Synthesis and Cytotoxic Evaluation of Carboxylic Acid-Functionalized Indenoisoquinolines

Abstract

In order to find out the influence of carboxylic acid functionalities in the N-lactam side chains of indenoisoquinolines on cytotoxic activities, several new compounds have been synthesized and structurally characterized by analytical and spectral methods. The incorporation of a carboxylic acid group into the lactam side chain of indenoisoquinolines results in differences in cytotoxicity. The results indicated that compound 18c displayed substantial cytotoxic specificity toward KB and HepG2 cancer cells.

Keywords

indenoisoquinolines carboxylic acid cytotoxic agents

Indenoisoquinolines are a class of non-camptothecin topoisomerase 1 poisons that display marked cytotoxic properties and , some of them, potent antitumor activities.^1,2 These highly fused compounds which contain a planar tetracyclic heteroring system equipped with multifarious functionalities as exemplified by the lead compound 1 (NCS 314622), indotecan 2 (NCS 724998), and indimitecan 3 (NCS 725776) (Figure 1) have been demonstrated to inhibit topoisomerase I enzymes by intercalating between the DNA base pairs and to stabilize a ternary complex consisting of the drug molecule, DNA, and topoisomerase I.³ During the past decade considerable effort has been made to improve the potencies and pharmacokinetic properties of these indenoisoquinolines. These modifications mainly focused on the introduction of methoxy, hydroxy, nitro groups, or nitrogen containing heterocycles into the A ring,⁴ B ring (side chain on the lactam nitrogen),^1,5 C ring,^6,7 and D ring.^8,9

Figure 1

Chemical structure of several bioactive indenoisoquinolines.

Functionalized carboxylic acids are often part of biologically active agents. They might provide a point of attachment for the synthesis of prodrugs so that the pharmacokinetics could be modulated and optimized. Furthermore, the physiochemical properties of the carboxylate ion make it an attractive moiety for installation into drug candidates. For example, the ionization of a carboxylic acid, at physiological pH (7.4), improves its ability to hydrogen bond with neighboring water molecules, and thus may improve its overall water solubility.¹⁰ The importance of the carboxylic acid functional group in drug design is illustrated by the fact that >450 marketed drugs are carboxylic acid containing molecules, including widely used nonsteroidal anti-inflammatory drugs, antibiotics, anticoagulants, and cholesterol-lowering statins.^10,11 A carboxylic acid group could possibly serve as a biologically active unit for incorporation with indenoisoquinoline skeleton in order to afford promising potent bioactive compounds. However, very little is known in the literature about the synthesis and bioactivities of indenoisoquinoline acids.^4,12,13 In that respect, this study presents the synthesis of a variety of novel indenoisoquinolines combining the indenoisoquinoline scaffold with the promising functionalized carboxylic acid moiety, linked together via the indenoisoquinoline lactam nitrogen, followed by a preliminary evaluation of the cytotoxic potential of these derivatives against two human cancer cell lines.

The synthesis of the indenoisoquinoline system has been performed by many methods in the literature. Several recently reported procedures are mostly based on (i) the oxidative cyclization of the cis-acid resulting from the condensation of homophthalic anhydrides and benzylidene Schiff bases,¹⁴ (ii) the condensation of primary amines with the appropriately substituted indenoisochromenones,¹⁴ (iii) the Suzuki-Miyaura cross-coupling followed by ring-closing metathesis,¹⁵ and (iv) the cobalt-catalyzed dual annulation of o-halobenzaldimines with suitable alkynes.¹⁶ The synthesis of the indenoisoquinolines was pursued in this work by applying the first method due to the ease in synthesis of intermediates and manipulation of starting materials to obtain indenoisoquinolines bearing the desired substituents.

In consideration of the chemical structure of indotecan (2) and indimitecan (3), the replacement of nitrogen containing groups in the N-functionalized side chain by the acetic acid group could give the promising potent biological compounds. In this way, the synthesis of indenoisoquinoline acid 9 is depicted in Scheme 1. Piperonal 5 reacted with glycine methyl ester hydrochloride to give Schiff base 6, which upon condensation with homophthalic acid anhydride furnished cis-acid 7 in good yield with excellent diastereoselectivity. The treatment of cis-acid 7 with thionyl chloride resulted in conversion to the acid chloride, dihydrogenation, and intramolecular Friedel-Crafts cyclization to provide the indenoisoquinoline ester 8.¹⁷ The ester 8 was then subjected to hydrolysis by sodium hydroxide in MeOH/H₂O (1:1) at 60°C to afford indenoisoquinoline acetic acid 9 in good yield.

