, 44.2, 24.6, 22.7; MS (ESI) m/z: 267 (100), 266 (36), 230 (15), 154 (11), 88 (25) 75 (10); HRMS (ESI) for C₁₇H₁₅ClN (M+H)+: calcd 268.0888, found 268.0884.

2.7

2.7 1-(4-Bromophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3d)

Pale yellow solid; mp 153–155 °C;¹H NMR (400 MHz, CDCl₃) δ 7.71–7.68 (m, 1H), 7.56–7.52 (m, 4H), 7.27 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.30–2.26 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 135.1, 135.0, 131.7, 128.2, 123.8, 123.4, 122.1, 120.6, 119.1, 118.8, 117.2, 115.3, 44.2, 24.6, 22.7; MS (ESI) m/z: 311 (100), 313 (98), 312 (40), 230 (20), 102 (15); HRMS (ESI) for C₁₇H₁₅BrN (M+H)+: calcd 312.0382, found 312.0376.

2.8

2.8 1-(p-Tolyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3e)

Ash colored solid; mp 101–103 °C;¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.24–7.22 (m, 3H), 7.07 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.28–2.24 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 134.0, 133.8, 132.1, 128.5, 125.7, 122.6, 122.3, 120.8, 119.1, 117.7, 116.4, 115.5, 43.0, 23.6, 21.7, 20.0; MS (ESI) m/z: 247 (100), 246 (35), 231 (8), 154 (10), 128 (16) 73 (4); HRMS (ESI) for C₁₈H₁₈N (M+H)+: calcd 248.1434, found 248.1431.

2.9

2.9 1-(4-Methoxyphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3f)

Pale yellow solid; mp 124–126 °C;¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 8.1 Hz, 1H), 7.62–7.60 (m, 2H), 7.20 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.01–6.95 (m, 3H), 4.18 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H), 2.29–2.25 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 157.7, 134.8, 128.7, 128.1, 123.7, 123.2, 122.0, 120.1, 118.9, 117.6, 116.4, 114.3, 55.3, 44.3, 24.9, 22.9; MS (ESI) m/z: 263 (100), 248 (92), 240 (11), 192 (60), 131 (12); HRMS (ESI) for C₁₈H₁₈NO (M+H)+: calcd 264.1383, found 264.1380.

2.10

2.10 4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (3g)

Ash colored solid; mp 133–135 °C;¹H NMR (400 MHz, CDCl₃) δ 7.75–7.71 (m, 3H), 7.66–7.64 (m, 2H), 7.37 (s, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.29–2.24 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 141.1, 135.2, 132.5, 126.4, 125.0, 123.3, 122.4, 121.2, 119.5, 119.6, 117.2, 114.7, 108.1, 44.4, 24.6, 22.5; MS (ESI) m/z: 258 (100), 242 (5), 230 (6), 202 (4), 128 (8); HRMS (ESI) for C₁₈H₁₅N₂ (M+H)+: calcd 259.1230, found 259.1226.

2.11

2.11 1-(Naphthalen-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3h)

Light brown solid; mp 113–115 °C;¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.89–7.85 (m, 3H), 7.83–7.80 (m, 2H), 7.49–7.45 (m, 1H), 7.43–7.39 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.32–2.25 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 135.0, 134.1, 133.5, 131.7, 128.1, 127.6, 127.7, 126.0, 126.1, 125.0, 124.2, 124.1, 123.8, 122.1, 120.5, 119.1, 117.6, 116.4, 44.2, 24.7, 22.6; MS (ESI) m/z: 283 (100), 254 (7), 226 (5), 141 (8), 139 (4); HRMS (ESI) for C₂₁H₁₈N (M+H)+: calcd 284.1434, found 284.1428.

2.12

2.12 1-(3a,7a-Dihydrobenzofuran-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3i)

Ash colored solid; mp 136–138 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.54–7.53 (m, 1H), 7.47–7.46 (m, 1H), 7.20–7.15 (m, 3H), 7.00 (d, J = 7.0 Hz, 1H), 6.85 (d, J = 0.4 Hz, 1H), 4.19 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.28–2.23 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 153.8, 153.4, 134.7, 130.1, 124.6, 122.8, 122.7, 122.5, 122.2, 121.0, 120.0, 119.5, 117.7, 110.4, 107.1, 98.7, 44.4, 24.5, 22.7; MS (ESI) m/z: 273 (100), 245 (6), 189 (3), 136 (6), 120 (3); HRMS (ESI) for C₁₉H₁₈NO (M+H)+: calcd 274.1226, found 274.1221.

