Molecules 2014, 19(2), 2523-2535; doi:10.3390/molecules19022523

Article
Synthesis and Antiproliferative Activity of Some Novel Triazole Derivatives from Dehydroabietic Acid
Mariano Walter Pertino 1,*, Valery Verdugo 1, Cristina Theoduloz 2 and Guillermo Schmeda-Hirschmann 1
1
Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile
2
Facultad de Ciencias de la Salud, Universidad de Talca, Casilla 747, Talca, Chile
*
Author to whom correspondence should be addressed; E-Mail: mwalter@utalca.cl; Tel.: +56-71-2241-8866.
Received: 24 January 2014; in revised form: 18 February 2014 / Accepted: 18 February 2014 /
Published: 21 February 2014

Abstract

: Dehydroabietic acid (DHA) is a naturally occurring diterpene with different and relevant biological activities. Previous studies have shown that some DHA derivatives display antiproliferative activity. However, the reported compounds did not include triazole derivatives. Starting from DHA (8,11,13-abietatrien-18-oic acid), and its alcohol dehydroabietinol (8,11,13-abietatrien-18-ol), four alkyl esters were prepared. The alkyl terpenes were treated with different aromatic azides to synthesize hybrid compounds using click chemistry. Some 16 new DHA hybrids were thus synthesized and their structures were confirmed by spectroscopic and spectrometric means. The antiproliferative activity of the new compounds was assessed towards human cell lines, namely normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells. Better antiproliferative effect was found for compound 5, with an IC50 of 6.1 μM and selectivity on SK-MES-1 cells. Under the same experimental conditions, the IC50 of etoposide, was 1.83 µM.
Keywords:
dehydroabietic acid; click chemistry; antiproliferative activity

1. Introduction

Synthesis or modification of known anticancer drugs is an important aspect of research. However, to date a vast amount of synthetic work has contributed to relatively small improvements over the prototype drugs [1]. There is a continuous need for new templates to be used in the design of potential chemotherapeutic agents. Dehydroabietic acid (DHA), a naturally occurring resin diterpene, and its derivatives, exhibit a broad spectrum of biological effects, including antiulcer [2,3], antimicrobial [4], antiviral [5], cytotoxic [3,6] and antitumor activities [7]. A recent patent on the use of abietic acid and derivatives as antitumor agents has been published [8].

The search for drugs based on natural products often has the problem of involving slow and complex synthetic pathways [9]. Click chemistry offers an alternative approach because it is a simple and selective reaction between azides and alkynes to generate triazoles. The 1,4-disubstituted triazole moiety is well known in medicinal chemistry. Before the discovery of the click chemistry reaction, more than 7,000 compound bearing a 1,4-disubstituted 1H-1,2,3-triazole had been reported. The triazole unit is stable to oxidation and reduction, and is quite resistant to metabolic degradation [10]. In the design of novel prototypes for new antitumor drugs, triazole rings became increasingly relevant in studies published in 2013 [11,12,13]. Stefely et al. [14] reported antiproliferative triazoles with an IC50 of 46 nM against MCF-7 human breast tumor cells. Moreover, the anti-angiogenic drug, 1,2,3-triazole carboxyamidotriazole is being investigated in clinical trials as a potential anticancer drug [15,16].

Recently, thiourea α-aminophosphonate derivatives were attached to DHA, searching for antitumor agents [7]. The authors measured cytotoxicity as the protocols for cell toxicity (cytotoxicity) and antiproliferative effects are different. Moreover, antitumoral activity requires animal experiments. The compounds showed moderate to high toxicity on NCI-H460, A549, HepG2 and SKOV3 cells. Some of the compounds were more toxic than the commercial anticancer drug 5-fluorouracil.

The click chemistry approach to design new antiproliferative/anticancer agents has acquired relevance in the last few years. In previous works, we reported the antiproliferative activity of dimeric labdane diterpenes, some of them synthesized using click chemistry [17] and 1,2,3-triazole-substituted oleanolic acid derivatives [18]. Kádár et al. [19] synthesized steroidal triazole derivatives to investigate their antiproliferative effects. The most promising compounds were studied to evaluate its mechanism of action, where apoptosis plays an important role. Moreover Li et al. [20] explored the addition of triazole rings to naphthalimide to obtain hybrids with cytotoxic activity. One of the new hybrids was more cytotoxic that the reference compound amonafide against the MCF-7, Hela and liver cancer 7721 cells, with IC50 values in the range of 0.323–1.02 µM. Under the same experimental conditions, the IC50 of amonafide was in the range of 1.68–4.27 µM. The results points out the potential of click chemistry to design new bioactive agents. However, other tools have to be included for a more rational and effective drug design, including molecular modeling and receptor studies. The aim of this study was to synthesize a series of hybrid molecules combining DHA with different aromatic-substituted triazoles and to assess the antiproliferative effect of the new compounds in a panel of human tumor cell lines. Recently, one of the alkyl esters prepared in this work (DHA propargyl ester) was incorporated to caprolactone polymer (polycaprolactone, PCL) by click chemistry reaction. The integration of DHA to PLC increases the glass-transition temperature of PCL and does excellent hydrophobicity and good degradability to the polymer [21].

2. Results and Discussion

Starting from DHA and its alcohol, four alkyl esters were prepared and then treated with different aromatic azides using click chemistry to produce 16 hybrid abietane-triazole compounds (Scheme 1 and Scheme 2). The new compounds were obtained in moderate to good yields. The method proved to be suitable to obtain series of derivatives from diterpenes and can be applied to other natural products to increase structural diversity. Compounds 116 are described for the first time. The structures of all the compounds were confirmed by spectroscopic and spectrometric means.

Molecules 19 02523 g001 200
Scheme 1. Preparation of DHA derivatives 14.

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Scheme 1. Preparation of DHA derivatives 14.
Molecules 19 02523 g001 1024
Molecules 19 02523 g002 200
Scheme 2. Preparation of dehydroabietinol derivatives 516.