Scheme 1

Synthesis of indenoisoquinoline acetic acid 9.

Analogously, the indenoisoquinoline acetic acids containing methoxy group in D ring were synthesized by procedure as illustrated in Scheme 2. The treatment of homophthalic acid anhydride with imine 11, prepared from 3-methoxybenzaldehyde 10, gave the cis-acid 12. Then, cis-acid 12 reacted with thionyl chloride to provide a mixture of indenoisoquinoline esters 13 and 14, which were separated by column chromatography. The latter were then hydrolyzed by sodium hydroxide to afford acids 15 and 16, respectively.

Scheme 2

Preparation of indenoisoquinoline acids 15 and 16.

Furthermore, several indenoisoquinolines containing carboxylic acid functionalized groups were synthesized starting from indenobenzopyran 17, prepared by methodology in our previous report.¹⁸ Thus, indenobenzopyran was treated with various primary amino acids in dimethylformamide (DMF) at 60°C for 22 to 25 hours to afford targeted acids 18a to 18e in 81% to 88% yields (Scheme 3). The chemical structures of synthesized indenoisoquinoline derivatives 8, 9, 13, 14, 15, 16, and 18a to 18e were confirmed using ¹H NMR, ¹³C NMR, and infrared (IR) spectroscopy (Supplemental Material).

Scheme 3

Synthetic route for the preparation of indenoisoquinolines 18a to 18e.

In the next part of this work, all the synthesized compounds were subjected to in vitro biological assessment against two human cancer cell lines (KB, epidermoid carcinoma; HepG2, hepatoma carcinoma) in order to evaluate their potential as cytotoxic agents, and the results are summarized in Table 1. Ellipticine was used as positive control. The presence of carboxylic acid groups in the lactam side chain of indenoisoquinoline scaffold gives different cytotoxic effects of these compounds. In the case of D-ring without substituents (compounds 18a-18e), the coupling of functionalized carboxylic acid groups into indenoisoquinoline moiety gave moderate cytotoxic activity against KB cell line and high activity against HepG2 cell line with IC₅₀ values ranging from 10 to 32 µM. Specifically, compound 18c was most active to KB and HepG2 cell lines with IC₅₀ value of 4.55 and 10.46 µM, respectively. However, the presence of the methylenedioxy or the methoxy group in the D-ring of indenoisoquinoline scaffold decreased the cytotoxicity effects. For instance, indenoisoquinoline acetic acids 9, 15, 16 and their ester derivatives 13, 14 were inactive against both human cancer cell lines at concentrations lower than 300 µM.

Table 1

Synthesis and Cytotoxic Evaluation of Indenoisoquinoline Derivatives.

Compounds (Yield, %)^a	IC₅₀ (µM) KB	IC₅₀ (µM) HepG2
8 (60)	245.23 ± 2.18	68.35 ± 1.95
9 (92)	>300	>300
13 (40)	>300	>300
14 (49)	>300	>300
15 (95)	>300	>300
16 (96)	>300	>300
18a (88)	138.03 ± 0.93	22.75 ± 1.67
18b (86)	122.32 ± 2.09	10.46 ± 1.56
18 c (85)	4.55 ± 2.01	12.65 ± 1.49
18d (81)	175.18 ± 3.03	32.11 ± 2.23
18e (81)	153.24 ± 0.78	25.29 ± 1.48
Ellipticine	0.85 ± 0.16	1.42 ± 0.16

^aIsolated yield.

In conclusion, a series of novel indenoisoquinolines containing carboxylic acid functional group in lactam side chain were designed and synthesized. Their biological activities were evaluated in vitro against KB and HepG2 cell lines. The results indicated that the presence of functionalized carboxylic acid group in indenoisoquinoline moiety had different effects for anticancer activities. In summary, compound 18 c displayed a promising potential for further elaboration toward novel anticancer agents.

Experimental

General

Solvents and chemicals were obtained from commercial sources and used without further purification. Flash column chromatography was performed using silica gel (60 Å, particle size 40-60 µm). Thin-layer chromatographic analysis was performed on precoated silica gel GF254-slides and visualized by either UV irradiation or Ce(SO₄)₂ staining. ¹H NMR spectra were recorded on a Bruker Avance (500 MHz) with samples dissolved in CDCl₃ and data are reported in ppm with the solvent signal as reference (δ = 7.26 ppm for ¹H NMR). IR spectra were measured on a Spectrum Two Perkin Elmer.

Preparation of Acid Compounds 7 and 12

A solution of imine derivative 6 or 11 (4.5 mmol) in dichloromethane (50 mL) was stirred at room temperature for 10 minutes. Homophthalic acid anhydride (5.4 mmol) was then added, and the reaction mixture was stirred at room temperature for 24 hours. Upon completion, the reaction mixture was concentrated in vacuo to give the intermediate compounds 7 or 12, respectively, which was used for the next step without purification.