2.13

2.13 Ethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetate (3j)

Yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J = 8.0 Hz, 1H), 7.03–7.00 (m, 2H), 6.89 (d, J = 7.0 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.73 (s, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.22–2.17 (m, 2H), 1.26–1.23 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 134.2, 125.1, 125.0, 121.5, 119.4, 118.4, 116.5, 106.7, 60.4, 44.0, 31.5, 24.4, 22.6, 14.1; MS (ESI) m/z: 170 (100), 142 (27), 243 (3), 83 (2); HRMS (ESI) for C₁₅H₁₈NO₂ (M+H)+: calcd 244.1332, found 244.1329.

2.14

2.14 1-Ethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3k)

Yellow liquid; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J = 7.7 Hz, 1H), 7.00–6.95 (m, 1H), 6.87 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 4.11–4.04 (m, 2H), 2.97 (t, J = 5.9 Hz, 2H), 2.78–2.74 (m, 2H), 2.22–2.19 (m, 2H), 1.32–1.29 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 134.4, 125.0, 122.5, 121.4, 118.7, 118.1, 117.2, 116.4, 43.6, 24.5, 23.0, 18.5, 15.0; MS (ESI) m/z: 185 (37), 170 (100), 168 (4), 142 (16), 115 (5); HRMS (ESI) for C₁₃H₁₆N (M+H)+: calcd 186.1277, found 186.1273.

2.15

2.15 MTT assay

Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells (5 × 10³ cells/well) were seeded to 96-well culture plate and cultured with or without compounds at 10 μM concentration (five different concentrations i.e., 10, 5, 1, 0.5, and 0.1 μM for dose response study) in duplicates for 24 h in a final volume of 200 μl. After treatment, the medium was removed and 20 μl of MTT (5 mg/ml in PBS) was added to the fresh medium. After 3 h incubation at 37 °C, 100 μl of DMSO was added to each well and plates were agitated for 1 min. Absorbance was read at 570 nm on a multi-well plate reader (Victor3, Perkin Emler). Percent inhibition of proliferation was calculated as a fraction of control (without compound).

3 Results and discussion

3.1

3.1 Chemistry

The starting compound (2) required for the synthesis of 3 was prepared (Bahner et al., 1952) via the reaction of 1 with α-bromo ketones in the presence of K₂CO₃ in 1,4-dioxane at 70–75 °C for 3–4 h. Initially, in certain cases the compound 2 was isolated and purified before use in the next step. However, at a later stage we observed that the purification of compound 2 was not necessary and the crude product isolated after usual work up could be used for the preparation of the target compound 3. Nevertheless, to establish the optimized reaction conditions we used the cyclization of 2-(3,4-dihydroquinolin-1(2H)-yl)-1-phenylethanone (2a) as a model reaction (Table 1). The reaction was performed in MeCN using various acid catalysts e.g. AcOH, CF₃CO₂H and p-TSA (p-toluenesulfonic acid) (entries 1–3, Table 3) when the desired product 3a was isolated in low yield only in third case (entry 3, Table 1). The change of solvent to toluene did not improve the product yield significantly (entry 4, Table 1). However, 3a was isolated in 53% yield when the reaction was performed in 1,4-dioxane (entry 5, Table 1). The duration of all these reactions was 24 h. To decrease the reaction time we performed the reaction under ultrasound irradiation using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz. To our delight the reaction was completed within 2 h affording 3a in 67% yield (entry 6, Table 1). All these reactions in the absence or presence of ultrasound were generally performed at 80 °C. The lowering of reaction temperature decreased the yield of 3a considerably (entry 7, Table 1). Thus, the condition of entry 6 was found to be optimum and used for further study.

