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Article

Grindstone Chemistry: Design, One-Pot Synthesis, and Promising Anticancer Activity of Spiro[acridine-9,2′-indoline]-1,3,8-trione Derivatives against the MCF-7 Cancer Cell Line

by
Perumal Gobinath
1,
Ponnusamy Packialakshmi
1,
Ali Daoud
2,
Saud Alarifi
2,
Akbar Idhayadhulla
1 and
Surendrakumar Radhakrishnan
1,*
1
Department of Chemistry, Nehru Memorial College, Affiliated Bharathidasan University, Puthanamapatti, Tamilnadu 621007, India
2
Department of Zoology, College of Sciences, King Saud University (KSU), P.O. Box 2455, Riyadh 11451, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(24), 5862; https://doi.org/10.3390/molecules25245862
Submission received: 10 November 2020 / Revised: 7 December 2020 / Accepted: 8 December 2020 / Published: 11 December 2020
(This article belongs to the Special Issue Indole Derivatives: Synthesis and Application II)
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Abstract

:
In this study, the synthesis of one-pot 10-phenyl-3,4,6,7-tetrahydro-1H-spiro [acridine-9,2′-indoline]-1,3,8-trione derivatives was achieved via a four-component cyclocondensation reaction, which was carried out in solvent-free conditions, and using p-toluenesulfonic acid (p-TSA) as a catalyst. The product was confirmed by FT-IR, 1H-NMR, 13C-NMR, mass spectra, and elemental analysis. Furthermore, the anticancer activity was screened for all compounds. Among these compounds, compound 1c was more effective (GI50 0.01 µm) against MCF-7 cancer cell lines than standard and other compounds. Therefore, the objective of this study was achieved with a few promising molecules having been demonstrated to be potential anticancer agents.

1. Introduction

The advantages of acridine as a helpful nucleus in medicinal chemistry has consequently led to new designs, and the growth of its bi- and tri-analogues for delivering superior effects in targeted therapy compared to mono-analogues. Additionally, at present isatin and its derivatives may also be the most helpful beginning resources or ancestors within the synthesis of a good variety of spirocyclic indoles [1]. The spiro oxindole may be an advantageous heterocyclic core present in a sizable number of novel inhibitors with microtubule assembly [2], whereas pteropodines act as positive modulators of muscarinic M2 and 5-HT2 receptors [3]. Moreover, the spiro oxindole system is also a nucleus scaffold of many non-natural pharmaceutical elements with a wide assortment of biological uses, such as inhibitors of the human NK-1 receptor [4], antimicrobials [5], antineoplastics [6], and antibiotics [7]. Primarily, anticancer potency, as well as a number of other factors such as topoisomerase and telomerase inhibition, initiation of ROS mediated oxidative stress, cell cycle arrest, and interaction with P-glycoprotein, also come into play which makes the acridine/acridone moiety a privileged scaffold for anticancer chemotherapy [8]. The acridines exhibit antiprotozoal [9], antihelmintic [10] antineoplastic [11] and antiviral [12] activities. The ‘Grindstone Chemistry’ technique has been used as an inexperienced and speedy methodology for the synthesis of organic compounds [13,14]. Grindstone Chemistry may involve a small alteration and has established that several reactions are often carried out in high yields by grinding two or more solids [15]. The formation of 10-phenyl-3,4,6,7-tetrahydro-1H-spiro [acridine-9,2′-indoline]-1,3,8-trione as a by-product is a part of our program aimed at the preparation of heterocyclic compounds [16,17,18,19,20,21,22,23,24], particularly spirooxindoles [25,26,27,28,29]. Some spiroindoles exhibit medicinally important activity, as shown in Figure 1. In Grindstone Chemistry, reactions are often performed by grinding the reactants for many minutes, without using any organic solvent. Apparently, this methodology is very effective for endothermic reactions. Based on the above results, we prepared new 10-phenyl-3,4,6,7–tetra hydro-1H-spiro [acridine-9,2-indolidine]-1,3,8-trione derivatives via Grindstone Chemistry and the new compounds were screened for anticancer activity.