Preparation of Indenoisoquinoline 8, 13, 14

The cis-acid 7 or 12 (4.0 mmol) was diluted in toluene (40 mL) with stirring for 5 minutes, and SOCl₂ (60 mL) was then added. After heating at reflux for 2 hours, the reaction mixture was cooled to room temperature overnight. Afterwards, the solvent was evaporated, and the resulting residue was redissolved in CH₂Cl₂ (10 mL) and H₂O (10 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL) and washed with brine (3 × 10 mL). Drying (Na₂SO₄), filtration of the drying agent, and removal of the solvent in vacuo afforded compound 8 or mixture of compounds 13 and 14, which was purified by means of column chromatography on silica gel (using mixture n-hexane /dichloromethane as an eluent).

Methyl 2-(5,12-dioxo-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]iso-quinolin-6(12H)-yl)acetate (8)

Red violet solid. MP: 207°C to 208°C. Yield 60%.

IR (KBr) cm⁻¹: 2913, 1743, 1667, 1610, 1580, 1549, 1497, 1477, 1431, 1375, 1304, 1271, 1229, 1072, 1033, 997, 979, 929, 830, 787.

¹H NMR (CDCl₃, 500 MHz) δ: 8.59 (1H, d, J = 8.0 Hz), 8.29 (1H, dd, J = 0.8 Hz, J = 8.3 Hz), 7.70 (1H, dt, J = 1.5 Hz, J = 7.5 Hz), 7.42 (1H, dt, J = 1.3 Hz, J = 7.3 Hz), 7.08 (1H, s), 6.77 (1H, s), 6.07 (2H, s), 5.26 (2H, s), 3.83 (3H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 189.2, 168.0, 163.0, 154.7, 151.5, 149.3, 134.2, 132.5, 132.2, 130.2, 128.7, 126.8, 123.2, 122.6, 108.2, 105.7, 104.0, 102.7, 53.1, 45.5.

Methyl 2-(8-methoxy-5,11-dioxo-5H-indeno[1,2-c]isoquinolin-6(11H)-yl)acetate (13)

Orange solid. MP: 207°C to 208°C. Yield 40%.

IR (KBr) cm⁻¹: 2922, 2851, 1740, 1696, 1658, 1611, 1576, 1550, 1500, 1467, 1419, 1368, 1322, 1274, 1221, 1082, 1036, 999, 979, 862, 784.

¹H NMR (CDCl₃, 500 MHz) δ: 8.69 (1H, d, J = 8.0 Hz), 8.35 to 8.3 (1H, m), 7.76 to 7.70 (1H, m), 7.56 to 7.52 (1H, m), 7.50 to 7.44 (1H, m), 6.83 (1H, d, J = 1.5 Hz), 6.71 (1H, dd, J = 2.0 Hz, J = 8.0 Hz), 5.30 (2H, s, H-1’), 3.85 (3H, s, H-18), 3.82 (3H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 189.7, 168.2, 163.0, 158.1, 153.2, 139.2, 135.0, 134.1, 132.2, 128.8, 127.4, 123.7, 123.6, 119.0, 116.4, 114.6, 109.2, 56.1, 53.1, 45.6.

Methyl 2-(10-methoxy-5,11-dioxo-5H-indeno[1,2-c]isoquinolin-6(11H)-yl)acetate (14)

Orange solid. MP: 207°C to 208°C. Yield 41%.

IR (KBr) cm⁻¹: 2953, 1741, 1693, 1652, 1613, 1579, 1554, 1499, 1474, 1443, 1414, 1275, 1185, 1157, 1070, 1047, 1014, 985, 873.

¹H NMR (CDCl₃, 500 MHz) δ: 8.76 (1H, d, J = 8.0 Hz), 8.35 (1H, dd, J = 0.8 Hz, J = 8.3 Hz), 7.74 (1H, dt, J = 1.3 Hz, J = 7.5 Hz), 7.48 (1H, dt, J = 0.8 Hz, J = 7.8 Hz), 7.37 (1H, m), 6.99 (1H, d, J = 9 Hz), 6.93 (1H, d, J = 7.5 Hz), 5.35 (2H, s), 4.00 (3H, s), 3.81 (3H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 189.4, 168.2, 163.2, 157.5, 152.9, 139.6, 135.2, 134.2, 131.5, 128.7, 127.3, 123.7, 123.6, 119.1, 116.5, 114.5, 109.1, 56.2, 53.1, 45.8.