To extend the scope and generality of this methodology, a number of ethanone derivatives (2) were treated with p-TSA in 1,4-dioxane under the conditions of entry 6 of Table 1. Both aromatic and aliphatic substituents as “R” group were examined (Table 2). The reaction proceeded well in all these cases affording the corresponding 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives (3) in good to acceptable yields (Table 2). Aromatic “R” moiety containing various type of substituents such as mild or strong electron-donating groups such as F, Cl, Br, Me, OMe (entries 1–6, Table 2) and electron-withdrawing such as CN (entry 7, Table 2) was examined and well tolerated except the case of CN. The presence of aromatic groups such as 2-naphthyl or benzofuran-2-yl was also tolerated (entries 8 and 9, Table 2). The aliphatic “R” moiety such as –CH₂CO₂Et and ethyl (entrys 10 and 11, Table 2) was generally found to be tolerated under the condition employed though the product yield was not particularly high in the first case possibly due to the cleavage of ester group leading to the corresponding acid thereby partial loss of the product 3j.

A plausible mechanism (Shikhaliev et al., 2003) for the ultrasound mediated synthesis of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives (3) in the presence of p-TSA is shown in Scheme 2. The cyclodehydration process seemed to proceed via generation of the protonated species E-1 (from compound 2) which on intramolecular cyclization afforded E-2. This intramolecular attack by the benzene ring was facilitated by the ring nitrogen of E-1. Re-aromatization of the benzene ring of E-2 followed by protonation of the hydroxyl group afforded E-3. The elimination of water molecule from E-3 and regeneration of proton completed the catalytic cycle affording the desired product 3. It is worthy to note that electron donating or withdrawing effect of “R” group attached to the carbonyl moiety could influence the electropositivity of carbonyl carbon thereby intramolecular cyclization of E-1. Thus the p-cyanophenyl group due to its electron withdrawing effect did not allow adequate degree of polarization of —C⚌OH⁺ bond to facilitate the intramolecular attack by the nucleophilic phenyl moiety at the carbonyl carbon.

Proposed reaction mechanism for the cyclodehydration of 2 leading to 3.

The results of Table 1 (entry 5 vs. 6) clearly suggest that the synthesis of compound 3 was accelerated in the presence of ultrasound though it is not clear if the ultrasound irradiation has effect on one or more of steps shown in Scheme 2. It is possible that the force created due to the cavitational collapse can drive all the steps. Being a well known phenomenon cavitation caused by ultrasound is involved with the growth, oscillation, and collapse of bubbles under the action of an acoustic field (Mason and Peters, 1991; Mason, 2007). The cavitational collapse on the other hand creates drastic conditions inside the medium within an extremely short period of time. For example, the temperature of 2000–5000 K and pressure up to 1800 atmosphere can be produced inside the collapsing cavity under sonic conditions. Also, strong physical effects including shear forces, jets, and shock waves are caused by this collapse outside the bubble. Thus, chemical transformations performed under ultrasound proceed with notable efficiency and speed due to these cavitation-induced overall effects. This perhaps explains the rate acceleration of the present reaction under ultrasound in the absence of which the reaction took relatively longer time (entry 5, Table 1).

3.2

3.2 Pharmacology

All the compounds of 3 synthesized based on the template B (Fig. 1) were evaluated for their potential anticancer properties in vitro. The cells used for our in vitro studies include human chronic myeloid leukemia cells such as K562, and non-cancerous human embryonic kidney cells such as HEK293. The effect of test compounds on cell viability was measured using a colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay after 24 h of treatment in culture medium containing PBS. The percentages of cell viability for most promising test compounds at 10 μM are presented in Table 3. The compounds that showed >50% activities were considered as active. As can be seen from Table 3 the compounds 3b, 3e and 3f showed significant activities against K562 Leukemia cells whereas other compounds were found to be less active or inactive. It is evident that the p-substituent on the benzene ring of the “R” group played a key role and F, Me as well as OMe were found to be favorable. Notably, all these compounds were found to be selective toward the growth inhibition of cancer cells as none of these compounds showed any significant effects when tested against HEK293 cells. The best active compound 3f was taken further for a dose response study (Table 4). The compound 3f showed consistent dose-dependent growth inhibition of K562 Leukemia cells across all the concentrations tested. In view of the fact that leukemia affected 352,000 people globally and caused 265,000 deaths in 2012 (World Cancer Report, 2014), the compound 3f was identified as a new cytotoxic agent and is of further interest.