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Scheme 2. Preparation of dehydroabietinol derivatives 516.
Molecules 19 02523 g002 1024

The compounds were then assessed for antiproliferative activity towards the following human cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells. IC50 values > 100 µM were considered inactive (Table 1).

Table Table 1. Antiproliferative activity of dehydroabietic acid derivatives 116 against MRC-5 normal fibroblasts and selected tumor cell lines. a

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Table 1. Antiproliferative activity of dehydroabietic acid derivatives 116 against MRC-5 normal fibroblasts and selected tumor cell lines. a
Compound(IC50 ± SD, µM) b
MRC-5AGSSK-MES-1J82
185.8 ± 4.679.9 ± 4.877.3 ± 4.746.3 ± 2.3
2>10090.2 ± 5.4>10076.3 ± 5.9
3>10094.4 ± 5.4>100>100
450.2 ± 3.166.0 ± 4.428.9 ± 2.128.1 ± 1.7
517.1 ± 0.644.5 ± 1.96.1 ± 0.383.3 ± 3.3
6>100>100>100>100
7>100 36.7 ± 1.539.7 ± 2.725.6 ± 1.9
8>10035.9 ± 1.737.0 ± 2.626.8 ± 1.8
973.3 ± 3.747.7 ± 2.943.6 ± 2.949.9 ± 2.9
10>10058.9 ± 3.442.7 ± 2.933.9 ± 1.7
11>100>100>100>100
12>100>100>100>100
13>100>100>100>100
14>100>100>100>100
1582.9 ± 4.574.9 ± 3.784.4 ± 5.1>100
1668.8 ± 4.556.9 ± 3.374.2 ± 5.475.0 ± 6.1
Etoposide c0.33 ± 0.020.58 ± 0.021.83 ± 0.093.49 ± 0.16

a Cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells; b Results are expressed as mean values ± SD. Each concentration was tested in sextuplicate together with the control and repeated two times in separate experiments; c Reference compound.

Among the triazoles prepared with the diterpene acid, the derivatives 1 and 4 presented antiproliferative activity towards all of the selected cell lines. The effect, however, is low. Compounds 2 and 3, differing in the number of CH2 groups of the linker or in the aromatic moiety were inactive against MRC-5 and SK-MES1cells. When comparing the pairs 12 and 34 bearing one or two CH2 units as linkers, the effect of 1 was higher than that of 2, suggesting that a longer chain decreases activity when R is a phenyl group. However, an opposite effect was found for the methyl phenyl sulfide derivatives. The best compound of this group was the derivative 4, with a (CH2)2 linker and a methyl phenyl sulfide substituent in the triazole ring. More derivatives with longer linker chains need to be prepared to have a clearer picture of the effect of this structural feature on the antiproliferative effect.

The compounds 516, were prepared with the diterpene alcohol. Among them, the compounds 1114 were inactive. All of them contain electron donors such as a methoxy group or a chlorine atom in the aromatic ring. Compounds 7 and 8 showed similar activity against AGS, SK-MES-1 and J82 cells and were inactive against fibroblasts, showing a good selectivity. This fact suggests that the length of the CH2 linker from 1 to 3 units do not have a relevant influence in the antiproliferative activity. The same trend was observed for the products 9 and 10, differing in the linker. For the pair 15 and 16, the best effect was observed for compound 16 with a longer linker. Overall the activity for the compounds should be considered as moderate.

The hybrid compound 5 with a phenyl ring was the most active product designed in this study, presenting IC50 values of 17.1 and 6.1 µM against MRC-5 and SK-MES-1 cells. The compound differs from 1 in the identity of the diterpene moiety and in the nature of the linker. In the slightly active compound 1, the diterpene is a carboxylic acid, while in 5, the terpene moiety is an alcohol. The effect of compound 5 was associated with some selectivity against the SK-MES-1 cells. The SK-MES-1 are lung cancer cells (HTB-58) derived from metastatic site. The selectivity of compound 5 towards SK-MES-1 cells suggest potential of the compound against lung cancer cells and encourages further studies using in vivo models. The difference in effect of compound 5 and 7 against SK-MES-1 cells can be related to the differences in the phenyl vs. benzyl ring in the triazole moiety. However, the effect is inverse for J82 bladder carcinoma cells. In summary, the new compounds present different degrees of antiproliferative activity, with derivative 5 displaying relevant effect against lung cancer cell line SK-MES-1, with an IC50 value of 6.1 µM. Under the same experimental conditions, the IC50 value of etoposide was 1.83 µM.

3. Experimental

3.1. General Procedures

Melting points were determined on a Koffler hot stage apparatus (Electrothermal 9100, Dubuque, IA, USA) and were uncorrected. Optical rotations were measured on a Jasco DIP 370 (Jasco Analytical Instruments, Easton, MD, USA) polarimeter in CHCl3 at 20 °C. IR spectra were recorded on a Nicolet Nexus 470 FT-IR instrument (Thermo Electron Corporation, Whaltham, MA, USA). The NMR spectra were recorded on a Bruker Avance 400 (Bruker, Rheinstetten, Germany) spectrometer at 400 MHz for 1H and 100 MHz for 13C in CDCl3. Chemical shifts are given in ppm with TMS as the internal standard. High-resolution mass spectra were measured on a VG Micromass ZAB-2F at 70 eV (Varian Inc., Palo Alto, CA, USA). Merck silica gel (0.063–0.2) was used for column chromatography (CC), pre-coated Si gel plates (Merck, Kieselgel 60 F254, 0.25 mm) were used for TLC analysis. TLC spots were visualized by spraying the chromatograms with p-anisaldehyde–ethanol–acetic acid–H2SO4 (2:170:20:10 v/v) and heating at 110 °C for 3 min. Reagents: N,N-Dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) were from Merck (Schuchardt, Germany). Propargyl alcohol, 3-butyn-1-ol, 4-pentynoic acid and 6-heptynoic acid were from Aldrich (Steinheim, Germany). Aromatic azides were from Aldrich. Copper (II) sulphatepentahydrate was from Aldrich (St. Louis, MO, USA) and sodium ascorbate was from Sigma (St. Louis, MO, USA).