2. Results and Discussion

2.1. Chemistry

The synthetic methodology was evaluated with isatins, substituted anilines, and 1,3-cyclohexanedione, and the procedure followed that of [35]. All synthesized compounds were characterized by IR, 1H and 13C-NMR analysis. The IR spectrum of the compounds (1a–1j) showed an absorption band at 3258 to 3500 cm−1 due to N–H stretching, an absorption band at 2922 to 3234 cm−1 due to Ar–H stretching, an absorption band at 1664 to 1716 cm−1 due to C=O stretching, and another absorption band at 1276 to 1516 cm−1 due to C–N stretching. Compound 1h exhibited an absorption band for the Cl–C group at 799 cm−1 and compounds 1b, 1f and 1i displayed an absorption band for the NO2–C group at 1504–1523 cm−1. The 1H NMR spectrum of compounds 1a–1j showed a singlet at δ 10.10 to 10.26, attributable to N–H protons present in the isatin ring. The 13C-NMR spectrum of compounds 1a–1j exhibited peaks at δ 126.9 to 127.8, corresponding to the 2- position of C in the isatin ring. The corresponding spiro-[acridine-9,2′-indoline]-1,3,8-trione 1a–1j was obtained in smart yields in similar conditions, which are shown in Table 1. We have not established an exact mechanism for the formation of spiro[acridine-9,2′-indoline]-1,3,8-trione derivatives, however, a sensible possibility is shown in Scheme 1. This scheme supposes that the initial addition of 1,3-cyclohexanedione to the isatin yielded the intermediate, which then reacted with an extra molecule of 1,3-cyclohexanedione. Finally, adding the substituted aniline to the intermediate, followed by cyclization, afforded the product 1a–1j. Scheme 2 indicates the synthesis of spiro acridine derivatives of 1a-1j.

Anticancer Activity

The compounds (1a–1j) were evaluated for anticancer activity. The MCF-7 cancer cell line was used to test all compounds at a cytotoxic assay dose of 100 µM at 48 h (MTT anticancer assay measuring the functionality of animal and human cells) Table 2 indicates the results of each test compound with the growth inhibitor concentration (GI50), total growth of inhibition (TGI), and lethal concentration (LC50) values. The cytotoxic effect of 1c (GI50 = 0.01 µM) was highly active, while 1b (GI50 = 0.02 µm) was substantially active, and 1i (GI50 = 0.03 µM) and 1j (GI50 = 0.04 µM) were reasonably active in the MCF-7 cell line. Other compounds also exhibited significant activity. The cytotoxicity values are presented in Table 2.

3. Experimental

All of the chemicals were synthetic grade and commercially purchased from Merck. The melting point was determined by an open capillary tube and it was uncorrected. The IR spectra were recorded in KBr on a Shimadzu 8201pc (4000–400 cm−1). 1H and 13C-NMR spectra were recorded on a Bruker Avance II NMR spectrometer 300 MHz with DMSO-d6 as the solvent, using tetramethylsilane (TMS) as an internal standard. Mass spectra (Perkin Elmer) and the elemental analysis (C, H, and N) were recorded using an elemental analyzer model (Varian EL III).