Table 4 In vitro antiproliferative effects of compound 3f against K562 Leukemia cells.

Compounds	% Inhibition of proliferation^a
Compounds	10 μM	5 μM	1 μM	0.1 μM	0.01 μM
3f	66	51	37	23	ND
Doxorubicin	82	70	59	47	32

ND = not determined.

a Average of three determinations.

4 Conclusion

In conclusion, a series of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized as potential cytotoxic agents. Synthesis of these compounds was carried out by using a Bischler type reaction that involved the cyclodehydration of 2-(3,4-dihydroquinolin-1(2H)-yl)-1-alkyl/aryl ethanones in the presence of p-TSA under ultrasound irradiation. A number of compounds were prepared using this methodology and tested for their in vitro antiproliferative properties against cancer (leukemia) and non-cancerous cell lines. Some of the compounds showed promising and selective cytotoxic effects toward leukemia cells. Overall, our study suggests that the 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline framework could be an attractive template for the identification of novel and potential anticancer agents and the corresponding synthetic strategy described could be useful for generating diversity based library of small molecules related to this scaffold.

Acknowledgments

The authors thank the management of Dr. Reddy’s Institute of Life Sciences, Hyderabad, India, for continuous support and encouragement.

References

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Ratoarinoro N., Wilhelm A.M., Berlan J., Delmas H., . Effects of ultrasound emitter type and power on a heterogeneous reaction. Chem. Eng. J.. 1992;50:27-31.
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Bahner C.T., Easley W.K., Stephen E., . Derivatives of Tetrahydroquinoline and Tetrahydroisoquinoline. J. Am. Chem. Soc.. 1952;74:4198-4199.
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Mason T.J., Peters D., . Practical Sonochemistry. New York, NY, USA: Ellis Horwood; 1991.
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World Cancer Report, 2014. World Health Organization. 2014, pp. (Chapter 5.13) ISBN 9283204298.

Introduction

Material and methods

General methods
Preparation of compound 2
General procedure for the preparation of compound 3
1-Phenyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3a)
1-(4-Fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3b)
1-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3c)
1-(4-Bromophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3d)
1-(p-Tolyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3e)
1-(4-Methoxyphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3f)
4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (3g)
1-(Naphthalen-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3h)
1-(3a,7a-Dihydrobenzofuran-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3i)
Ethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetate (3j)
1-Ethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3k)
MTT assay

Results and discussion

Chemistry
Pharmacology

Conclusion

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[1] Stanton J.L., Ackerman M.H., . Synthesis and anticonvulsant activity of some tetracyclic indole derivatives. J. Med. Chem.. 1983;26:986-989.
[Google Scholar]

[2] Al-awar R.S., Ray J.E., Hecker K.A., Huang J., Waid P.P., Shih C., Brooks H.B., Spencer C.D., Watkins S.A., Patel B.R., Stamm N.B., Ogg C.A., Schultz R.M., Considine E.L., Faul M.M., Sullivan K.A., Kolis S.P., Grutsch J.L., Joseph S., . 1,7-Annulated indolocarbazoles as cyclin-dependent kinase inhibitors. Bioorg. Med. Chem. Lett.. 2004;14:3217-3220.
[Google Scholar]

[3] Paris D., Cottin M., Demonchaux P., Augert G., Dupassieux P., Lenoir P., Peck M.J., Jasserand D., . Synthesis, structure-activity relationships, and pharmacological evaluation of pyrrolo[3,2,1-ij]quinoline derivatives: potent histamine and platelet activating factor antagonism and 5-lipoxygenase inhibitory properties. Potential therapeutic application in asthma. J. Med. Chem.. 1995;38:669-685.
[Google Scholar]

[4] Isaac M., Slassi A., O’Brien A., Edwards L., MacLean N., Bueschkens D., Lee D.K.H., McCallum K., Lannoy L.D., Demchyshyn I., Kamboj R., . Pyrrolo[3,2,1-ij]quinoline derivatives, a 5-HT2c receptor agonist with selectivity over the 5-HT2a receptor: potential therapeutic applications for epilepsy and obesity. Bioorg. Med. Chem. Lett.. 2000;10:919-921.
[Google Scholar]

[5] Bass R.J., Koch R.C., Richards H.C., Thorpe J.E., . J. Agric. Food Chem.. 1981;29:576-579.