3.2. Obtention of Dehydroabietic Acid Derivatives

Dehydroabietic acid (DHA) was obtained from commercial rosin as described previously [22]. Some 300 g of rosin with 300 mg of 5% Pd/C were heating at 280 °C under a constant flow of N2 for 2 h. The generated crude product was purified by CC on silica gel with petroleum ether–ethyl acetate (8:2) to obtain dehydroabietic acid as colorless crystals after recrystallization in MeOH/H2O (164 g, 55% w/w yield). DHA was methylated with a solution of CH2N2 in ethyl ether to afford the corresponding dehydroabietic acid methyl ester (94%). Reduction of the methyl ester with LiAlH4 in dry tetrahydrofuran at reflux gave dehydroabietinol (78% yield).

3.2.1. Preparation of Alkynyl Esters

Esterification of DHA and dehydroabietinol was performed using DCC/DMAP and appropriate alcohol (propargyl alcohol or 3-butyn-1-ol) or acid (4-pentynoic acid or 6-heptynoic acid) according to reference [18]. Briefly, DHA or alkynyl acid (1 eq) was dissolved in dry CH2Cl2 at room temperature under constant stirring. Then, DCC (1 eq) was added, followed by a catalytic amount of DMAP and alkynyl alcohol or dehydroabietinol (1 eq) dissolved in dry CH2Cl2. The reaction was stopped by adding H2O, extracted with CH2Cl2, dried over Na2SO4, concentrated and purified (60%–81% yield).

3.2.2. General Procedure for the Synthesis of Triazole 116

The alkynyl esters (1 eq) and the corresponding azide (1 eq) were dissolved in t-BuOH/H2O (1:1), followed by the addition of CuSO4·5H2O (2 mol%) and sodium ascorbate (10 mol%). The mixture was stirred at room temperature for 24 h. The reaction was stopped by adding H2O, extracted with CH2Cl2, dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (54%–87% yield).

18-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-8,11,13-abietatrienoate (1). pale yellow resin; Molecules 19 02523 i001+27 (c 0.016, CHCl3); IR νmax (film) 2928, 2870, 1720, 1461, 1245, 755 cm−1; 1H-NMR (CDCl3): δ 8.02 (1H, s, H-3'), 7.72 (2H, d, J = 7.8 Hz, H-2'' and H-6''), 7.54 (2H, t, J = 7.8 Hz, H-3'' and H-5''), 7.46 (1H, t, J = 7.3 Hz, H-4''), 7.14 (1H, d, J = 8.2 Hz, H-11), 6.98 (1H, dd, J = 8.2, 1.5 Hz, H-12), 6.84 (1H, d, J = 1.5 Hz, H-14), 5.30 (2H, s, H-1'), 2.88 (2H, m, H-7), 2.79 (1H, m, H-15), 2.28 (1H, brd, J = 12.7 Hz, H-1β), 2.24 (1H, dd, J = 12.2, 1.2 Hz, H-5), 1.28 (3H, s, H-19), 1.21 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.20 (3H, s, H-20);13C-NMR (CDCl3): δ 178.96 (C-18), 147.15 (C-9), 146.13 (C-13), 144.93 (C-2'), 137.34 (C-1''), 135.02 (C-8), 130.21 (2C, C-3'' and C-5''), 129.34 (C-4''), 127.32 (C-14), 124.57 (C-11), 124.33 (C-12), 121.06 (2C, C-2'' and C-6''), 123.64 (C-3'), 58.12 (C-1'), 48.04 (C-4), 45.24 (C-5), 38.29, 37.34, 36.82, 33.85, 30.38, 25.57, 24.38 (2C, C-16 and C-17), 22.09, 18.92, 16.91; EIMS m/z 458.2462 [M+H]+ (calcd for C29H36N3O2, 458.2807).

18-(2-(1-Phenyl-1H-1,2,3-triazol-4-yl)ethyl)-8,11,13-abietatrienoate (2). colorless resin; Molecules 19 02523 i001+17 (c 0.025, CHCl3); IR νmax (film) 2930, 2865, 1726, 1470, 1245, 761 cm−1; 1H-NMR (CDCl3): δ 7.79 (1H, s, H-4'), 7.63 (2H, d, J = 7.6 Hz, H-2'' and H-6''), 7.50 (2H, t, J = 7.6 Hz, H-3'' and H-5''), 7.42 (1H, t, J = 7.3 Hz, H-4''), 7.16 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.2 Hz, H-12), 6.84 (1H, brs, H-14), 4.43 (2H, t, J = 6.6 Hz, H-1'), 3.15 (2H, t, J = 6.6 Hz, H-2'), 2.83 (2H, m, H-7), 2.71 (1H, m, H-15), 2.29 (1H, brd, J = 12.2 Hz, H-1β), 2.24 (1H, dd, J = 12.2, 1.2, H-5), 1.26 (3H, s, H-19), 1.21 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.19 (3H, s, H-20); 13C-NMR (CDCl3): δ 178.35 (C-18), 146.73 (C-9), 145.68 (C-13), 144.90 (C-3'), 137.03 (C-1''), 134.49 (C-8), 129.71 (2C, C-3'' and C-5''), 128.56 (C-4''), 126.85 (C-14), 124.11 (C-11), 123.90 (C-12), 120.37 (2C, C-2'' and C-6''), 119.70 (C-4'), 63.10 (C-1'), 47.62 (C-4), 44.83 (C-5), 37.96, 36.89, 36.60, 33.38, 29.99, 25.59, 25.14, 23.92 (2C, C-16 and C-17), 21.70, 18.52, 16.50; EIMS m/z 472.2695 [M+H]+ (calcd for C30H38N3O2, 472.2964).