Preparation of Compounds 9, 15, 16

A respective solution of compound 8, 13, or 14 (1.1 mmol) in MeOH/H₂O (40 mL) was stirred at room temperature for 15 minutes. Sodium hydroxide (11 mmol) was then added, and the reaction mixture was stirred at 60°C overnight. Upon completion, the reaction mixture was concentrated in vacuo, and the residue was neutralized with HCl 10% and extracted with EtOAc (3 × 10 mL). Drying (Na₂SO₄), filtration of the drying agent, and removal of the solvent in vacuo afforded indenoisoquinoline acids 9, 15, and 16 in 92%, 95%, and 96% yields, respectively.

2-(5,12-Dioxo-5,12-dihydro-6H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2- c]isoquinolin-6-yl)acetic acid (9)

Violet solid. MP: 210°C to 211°C. Yield 92%.

IR (KBr) cm⁻¹: 3427, 2960, 2928, 2861, 1727, 1649, 1462, 1377, 1273, 1123, 1072, 1036, 740, 708.

¹H NMR (CDCl₃, 500 MHz) δ: 8.49 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J = 7.5 Hz), 7.81 (1H, m), 7.50 (1H, m), 7.17 (2H, s), 6,19 (2H, s), 5.27 (2H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 188.8, 169.3, 162.2, 155.9, 151.3, 149.1, 134.4, 131.9, 131.8, 129.3, 128.2, 126.8, 122.2, 121.8, 106.1, 105.3, 104.9, 103.0, 45.7.

2-(8-Methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]iso quinolin-6-yl)acetic acid (15)

Orange solid. MP: 208°C. Yield 95%.

IR (KBr) cm⁻¹: 3442, 2956, 2929, 2865, 1728, 1606, 1549, 1502, 1465, 1420, 1368, 1280, 1178, 1123, 1073, 1036, 980, 864, 784, 747, 708, 639, 575.

¹H NMR (CDCl₃, 500 MHz) δ: 8.58 (1H, d, J = 8.0 Hz), 8.22 (1H, d, J = 8.0 Hz), 7.84 (1H, m), 7.57–7.50 (2H, m), 7.05 (1H, d, J = 1.5 Hz), 6.92 (1H, dd, J = 1.5 Hz, J = 8.0 Hz), 5.27 (2H, s), 3.83 (3H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 189.1, 169.3, 163.6, 162.1, 154.4, 138.8, 134.2, 131.8, 128.2, 127.4, 126.3, 124.6, 122.7, 122.6, 112.5, 112.2, 108.0, 56.0, 45.8.

2-(10-Methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]iso quinolin-6-yl)acetic acid (16)

Orange solid. MP: 209°C. Yield 96%.

IR (KBr) cm⁻¹: 3441, 2929, 2959, 2860, 1728, 1654, 1608, 1550, 1462, 1382, 1278, 1124, 1070, 1040, 985, 946, 872, 799, 757.

¹H NMR (CDCl₃, 500 MHz) δ: 8.59 (1H, d, J = 8.0 Hz), 8.20 (1H, d, J = 7.5 Hz), 7.83 (1H, t, J = 7.5 Hz), 7.55–7.48 (2H, m), 7.20 (1H, d, J = 8.5 Hz), 7.15 (1H, d, J = 7.5 Hz), 5.23 (2H, s), 3.90 (3H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 188.4, 169.2, 162.2, 156.9, 153.8, 138.7, 135.8, 134.1, 131.9, 128.1, 127.2, 122.8, 122.6, 117.9, 117.4, 115.8, 106.9, 55.9, 46.0.

Preparation of Indenoisoquinoline Acids 18a to 18e

To a solution of indenobenzopyran 17 (1 mmol) in DMF (20 mL) was added acid amine (1.1 mmol), and the reaction mixture was heated to 60°C for 24 hours. Upon completion, water (30 mL) was added to the reaction mixture, and the resulting solution was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with HCl 5% (5 × 10 mL). Drying (Na₂SO₄), filtration of the drying agent, and removal of the solvent in vacuo afforded crude indenoisoquinolines 18a to 18e, which were purified by means of column chromatography on silica gel (using mixture EtOAc/MeOH as an eluent).

2-(5,11-Dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetic acid (18a)

Orange solid. MP: 286°C to 287°C. Yield 88%.

IR (KBr) cm⁻¹: 3414, 3022, 2929, 2848, 2850, 1737, 1695, 1645, 1606, 1573, 1546, 1498, 1456, 1417, 1379, 1313, 1240, 1192, 1099, 1080, 962, 750, 694.