[6] Matesic L., Locke J.M., Vine K., Ranson M., Bremner J.B., Skropeta D., . Synthesis and anti-leukaemic activity of pyrrolo[3,2,1-hi]indole-1,2- diones, pyrrolo[3,2,1-ij]quinoline-1,2-diones and other polycyclic isatin derivatives. Tetrahedron. 2012;68:6810-6819.
[Google Scholar]

[7] Layek M., Rao A.V.D., Gajare V., Kalita D., Barange D.K., Islam A., Mukkanti K., Pal M., . C—N bond forming reaction under copper catalysis: a new synthesis of 2-substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines. Tetrahedron Lett.. 2009;50:4878-4881.
[Google Scholar]

[8] Layek M., Gajare V., Kalita D., Islam A., Mukkanti K., Pal M., . Pd/C–Cu in coupling-cyclization process: a general synthesis of 2-substituted 6-oxopyrrolo[3,2,1-ij]quinoline derivatives. Tetrahedron Lett.. 2009;50:3867-3871.
[Google Scholar]

[9] Layek M., Appi Reddy M., Rao A.V.D., Alvala M., Arunasree M.K., Islam A., Mukkanti K., Pal M., . Transition metal mediated construction of pyrrole ring on 2,3-dihydroquinolin-4(1H)-one: synthesis and pharmacological evaluation of novel tricyclic heteroarenes. Org. Biomol. Chem.. 2011;9:1004-1007.
[Google Scholar]

[10] Rao S.S., Rambabu D., Layek M., Kumar K.L., Rao M.V.B., Haldar D., Pal M., . Cu-mediated synthesis of 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones as potential inhibitors of sirtuins. Lett. Drug Des. Discov.. 2014;11:199-206.
[Google Scholar]

[11] Rao V.K., Chhikara B.S., Shirazi A.N., Tiwari R., Parang K., Kumar A., . 3-Substituted indoles: one-pot synthesis and evaluation of anticancer and Src kinase inhibitory activities. Bioorg. Med. Chem. Lett.. 2011;21:3511-3514.
[Google Scholar]

[12] Marchand P., Puget A., Baut G.L., Emig P., Czech M., Günther E., . Palladium(II)-catalyzed heterocyclisation of 8-arylethynyl-1,2,3,4-tetrahydroquinolines: a facile route to 2-aryl-5,6-dihydro-4 H-pyrrolo[3,2,1- ij]quinoline derivatives. Tetrahedron. 2005;61:4035-4041.
[Google Scholar]

[13] Blurton P., Brickwood A., Dhanak D., . Palladium catalysed coupling of iodoquinolines and acetylenes – a novel entry to the pyrrolo[3,2,1-ij]quinoline nucleus. Heterocycles. 1997;45:2395-2403.
[Google Scholar]

[14] Dorow R.L., Herrinton P.M., Hohler R.A., Maloney M.T., Mauragis M.A., McGhee W.E., Moeslein J.A., Strohbach J.W., Veley M.F., . Development of an efficient synthesis of the pyrrolquinolone PHA-529311. Org. Process Res. Dev.. 2006;10:493-499.
[Google Scholar]

[15] Bischler A., Brion H., . Ueber die Entstehung einiger substituirter indole. Chem. Ber.. 1892;25:2860-2879.
[Google Scholar]

[16] Bischler A., Fireman P., . Chem. Ber.. 1893;26:1346-1349.