18-((((1-Phenylthio)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8,11,13-abietatrienoate (3). pale yellow resin; Molecules 19 02523 i001+33 (c 0.013, CHCl3); IR νmax (film) 2922, 2852, 1714, 1442, 1238, 742 cm−1; 1H-NMR (CDCl3): δ 7.59 (1H, s, H-3'), 7.29 (5H, m, Ph), 7.11 (1H, d, J = 8.1 Hz, H-11), 6.96 (1H, brd, J = 8.1 Hz, H-12), 6.81 (1H, brs, H-14), 5.50 (2H, s, CH2S), 5.16 (2H, s, H-1'), 2.81 (2H, m, H-7), 2.72 (1H, m, H-15), 2.26 (1H, brd, J = 12.7 Hz, H-1β), 2.14 (1H, dd, J = 12.2, 1.5, Hz, H-5), 1.22 (3H, s, H-19), 1.17 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.16 (3H, s, H-20); 13C-NMR (CDCl3): δ 178.90 (C-18), 147.05 (C-9), 146.12 (C-13), 143.92 (C-2'), 134.91 (C-8), 132.63 (2C, C-2'' and C-6''), 131.98 (C-1''), 129.88 (2C, C-3'' and C-5''), 129.18 (C-4''), 127.24 (C-14), 124.50 (C-11), 124.30 (C-12), 123.66 (C-3'), 57.93 (C-1'), 54.35 (CH2S), 47.96 (C-4), 45.18 (C-5), 38.25, 37.26, 36.78, 33.97, 30.31, 25.46, 24.29 (2C, C-16 and C-17), 22.03, 18.34, 16.77; EIMS m/z 504.2641 [M+H]+ (calcd for C30H38N3O2S, 504.2684).

18-(2-(((1-Phenylthio)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8,11,13-abietatrienoate (4). pale yellow resin; Molecules 19 02523 i001+14 (c 0.014, CHCl3); IR νmax (film) 2928, 2867, 1722, 1440, 1242, 749 cm−1; 1H-NMR (CDCl3): δ 7.36 (1H, s, H-4'), 7.29 (5H, m, Ph), 7.14 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.86 (1H, brs, H-14), 5.45 (2H, s, CH2S), 4.29 (2H, t, J = 6.6 Hz, H-1'), 3.03 (2H, t, J = 6.6 Hz, H-2'), 2.82 (2H, m, H-7), 2.70 (1H, m, H-15), 2.28 (1H, brd, J = 12.7 Hz, H-1β), 2.12 (1H, dd, J = 12.2, 1.5 Hz, H-5), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.21 (3H, s, H-19), 1.18 (3H, s, H-20); 13C-NMR (CDCl3): δ 178.24 (C-18), 146.77 (C-9), 145.74 (C-13), 144.81 (C-3'), 134.54 (C-8), 131.92 (C-1''), 131.79 (2C, C-2'' and C-6''), 129.24 (2C, C-3'' and C-5''), 128.50 (C-4''), 126.87 (C-14), 124.11 (C-11), 123.93 (C-12), 120.95 (C-4'), 63.15 (C-1'), 53.46 (CH2S), 47.55 (C-4), 44.82 (C-5), 37.96, 36.85, 36.50, 33.92, 29.91, 25.59, 25.08, 23.97 (2C, C-16 and C-17), 21.57, 18.49, 16.44; EIMS m/z 518.2164 [M+H]+ (calcd for C31H40N3O2S, 518.2841).

18-(3-(1-Phenyl-1H-1,2,3-triazol-4-yl)propanoyloxy)-8,11,13-abietatriene (5). white resin; Molecules 19 02523 i001+20 (c 0.022, CHCl3); IR νmax (film) 2925, 2864, 1726, 1463, 1246, 761 cm−1; 1H-NMR (CDCl3): δ 7.78 (1H, s, H-5'), 7.70 (2H, d, J = 7.6 Hz, H-2'' and H-6''), 7.53 (2H, t, J = 7.6 Hz, H-3'' and H-5''), 7.42 (1H, t, J = 7.3 Hz, H-4''), 7.16 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.86 (1H, brs, H-14), 3.98 (1H, d, J = 10.9 Hz, H-18) 3.75 (1H, d, J = 10.9 Hz, H-18), 3.11 (2H, t, J = 7.3 Hz, H-3'), 2.86 (2H, m, H-7), 2.81 (1H, m, H-15), 2.79 (2H, t, J = 7.3 Hz, H-2'), 2.26 (1H, brd, J = 12.7 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.20 (3H, s, H-20), 0.92 (3H, s, H-19); 13C-NMR (CDCl3): δ 173.30 (C-1'), 147.51 (C-4'), 147.46 (C-9), 146.02 (C-13), 137.54 (C-1''), 135.06 (C-8), 130.11 (2C, C-3'' and C-5''), 128.96 (C-4''), 127.28 (C-14), 124.71 (C-11), 124.32 (C-12), 120.82 (2C, C-2'' and C-6''), 119.91 (C-5'), 73.16 (C-18), 44.78 (C-5), 38.65, 37.82, 37.20, 35.96, 34.03, 33.84, 30.65, 25.78, 24.39 (2C, C-16 and C-17), 21.46, 19.42, 18.91, 17.84; EIMS m/z 486.3360 [M+H]+ (calcd for C31H40N3O2, 486.3120).