3.1. Synthesis of Compounds 1a–1j

A mixture of isatin (10 mmol), phenylamine (10 mmol), and 1,3-cyclohexanedione (20 mmol), as well as p-toluenesulfonic acid (p-TSA) as a catalyst, were ground for 3–4 min, leading to a red color of 10-phenyl-3,4,6,7-tetrahydro-1H-spiro[acridine-9,2′-indoline]-1,3,8-trione. The final product was washed with water and recrystallized with ethanol. The purity of the compound was checked by TLC. Hexane was used as eluting solvent in TLC. The product was separated by column chromatography. All the compounds were recrystallized by ethanol (see Supplementary Materials).
1.0-phenyl-3,4,6,7-tetrahydro-spiro[acridine-9,3-indoline]-1,2,8-trione (1a): Brown powder; mp 108–110 °C; IR: 3334 (NH), 3234 (Ar-H),1716 (C=O), 1448 (C-N); 1H NMR (CDCl3, 500 MHz): δ = 10.06 (s, 1H,NH), 7.34–6.81 (m, 4H, N-Ph), 7.30–7.07 (m, 4H, Ph-isatin), 3.16 (m, 4H, CHD), 2.82 (m, 4H, CHD), 1.67 (dd, 4H, J= 7.5, 1.5 Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 168.2, 153.3, 141.2, 141.1, 129.6, 129.5, 127.8, 124.8, 122.8, 122.4, 115.2, 108.2, 51.3, 36.0, 21.3, 18.7; EI-MS: 411 (M+, 29.7%); Analysis calculated for C26H22N2O3: C, 76.08; H, 5.40; Found: C, 76.06; H, 5.39.
10-(4-nitrophenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]1,2’,8(2H,5H,10H)-trione (1b): Yellow needles; mp 108–110 °C; IR: 3350 (NH), 2920 (Ar-H), 1680 (C=O), 1516 (C-N), 1523 (NO2); 1H NMR (CDCl3,500 MHz): δ = 10.11 (s, 1H, NH), 8.01–6.62 (m, 4H, N-Ph), 7.31–7.09 (m, 4H, Ph (isatin)), 3.18 (m, 4H, CHD), 2.83 (m, 4H, CHD), 1.68 (dd, 4H, J = 7.5, 1.5 Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 168.3, 153.4, 147.3, 141.2, 137.9, 129.7, 127.9, 124.7, 123.9, 115.3, 108.3, 51.4, 36.1, 21.4, 18.8; EI-MS: 455 (M+, 29.7%); Analysis calculated for C26H21N3O5; C, 68.56; H, 4.56; Found: C, 68.54; H, 4.53.
10-(4-methoxyphenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H, 10H)-trione (1c): Yellow needles; mp 108–110 °C; IR: 3425 (NH), 2922 (Ar-H), 1664 (C=O), 1452 (C-N); 1H NMR (CDCl3,500 MHz): δ = 10.12 (s, 1H, NH), 7.32−7.10 (m, 4H, Ph (isatin)), 6.74−6.00 (m, 4H, N-Ph), 3.83 (s, 3H, -OCH3), 3.19 (m, 4H, CHD), 2.84(dd, 4H, J = 7.5, 1.5 Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 168.4, 153.3, 141.3, 133.5, 129.8, 127.6,123.5, 115.4, 115.1, 108.4, 55.8, 51.5, 36.2, 21.5, 18.8; EI-MS: 441 (M+, 30.4%); Elemental analysis calculated value for C27H24N2O4; C, 73.62; H, 5.49; Found: C, 73.61; H, 5.48.
10-(2-methoxyphenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H, 10H)-trione (1d): Yellow needles; mp 108–110 °C; IR: 3456 (NH), 3112 (Ar-H), 1709 (C=O), 1336 (C-N); 1H NMR (CDCl3,500 MHz): δ = 10.14 (s, 1H, NH), 7.33−7.12 (m, 4H, Ph (isatin)), 6.85−6.12 (m, 4H, N-Ph), 3.83 (s, 3H, -OCH3), 3.20 (m, 4H, CHD), 2.85 (dd, 4H, J = 7.5, 1.5 Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 168.5, 153.5, 148.9, 141.0, 129.5, 128.2, 127.8, 127.5, 125.2, 122.6, 115.2, 110.1, 108.3, 55.8, 51.6, 36.3, 21.6, 18.9; EI-MS: 441 (M+, 30.4%); Analysis calculated value for C27H24N2O4; C, 73.62; H, 5.49; Found: C, 73.61; H, 5.48.