¹H NMR (CDCl₃, 500 MHz) δ: 8.65 (1H, d, J = 8.0 Hz), 8.29 (1H, d, J = 8.0 Hz), 7.72 (1H, dt, J = 1.5 Hz, J = 8.0 Hz), 7.58 (1H, d, J = 6.5 Hz), 7.44 (1H, dt, J = 1.0 Hz, J = 8.0 Hz), 7.32 to 7.38 (3H, m), 5.27 (2H, s).

¹³C NMR (CDCl₃, 125 Hz) δ: 190.4, 169.3, 163.4, 155.8, 137.1, 134.6, 134.2, 133.4, 132.4, 131.1, 128.4, 127.4, 123.5, 123.3, 123.1, 121.8, 108.9, 45.8.

(S)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-3-methylbutanoic acid (18b)

Red solid. MP: 168°C to 169°C. Yield 86%.

IR (KBr) cm⁻¹: 3390, 2958, 2926, 2866, 2358, 1728, 1701, 1645, 1606, 1546, 1498, 1456, 1379, 1317, 1271, 1195, 1078, 1080, 993, 760, 700.

¹H NMR (CDCl₃, 500 MHz) δ: 8.45 (1H, d, J = 8.0 Hz), 8.00 (1H, d, J = 8.0 Hz), 7.57 (1H, d, J = 7.0 Hz), 7.50 (1H, t, J = 8.0 Hz), 7.17 to 7.44 (4H, m), 4.64 (1H, d, J = 9.5 Hz), 2.84 (1H, m), 1.13 (3H, d, J = 5.5 Hz), 0.51 (3H, d, J = 6.5 Hz).

(S)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-3-phenylpropanoic acid (18c)

Red solid. MP: 124°C to 125°C. Yield 85%.

IR (KBr) cm⁻¹: 3385, 2956, 2924, 2854, 2358, 1726, 1697, 1647, 1604, 1570, 1544, 1498, 1450, 1411, 1379, 1197, 1024, 754, 700.

¹H NMR (CDCl₃, 500 MHz) δ: 8.51 (1H, d, J = 8.0 Hz), 8.16 (1H, d, J = 8.0 Hz), 7.62 (1H, J = 7.0 Hz), 7.31 to 7.36 (2H, m), 7.05 to 7.12 (3 H, m), 6.83 to 6.94 (5H, m), 5.33 (1H, m), 3.56 (1H, d, J = 7.0 Hz), 3.24 (1H, d, J = 1.5 Hz).

(S)-2-(5,11-Dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-3-(4-hydroxyphenyl)propanoic acid (18d)

Red solid. MP: 183°C to 184°C. Yield 81%.

IR (KBr) cm⁻¹: 3373, 2918, 2850, 1691, 1654, 1600, 1546, 1514, 1498, 1458, 1411, 1379, 1246, 1201, 1022, 813, 758, 694.

¹H NMR (CDCl₃, 500 MHz) δ: 8.53 (1H, d, J = 8.0 Hz), 8.16 (1H, d, J = 7.5 Hz), 7.60 (1H, t, J = 7.5, J = 8.0 Hz), 7.47 (1H, t, J = 7.5 Hz), 7.33 (1H, d, J = 7.0 Hz), 7.18 (1H, d, J = 7.0 Hz), 7.08 (1H, t, J = 7.5 Hz), 7.00 (1H, t, J = 7.5 Hz), 6.63 (2H, d, J = 8.0 Hz), 6.30 (2H, J = 8.0 Hz), 5.30 (1H, m), 5.30 (1H, m), 3.60 (1H, d, J = 10.0 Hz), 3.48 (1H, d, J = 11.0 Hz).

(S)-3-(3,4-Dihydroxyphenyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno [1,2-c]isoquinolin-6-yl)propanoic acid (18e)

Red solid. MP: 188°C to 189°C. Yield 80%.

¹H NMR (CDCl₃, 500 MHz) δ: 8.62 (1H, d, J = 8.0 Hz), 8.29 (1H, d, J = 8.0 Hz), 7.56 (1H, t, J = 8.0 Hz), 7.50 to 7.52 (2H, m), 7.42 (1H, d, J = 7.0 Hz), 7.28 to 7.41 (2H, m), 6.43 (1H, d, J = 2.0 Hz), 6.37 (1H, d, J = 8.0 Hz), 6.30 (1H, dd, J = 2.0, J = 8.0 Hz) 5.69 (1H, dd, J = 5.0, J = 10.0 Hz), 3.57 (2H, m).

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors are indebted to the Vietnamese National Foundation for Science and Technology Development (NAFOSTED, code: 104.01-2017.27) for financial support.

Supplemental Material

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