18-(5-(1-Phenyl-1H-1,2,3-triazol-4-yl)pentanoyloxy)-8,11,13-abietatriene (6). white resin; Molecules 19 02523 i001+25 (c 0.014, CHCl3); IR νmax (film) 2930, 2864, 1726, 1461, 1248, 761 cm−1; 1H-NMR (CDCl3): δ 7.70 (1H, s, H-7'), 7.71 (2H, d, J = 7.4 Hz, H-2'' and H-6''), 7.53 (2H, t, J = 7.4 Hz, H-3'' and H-5''), 7.42 (1H, t, J = 7.4 Hz, H-4''), 7.18 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.88 (1H, brs, H-14), 3.97 (1H, d, J = 10.9 Hz, H-18) 3.71 (1H, d, J = 10.9 Hz, H-18), 2.85 (2H, m, H-7), 2.83 (1H, m, H-15), 2.80 (2H, t, J = 7.3 Hz, H-5'), 2.36 (2H, t, J = 7.3 Hz, H-2'), 2.27 (1H, brd, J = 12.9 Hz, H-1β), 1.23 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.21 (3H, s, H-20), 0.93 (3H, s, H-19); 13C-NMR (CDCl3): δ 174.13 (C-1'), 148.86 (C-6'), 147.54 (C-9), 146.03 (C-13), 137.66 (C-1''), 135.12 (C-8), 130.09 (2C, C-3'' and C-5''), 128.87 (C-4''), 127.29 (C-14), 124.71 (C-11), 124.31 (C-12), 120.83 (2C, C-2'' and C-6''), 119.33 (C-7'), 72.84 (C-18), 44.68 (C-5), 38.70, 37.84, 37.20, 35.99, 34.47, 33.83, 30.66, 29.19, 25.78, 25.74, 24.94, 24.38 (2C, C-16 and C-17), 19.39, 18.95, 17.91; EIMS m/z 514.3686 [M+H]+ (calcd for C31H44N3O2, 514.3433).

18-(3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propanoyloxy)-8,11,13-abietatriene (7). pale yellow resin; Molecules 19 02523 i001+16 (c 0.039, CHCl3); IR νmax (film) 2934, 2867, 1726, 1458, 1240, 727 cm−1; 1H-NMR (CDCl3): δ 7.36 (1H, s, H-5'), 7.34 (2H, d, J = 7.6 Hz, H-2'' and H-6''), 7.24 (2H, t, J = 7.6 Hz, H-3'' and H-5''), 7.22 (1H, t, J = 7.3 Hz, H-4''), 7.17 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.88 (1H, brs, H-14), 5.43 (2H, s, CH2Ph), 3.94 (1H, d, J = 10.9 Hz, H-18) 3.71 (1H, d, J = 10.9 Hz, H-18), 3.00 (2H, t, J = 7.3 Hz, H-3'), 2.85 (2H, m, H-7), 2.80 (1H, m, H-15), 2.70 (2H, t, J = 7.3 Hz, H-2'), 2.27 (1H, brd, J = 12.7 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.21 (3H, s, H-20), 0.90 (3H, s, H-19); 13C-NMR (CDCl3): δ 173.24 (C-1'), 147.47 (C-9), 147.24 (C-4'), 146.02 (C-13), 135.24 (C-1''), 135.07 (C-8), 129.48 (2C, C-3'' and C-5''), 129.06 (C-4''), 128.40 (2C, C-2'' and C-6''), 127.29 (C-14), 124.71 (C-11), 124.33 (C-12), 121.44 (C-5'), 73.06 (C-18), 54.40 (CH2Ph), 44.77 (C-5), 38.66, 37.83, 37.19, 35.93, 34.04, 33.84, 30.65, 25.79, 24.40 (2C, C-16 and C-17), 21.51, 19.41, 18.92, 17.83; EIMS m/z 500.2639 [M+H]+ (calcd for C32H42N3O2, 500.3277).

18-(5-(1-Benzyl-1H-1,2,3-triazol-4-yl)pentanoyloxy)-8,11,13-abietatriene (8). pale yellow resin; Molecules 19 02523 i001+10 (c 0.091, CHCl3); IR νmax (film) 2934, 2867, 1729, 1458, 1220, 751 cm−1; 1H-NMR (CDCl3): δ 7.36 (1H, s, H-7'), 7.34 (2H, d, J = 7.6 Hz, H-2'' and H-6''), 7.25 (2H, t, J = 7.6 Hz, H-3'' and H-5''), 7.22 (1H, t, J = 7.3 Hz, H-4''), 7.19 (1H, d, J = 8.1 Hz, H-11), 7.00 (1H, brd, J = 8.1 Hz, H-12), 6.90 (1H, brs, H-14), 5.48 (2H, s, CH2Ph), 3.95 (1H, d, J = 10.9 Hz, H-18) 3.70 (1H, d, J = 10.9 Hz, H-18), 2.85 (2H, m, H-7), 2.80 (1H, m, H-15), 2.69 (2H, t, J = 7.3 Hz, H-5'), 2.32 (2H, t, J = 7.3 Hz, H-2'), 2.27 (1H, brd, J = 12.9 Hz, H-1β), 1.23 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.22 (3H, s, H-20), 0.94 (3H, s, H-19); 13C-NMR (CDCl3): δ 174.13 (C-1'), 148.63 (C-6'), 147.55 (C-9), 146.02 (C-13), 135.36 (C-1''), 135.13 (C-8), 129.47 (2C, C-3'' and C-5''), 129.03 (C-4''), 128.37 (2C, C-2'' and C-6''), 127.30 (C-14), 124.73 (C-11), 124.32 (C-12), 121.04 (C-7'), 72.80 (C-18), 54.38 (CH2Ph), 44.68 (C-5), 38.71, 37.84, 37.19, 35.97, 34.45, 33.83, 30.67, 29.23, 25.81, 24.97, 24.41 (2C, C-16 and C-17), 19.39, 18.95, 17.91; EIMS m/z 528.4121 [M+H]+ (calcd for C34H46N3O2, 528.3590).