10-(m-tolyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H,10H)-trione (1e): Yellow needles; mp 108–110 °C; IR: 3500 (NH), 3096 (Ar-H), 1695 (C=O), 1276 (C-N); 1H NMR (CDCl3, 500 MHz): δ = 10.16 (s, 1H, NH), 7.34−7.13 (m, 4H, Ph (isatin)), 7.08−5.70 (m, 4H, N-Ph), 3.21 (m, 4H, CHD), 2.88 (dd, 4H, J = 7.5, 1.5 Hz, CHD), 2.34 (s, 3H, CH3); 13C-NMR (CDCl3, 125 MHz): 168.6, 153.6, 141.1, 129.6, 129.4, 127.4, 124.2, 119.8, 119.0, 115.3, 108.4, 51.7, 36.4, 21.7, 19.0; EI-MS: 425 (M+, 30.3%); Elemental analysis calculated value for C27H24N2O3; C, 76.39; H, 5.70; Found: C, 76.37; H, 5.68.
10-(2-nitrophenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H,10H)-trione (1f): Yellow needles; mp 108–110 °C; IR: 3425 (NH), 2922 (Ar-H), 1664 (C=O), 1452 (C-N), 1504 (NO2); 1H NMR (CDCl3,500 MHz): δ = 10.18 (s, 1H, NH), 8.01−6.89 (m, 4H, N-Ph), 7.35−7.14 (m, 4H, Ph (isatin)), 3.22 (m, 4H, CHD), 2.86 (dd, 4H, J = 7.5, 1.5Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 168.7, 153.7, 147.8, 134.6, 130.5, 129.9, 129.3, 127.3, 126.6, 124.8, 115.4, 108.6, 51.8, 36.5, 21.8, 19.2; EI-MS: 456 (M+, 29.7%);Elemental analysis calculated value for C26H21N3O5; C, 68.56; H, 4.65; Found: C, 68.54; H, 4.64.
10-(p-tolyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H,10H)-trione (1g): Yellow needles; mp 108–110 °C; IR: 3221 (NH), 3029 (Ar-H), 1703 (C=O), 1276 (C-N); 1H NMR (CDCl3, 500 MHz): δ = 10.20 (s, 1H, NH), 7.36–7.15 (m, 4H, Ph (isatin)), 6.98–6.08 (m, 4H, N-Ph), 3.23 (m, 4H, CHD), 2.87 (dd, 4H, J = 7.5, 1.5 Hz, CHD), 2.34 (s,3H, CH3); 13C-NMR (CDCl3, 125 MHz): 168.8, 153.8, 138.2, 131.2, 129.8, 129.2, 127.2, 123.2, 115.6, 108.7, 51.9, 36.6, 21.9, 19.3; EI-MS: 425 (M+, 30.3%); Elemental analysis calculated value for C27H24N2O3; C, 76.39; H, 5.70; Found: C, 76.37; H, 5.67.
10-(2-chlorophenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H,10H)-trione (1h): Yellow needles; mp 108–110 °C; IR: 3258 (NH), 3012 (Ar-H), 1695 (C=O), 1452 (C-N), 799 (Cl); 1H NMR (CDCl3, 500 MHz): δ = 10.22 (s, 1H, NH),7.40–6.57 (m, 4H, N-Ph), 7.37–7.16 (m, 4H, Ph (isatin)), 3.24 (m, 4H, CHD), 2.88 (dd, 4H, J = 7.5, 1.5 Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 168.9, 153.9, 144.2, 132.2, 130.7, 29.1, 127.1, 127.6, 125.4,123.8, 115.7, 108.8, 52.0, 36.7, 22.0, 19.4; EI-MS: 446 (M+, 36.7%); Elemental analysis calculated value for C26H21N2O3; C, 70.19; H,4.76; Found: C, 70.17; H, 4.74.
10-(2,4-dinirophenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H, 10H)-trione (1i): Yellow needles; mp 108–110 °C; IR: 3350 (NH), 3027 (Ar-H), 1664 (C=O), 1452 (C-N), 1516 (NO2); 1H NMR (CDCl3,500 MHz): δ = 10.24 (s, 1H, NH), 8.85–7.15 (m, 4H, N-Ph), 7.38–7.17 (m, 4H, Ph (isatin)), 3.25 (m, 4H, CHD), 2.89 (dd, 4H, J = 7.5, 1.5 Hz, CHD); 13C-NMR (CDCl3, 125 MHz): 167.0, 154.0, 147.9, 138.8, 138.0, 130.8, 129.2, 127.0, 120.8, 118.1, 115.8, 108.9, 52.3, 36.8, 22.1, 19.5; EI-MS: 501 (M+, 30.1%); Elemental analysis calculated value for C26H20N4O7; C, 62.40; H, 4.03; Found: C, 62.38; H, 4.01.
10-(4-bromophenyl)-3,4,6,7-tetrahydro-1H-spiro[acridine-9,3’-indoline]-1,2’,8(2H,5H,10H)-trione (1j): Yellow needles; mp 108–110 °C; IR: 3425 (NH), 2922 (Ar-H), 1664 (C=O), 1452 (C-N); 1H NMR (CDCl3,500 MHz): δ = 10.26 (s,1H, NH), 7.54–7.35 (m, 4H, N-Ph), 7.39–7.18 (m, 4H, Ph (isatin)), 3.26 (m, 4H, CHD),2.90 (dd, 4H, J = 7.5, 1.5Hz,CHD); 13C-NMR (CDCl3, 125 MHz): 167.1, 154.2, 140.2, 130.1, 129.5, 125.4,126.9, 116.7, 115.9, 109.1, 52.4, 36.9, 22.3, 19.6; EI-MS: 490 (M+, 28.6%); Elemental analysis calculated value for C26H21N2O3; C, 70.19; H, 4.76; Found: C, 70.17; H, 4.74.