[17] Shikhaliev Kh.S., Leshcheva E.V., Solov’ev A.S., . 2,2,4-Trimethylhydroquinones in the Bischler–Melau reaction. Chem. Heterocycl. Comp.. 2003;39:335-339.
[Google Scholar]

[18] Wijngaarden I.v., Hamminga D., Hes R.v., Standaar P.J., Tipker J., Tulp M.T.M., Mol F., Olivier B., de Jonge A., . Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. J. Med. Chem.. 1993;36:3693-3699.
[Google Scholar]

[19] Zhu G., Conner S.E., Zhou X., Chan H.-K., Shih C., Engler T.A., Al-awar R.S., Brooks H.B., Watkins S.A., Spencer C.D., Schultz R.M., Dempsey J.A., Considine E.L., Patel B.R., Ogg C.A., Vasudevan V., Lytle M.L., . Synthesis of 1,7-annulated indoles and their applications in the studies of cyclin dependent kinase inhibitors. Bioorg. Med. Chem. Lett.. 2004;14:3057-3061.
[Google Scholar]

[20] Adam-Worrall, J., 2005. Tricyclic 1-[(3-indol-3-yl)carbonyl] piperazine derivatives as cannabinoid cb1 receptor agonists. World Patent Application No WO 2005/058327 A1, Jan 30, 2005.

[21] Li J.T., Wang S.X., Chen G.F., Li T.S., . Some applications of ultrasound irradiation in organic synthesis. Curr. Org. Synth.. 2005;2:415-436.
[Google Scholar]

[22] Ratoarinoro N., Wilhelm A.M., Berlan J., Delmas H., . Effects of ultrasound emitter type and power on a heterogeneous reaction. Chem. Eng. J.. 1992;50:27-31.
[Google Scholar]

[23] Bahner C.T., Easley W.K., Stephen E., . Derivatives of Tetrahydroquinoline and Tetrahydroisoquinoline. J. Am. Chem. Soc.. 1952;74:4198-4199.
[Google Scholar]

[24] Mason T.J., Peters D., . Practical Sonochemistry. New York, NY, USA: Ellis Horwood; 1991.

[25] Mason T.J., . Sonochemistry and the environment—providing a “green” link between chemistry, physics and engineering. Ultrason. Sonochem.. 2007;14:476-483.
[Google Scholar]

[26] World Cancer Report, 2014. World Health Organization. 2014, pp. (Chapter 5.13) ISBN 9283204298.

Entry	Compound 3; R =	% Inhibition of proliferation^a
		K562 Leukemia	HEK293^b Non-cancerous
1	3a; Ph	38.0	0.3
2	3b; C₆H₄F-p	50.9	0.5
3	3c; C₆H₄Cl-p	35.6	1.6
4	3d; C₆H₄Br-p	33.8	1.2
5	3e; C₆H₄Me-p	51.2	0.7
6	3f; C₆H₄OMe-p	65.7	2.8
7	3g; C₆H₄CN-p	33.8	2.1
8	3h; 2-Naphthyl	23.0	3.9
9	3i; Benzofuran-2-yl	24.8	2.4
10	3j; CH₂CO₂Et	35.1	1.6
11	3k; Et	21.1	0.8

Entry	Catalyst	Solvent	Time (h)	% Yield^b
1	AcOH	MeCN	28	0
2	CF₃CO₂H	MeCN	28	Trace
3	p-TSA	MeCN	28	21
4	p-TSA	Toluene	28	27
5	p-TSA	1,4-Dioxane	28	53
6	p-TSA	1,4-Dioxane	2	67^c
7	p-TSA	1,4-Dioxane	2	49^c,d

Ultrasound mediated synthesis of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives and their pharmacological evaluation

Abstract

Keywords

Pyrrolo[3,2,1-ij]quinoline

Cyclodehydration

Ultrasound

Cytotoxicity

1 Introduction

2 Material and methods

2.1 General methods

2.2 Preparation of compound 2

2.3 General procedure for the preparation of compound 3

2.4 1-Phenyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3a)

2.5 1-(4-Fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3b)

2.6 1-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3c)

2.7 1-(4-Bromophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3d)

2.8 1-(p-Tolyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3e)

2.9 1-(4-Methoxyphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3f)

2.10 4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (3g)

2.11 1-(Naphthalen-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3h)

2.12 1-(3a,7a-Dihydrobenzofuran-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3i)

2.13 Ethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetate (3j)

2.14 1-Ethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3k)

2.15 MTT assay

3 Results and discussion

3.1 Chemistry

3.2 Pharmacology

4 Conclusion

Acknowledgments

References

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