18-(3-(((1-Phenylthio)methyl)-1H-1,2,3-triazol-4-yl)propanoyloxy)-8,11,13-abietatriene (9). yellow resin; Molecules 19 02523 i001+7 (c 0.197, CHCl3); IR νmax (film) 2931, 2864, 1726, 1442, 1250, 749 cm−1; 1H-NMR (CDCl3): δ 7.37 (1H, s, H-5'), 7.31 (5H, m, Ph), 7.20 (1H, d, J = 8.1 Hz, H-11), 7.02 (1H, brd, J = 8.1 Hz, H-12), 6.92 (1H, brs, H-14), 5.51 (2H, s, CH2S), 4.00 (1H, d, J = 10.9 Hz, H-18) 3.73 (1H, d, J = 10.9 Hz, H-18), 3.02 (2H, t, J = 7.3 Hz, H-3'), 2.87 (2H, m, H-7), 2.82 (1H, m, H-15), 2.72 (2H, t, J = 7.3 Hz, H-2'), 2.28 (1H, brd, J = 12.7 Hz, H-1β), 1.25 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.23 (3H, s, H-20), 0.94 (3H, s, H-19); 13C-NMR (CDCl3): δ 173.11 (C-1'), 147.47 (C-9), 147.37 (C-4'), 146.04 (C-13), 135.08 (C-8), 132.50 (3C, C-1'', C-2'' and C-6''), 129.86 (2C, C-3'' and C-5''), 128.99 (C-4''), 127.31 (C-14), 124.74 (C-11), 124.36 (C-12), 121.09 (C-5'), 73.00 (C-18), 53.96 (CH2S), 44.72 (C-5), 38.68, 37.84, 37.23, 35.94, 33.97, 33.86, 30.67, 25.83, 24.44 (2C, C-16 and C-17), 21.49, 19.41, 18.94, 17.89; EIMS m/z 532.3104 [M+H]+ (calcd for C32H42N3O2S, 532.2997).

18-(5-(((1-Phenylthio)methyl)-1H-1,2,3-triazol-4-yl))pentanoyloxy)-8,11,13-abietatriene (10). yellow resin; Molecules 19 02523 i001+11 (c 0.256, CHCl3); IR νmax (film) 2937, 2867, 1725, 1467, 1251, 749 cm−1; 1H-NMR (CDCl3): δ 7.32 (5H, m, Ph), 7.28 (1H, s, H-7'), 7.21 (1H, d, J = 8.1 Hz, H-11), 7.03 (1H, brd, J = 8.1 Hz, H-12), 6.92 (1H, brs, H-14), 5.59 (2H, s, CH2S), 4.00 (1H, d, J = 10.9 Hz, H-18), 3.74 (1H, d, J = 10.9 Hz, H-18), 2.87 (2H, m, H-7), 2.85 (1H, m, H-15), 2.70 (2H, t, J = 7.3 Hz, H-5'), 2.34 (2H, t, J = 7.3 Hz, H-2'), 2.32 (1H, brd, J = 12.9 Hz, H-1β), 1.25 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.24 (3H, s, H-20), 0.96 (3H, s, H-19); 13C-NMR (CDCl3): δ 174.08 (C-1'), 148.69 (C-6'), 147.54 (C-9), 146.02 (C-13), 135.12 (C-8), 132.64 (2C, C-2'' and C-6''), 132.48 (C-1''), 129.86 (2C, C-3'' and C-5''), 129.02 (C-4''), 127.31 (C-14), 124.74 (C-11), 124.34 (C-12), 120.71 (C-7'), 72.80 (C-18), 54.04 (CH2S), 44.68 (C-5), 38.72, 37.85, 37.21, 35.99, 34.29, 33.87, 30.69, 29.14, 25.82, 25.70, 24.85, 24.43 (2C, C-16 and C-17), 19.41, 18.97, 17.94; EIMS m/z 560.4263 [M+H]+ (calcd for C34H46N3O2S, 560.3310).

18-(3-(1-(4-Anisidyl)-1H-1,2,3-triazol-4-yl)propanoyloxy)-8,11,13-abietatriene (11). white resin; Molecules 19 02523 i001+21 (c 0.017, CHCl3); IR νmax (film) 2928, 2864, 1726, 1442, 1257, 833 cm−1; 1H-NMR (CDCl3): δ 7.70 (1H, s, H-5'), 7.59 (2H, d, J = 9.0 Hz, H-2'' and H-6''), 7.16 (1H, d, J = 8.1 Hz, H-11), 7.00 (2H, d, J = 9.0 Hz, H-3'' and H-5''), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.86 (1H, brs, H-14), 3.98 (1H, d, J = 10.9 Hz, H-18), 3.86 (3H, s, PhOMe), 3.75 (1H, d, J = 10.9 Hz, H-18), 3.10 (2H, t,J = 7.3 Hz, H-3'), 2.87 (2H, m, H-7), 2.82 (1H, m, H-15), 2.78 (2H, t, J = 7.3 Hz, H-2'), 2.26 (1H, brd, J = 12.7 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.20 (3H, s, H-20), 0.93 (3H, s, H-19); 13C-NMR (CDCl3): δ 173.32 (C-1'), 160.07 (C-4''), 147.46 (C-9), 147.29 (C-4'), 146.01 (C-13), 135.06 (C-8), 131.05 (C-1''), 127.28 (C-14), 124.71 (C-11), 124.32 (C-12), 122.45 (2C, C-2'' and C-6''), 120.09 (C-5'), 115.11 (2C, C-3'' and C-5''), 73.15 (C-18), 56.03 (OMe), 44.79 (C-5), 38.66, 37.83, 37.20, 35.96, 34.08, 33.84, 30.65, 25.78, 24.40 (2C, C-16 and C-17), 21.47, 19.42, 18.92, 17.84; EIMS m/z 516.4582 [M+H]+ (calcd for C32H42N3O3, 516.3226).