3.2. Cytotoxic Activity

The newly synthesized compounds (1a–1j) were screened for their cytotoxic activity according to the procedure suggested in previous literature [36].

4. Conclusions

We have reported a one-pot, and four-component methodology for the synthesis of 10-phenyl-3,4,6,7-tetrahydro-1H-spiro[acridine-9,2-indolidine]-1,3,8-trione derivatives via Grindstone Chemistry. The cytotoxic activity was screened for all compounds, demonstrating that compound 1c was highly active (GI50 0.01 µm) against MCF-7 cancer cell lines in comparison to doxorubicin and other compounds. In conclusion, the synthesized acridine-based indole derivatives can be considered as potential therapeutic lead molecules for anticancer activity.

Supplementary Materials

The following are available online, 1H-NMR and 13C-NMR Spectrum of the compounds 1a–1j.

Author Contributions

P.G.: organic compound preparation; P.P.: preparation of synthetic compound and chemical data analysis; A.D.: formal analysis; S.A.: financial support; A.I.: spectral analysis and S.R.: investigation of all part of this manuscript chemistry and biology. Original drafts were prepared and the manuscript was written through the contributions of all authors. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Researchers Supporting Project number (RSP-2020/27), King Saud University, Riyadh, Saudi Arabia.

Acknowledgments

This work was funded by the Researchers Supporting Project number (RSP-2020/27), King Saud University, Riyadh, Saudi Arabia.

Conflicts of Interest

There are no conflicts to declare.