18-(5-(1-(4-Anisidyl)-1H-1,2,3-triazol-4-yl)pentanoyloxy)-8,11,13-abietatriene (12). white resin; Molecules 19 02523 i001+12 (c 0.060, CHCl3); IR νmax (film) 2937, 2867, 1729, 1461, 1257, 830 cm−1; 1H-NMR (CDCl3): δ 7.61 (1H, s, H-7'), 7.60 (2H, d, J = 8.9 Hz, H-2'' and H-6''), 7.17 (1H, d, J = 8.1 Hz, H-11), 7.00 (2H, d, J = 9.0 Hz, H-3'' and H-5''), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.88 (1H, brs, H-14), 3.97 (1H, d, J = 10.9 Hz, H-18), 3.86 (3H, s, PhOMe), 3.71 (1H, d, J = 10.9 Hz, H-18), 2.86 (2H, m, H-7), 2.81 (1H, m, H-15), 2.78 (2H, t, J = 7.3 Hz, H-5'), 2.35 (2H, t, J = 7.3 Hz, H-2'), 2.27 (1H, brd, J = 12.9 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.21 (3H, s, H-20), 0.93 (3H, s, H-19); 13C-NMR (CDCl3): δ 174.15 (C-1'), 160.01 (C-4''), 148.66 (C-6'), 147.54 (C-9), 146.02 (C-13), 135.12 (C-8), 131.17 (C-1''), 127.29 (C-14), 124.71 (C-11), 124.30 (C-12), 122.49 (2C, C-2'' and C-6''), 119.54 (C-7'), 115.10 (2C, C-3'' and C-5''), 72.84 (C-18), 56.03 (OMe), 44.68 (C-5), 38.69, 37.83, 37.19, 35.99, 34.47, 33.83, 30.66, 29.23, 25.79, 25.74, 24.95, 24.38 (2C, C-16 and C-17), 19.39, 18.94, 17.90; EIMS m/z 544.4256 [M+H]+ (calcd for C34H46N3O3, 544.3539).

18-(3-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)propanoyloxy)-8,11,13-abietatriene (13). white resin; Molecules 19 02523 i001+19 (c 0.014, CHCl3); IR νmax (film) 2928, 2864, 1726, 1460, 1248, 776 cm−1; 1H-NMR (CDCl3): δ 7.78 (1H, s, H-5'), 7.76 (1H, s, H-2''), 7.61 (1H, d, J = 8.0 Hz, H-6''), 7.45 (1H, t, J = 8.0 Hz, H-5''), 7.39 (1H, d, J = 8.0 Hz, H-4''), 7.16 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.86 (1H, brs, H-14), 3.98 (1H, d, J = 10.9 Hz, H-18) 3.75 (1H, d, J = 10.9 Hz, H-18), 3.11 (2H, t, J = 7.3 Hz, H-3'), 2.86 (2H, m, H-7), 2.80 (1H, m, H-15), 2.78 (2H, t, J = 7.3 Hz, H-2'), 2.26 (1H, brd, J = 12.7 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.20 (3H, s, H-20), 0.92 (3H, s, H-19); 13C-NMR (CDCl3): δ 173.23 (C-1'), 147.81 (C-4'), 147.45 (C-9), 146.03 (C-13), 138.36 (C-3''), 135.94 (C-1''), 135.04 (C-8), 131.20 (C-5''), 129.00 (C-4''), 127.28 (C-14), 124.71 (C-11), 124.33 (C-12), 121.02 (C-2''), 119.85 (C-5'), 118.72 (C-6''), 73.15 (C-18), 44.74 (C-5), 38.64, 37.82, 37.21, 35.96, 33.90, 33.84, 30.64, 25.77, 24.40 (2C, C-16 and C-17), 21.40, 19.41, 18.91, 17.84; EIMS m/z 520.2411 [M+H]+ (calcd for C31H39ClN3O2, 520.2731).

18-(5-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)pentanoyloxy)-8,11,13-abietatriene (14). pale yellow resin; Molecules 19 02523 i001+17 (c 0.012, CHCl3); IR νmax (film) 2934, 2864, 1726, 1461, 1241, 782 cm−1; 1H-NMR (CDCl3): δ 7.76 (1H, s, H-2''), 7.69 (1H, s, H-5'), 7.63 (1H, d, J = 8.0 Hz, H-6''), 7.45 (1H, t, J = 8.0 Hz, H-5''), 7.39 (1H, d, J = 8.0 Hz, H-4''), 7.17 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.88 (1H, brs, H-14), 3.97 (1H, d, J = 10.9 Hz, H-18) 3.72 (1H, d, J = 10.9 Hz, H-18), 2.86 (2H, m, H-7), 2.83 (1H, m, H-15), 2.80 (2H, t, J = 7.3 Hz, H-5'), 2.35 (2H, t, J = 7.3 Hz, H-2'), 2.27 (1H, brd, J = 12.9 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.20 (3H, s, H-20), 0.94 (3H, s, H-19); 13C-NMR (CDCl3): δ 174.06 (C-1'), 149.16 (C-6'), 147.55 (C-9), 146.04 (C-13), 138.48 (C-3''), 135.91 (C-1''), 135.10 (C-8), 131.16 (C-5''), 128.90 (C-4''), 127.28 (C-14), 124.70 (C-11), 124.30 (C-12), 121.03 (C-2''), 119.19 (C-7'), 118.75 (C-6''), 72.83 (C-18), 44.70 (C-5), 38.73, 37.84, 37.21, 36.00, 34.43, 33.83, 30.65, 29.10, 25.75, 25.68, 24.90, 24.36 (2C, C-16 and C-17), 19.40, 18.94, 17.90; EIMS m/z 548.4267 [M+H]+ (calcd for C33H43ClN3O2, 548.3044).