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Molecules 25 05862 g001 550
Figure 1. Some medicinally important compounds with spiroindole acridine derivatives [30,31,32,33,34].
Figure 1. Some medicinally important compounds with spiroindole acridine derivatives [30,31,32,33,34].
Molecules 25 05862 g001
Molecules 25 05862 sch001 550
Scheme 1. Proposed mechanism for the synthesis of spiro [acridine-9,2′-indoline]-1,3,8-trione.
Scheme 1. Proposed mechanism for the synthesis of spiro [acridine-9,2′-indoline]-1,3,8-trione.
Molecules 25 05862 sch001
Molecules 25 05862 sch002 550
Scheme 2. One-pot synthesis of spiro[acridine-9,2′-indoline]-1,3,8-trione derivatives.
Scheme 2. One-pot synthesis of spiro[acridine-9,2′-indoline]-1,3,8-trione derivatives.
Molecules 25 05862 sch002
Table
Table 1. Optimization of the reaction conditions for compounds (1a–1j).
Table 1. Optimization of the reaction conditions for compounds (1a–1j).
CompoundsRTime (Min)Yield (%)
1aPh1092
1b-4-NO2-C6H41091
1c-4-OCH3-C6H41088
1d-2-OCH3-C6H41087
1e-3-CH3-C6H41095
1f-2-NO2-C6H41082
1g-4-CH3-C6H41094
1h-2-Cl-C6H41087
1i-2,4-NO2-C6H41078
1j-4-Br-C6H41091
Table
Table 2. Anticancer activity of compounds (1a–1j).
Table 2. Anticancer activity of compounds (1a–1j).
CompoundsMCF-7 Cell Line
GI50 (µM)TGI (µM)LC50 (µM)
1a02.7 ± 0.1106.5 ± 1.0608.1 ± 0.02
1b0.02 ± 0.290.41 ± 2.320.87 ± 0.24
1c0.01 ± 0.340.02± 1.190.71 ± 1.21
1d0.09 ± 0.610.55 ± 0.381.40 ± 1.15
1e0.19 ± 0.930.20 ± 1.320.70 ± 1.17
1f0.52 ± 0.0910.1 ± 2.2222.1 ± 0.12
1g0.35 ± 0.830.66 ± 1.1214.2 ± 0.82
1h0.26 ± 0.1404.4 ± 1.0909.7 ± 0.28
1i0.03 ± 0.490.69 ± 0.612.12 ± 0.21
1j0.04 ± 0.340.34 ± 0.551.01 ± 0.18
Doxorubicin0.02 ± 0. 700.21 ± 0. 190.74 ± 0.35
Sample Availability: Samples of the compounds are available from the authors.
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Gobinath, P.; Packialakshmi, P.; Daoud, A.; Alarifi, S.; Idhayadhulla, A.; Radhakrishnan, S. Grindstone Chemistry: Design, One-Pot Synthesis, and Promising Anticancer Activity of Spiro[acridine-9,2′-indoline]-1,3,8-trione Derivatives against the MCF-7 Cancer Cell Line. Molecules 2020, 25, 5862. https://doi.org/10.3390/molecules25245862

AMA Style

Gobinath P, Packialakshmi P, Daoud A, Alarifi S, Idhayadhulla A, Radhakrishnan S. Grindstone Chemistry: Design, One-Pot Synthesis, and Promising Anticancer Activity of Spiro[acridine-9,2′-indoline]-1,3,8-trione Derivatives against the MCF-7 Cancer Cell Line. Molecules. 2020; 25(24):5862. https://doi.org/10.3390/molecules25245862

Chicago/Turabian Style

Gobinath, Perumal, Ponnusamy Packialakshmi, Ali Daoud, Saud Alarifi, Akbar Idhayadhulla, and Surendrakumar Radhakrishnan. 2020. "Grindstone Chemistry: Design, One-Pot Synthesis, and Promising Anticancer Activity of Spiro[acridine-9,2′-indoline]-1,3,8-trione Derivatives against the MCF-7 Cancer Cell Line" Molecules 25, no. 24: 5862. https://doi.org/10.3390/molecules25245862

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