18-(3-(1-(4-Toluenesulfonyl)-1H-1,2,3-triazol-4-yl)propanoyloxy)-8,11,13-abietatriene (15). pale yellow resin; Molecules 19 02523 i001+22 (c 0.022, CHCl3); IR νmax (film) 2934, 2864, 1729, 1461, 1240, 816 cm−1; 1H-NMR (CDCl3): δ 7.97 (2H, d, J = 8.1 Hz, H-2'' and H-6''), 7.91 (1H, s, H-5'), 7.37 (2H, d, J = 8.1 Hz, H-3'' and H-5''), 7.17 (1H, d, J = 8.1 Hz, H-11), 6.99 (1H, brd, J = 8.1 Hz, H-12), 6.88 (1H, brs, H-14), 3.94 (1H, d, J = 10.9 Hz, H-18) 3.72 (1H, d, J = 10.9 Hz, H-18), 3.02 (2H, t, J = 7.3 Hz, H-3'), 2.88 (2H, m, H-7), 2.81 (1H, m, H-15), 2.69 (2H, t, J = 7.3 Hz, H-2'), 2.43 (3H, s, PhMe), 2.27 (1H, brd, J = 12.7 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.20 (3H, s, H-20), 0.90 (3H, s, H-19); 13C-NMR (CDCl3): δ 172.82 (C-1'), 147.59 (C-4'), 147.44 (C-9), 146.64 (C-4''), 146.04 (C-13), 135.04 (C-8), 133.59 (C-1''), 130.82 (2C, C-2'' and C-6''), 129.05 (2C, C-3'' and C-5''), 127.30 (C-14), 124.68 (C-11), 124.33 (C-12), 121.43 (C-5'), 73.25 (C-18), 44.76 (C-5), 38.65, 37.81, 37.17, 35.95, 33.84, 33.50, 30.62, 25.77, 24.39 (2C, C-16 and C-17), 21.18, 19.40, 18.89, 17.80; EIMS m/z 564.3065 [M+H]+ (calcd for C32H42N3O4S, 564.2896).

18-(5-(1-(4-Toluenesulfonyl)-1H-1,2,3-triazol-4-yl)pentanoyloxy)-8,11,13-abietatriene (16). pale yellow resin; Molecules 19 02523 i001+30 (c 0.035, CHCl3); IR νmax (film) 2937, 2867, 1726, 1451, 1250, 816 cm−1; 1H-NMR (CDCl3): δ 7.93 (2H, d, J = 8.1 Hz, H-2'' and H-6''), 7.72 (1H, s, H-5'), 7.32 (2H, d, J = 8.1 Hz, H-3'' and H-5''), 7.18 (1H, d, J = 8.1 Hz, H-11), 7.01 (1H, brd, J = 8.1 Hz, H-12), 6.89 (1H, brs, H-14), 3.99 (1H, d, J = 10.9 Hz, H-18) 3.66 (1H, d, J = 10.9 Hz, H-18), 2.86 (2H, m, H-7), 2.83 (1H, m, H-15), 2.81 (2H, t,J = 7.3 Hz, H-5'), 2.43 (3H, s, PhMe), 2.24 (2H, t, J = 7.3 Hz, H-2'), 2.20 (1H, brd, J = 12.9 Hz, H-1β), 1.22 (6H, d, J = 6.9 Hz, H-16 and H-17), 1.21 (3H, s, H-20), 0.93 (3H, s, H-19); 13C-NMR (CDCl3): δ 174.20 (C-1'), 148.65 (C-6'), 147.60 (C-9), 146.10 (C-13), 145.42 (C-4''), 135.18 (C-8), 133.20 (C-1''), 129.98 (2C, C-2'' and C-6''), 128.76 (2C, C-3'' and C-5''), 127.33 (C-14), 124.72 (C-11), 124.33 (C-12), 119.33 (C-7'), 72.73 (C-18), 44.58 (C-5), 38.74, 37.83, 37.23, 35.94, 34.38, 33.83, 30.64, 28.63, 25.77, 25.70, 24.82, 24.40 (2C, C-16 and C-17), 22.08, 19.36, 18.92, 17.90; EIMS m/z 592.3027 [M+H]+ (calcd for C34H46N3O4S, 592.3209).

3.3. Antiproliferative Assay

All human cell lines used in this work were purchased from the American Type Culture Collection (ATCC, Manasas, VA, USA). Normal lung MRC-5 fibroblasts (CCL-171), SK-MES-1 lung cancer cells (HTB-58) and J82 bladder carcinoma cells (HTB-1) were grown as monolayers in minimum essential Eagle medium (MEM) with Earles’s salts, 2 mM L-glutamine and 1.5 g/L sodium bicarbonate. Gastric adenocarcinoma AGS cells (CRL-1739) were grown as monolayers in Ham F-12 medium containing 1 mM L-glutamine and 1.5 g/L sodium bicarbonate. All media were supplemented with 10% heat-inactivated FBS, 100 IU/mL penicillin and 100 µg/mL streptomycin. Cells were grown in a humidified incubator with 5% CO2 in air at 37 °C. For the antiproliferative assay, cells were plated at a density of 5 × 104 cells/mL. Cells were seeded in 96-well plates (100 µL/well). One day after seeding, cells were treated with medium containing the compounds at concentrations ranging from 0 up to 100 µM during 3 days. The compounds were dissolved in DMSO (1% final concentration) and complete medium. Untreated cells (medium containing 1% DMSO) were used as 100% viability controls. Etoposide (98% purity, Sigma-Aldrich, St. Louis, MO, USA) was used as reference compound. Each concentration was tested in sextuplicate and experiments were repeated 2 times. Cell viability was determined by means of the MTT reduction assay at the end of the incubation with the products. The results were transformed to percentage of controls and the IC50 value was obtained adjusting the dose-response curve to a sigmoidal model. The software used was OriginPro 8.1 [23].

4. Conclusions

Sixteen dehydroabietic acid trizaole derivatives were prepared using click chemistry. The derivatives contain structural differences such as variability of aromatic rings and linkers which allow performing structure–activity relationship. The compounds were assessed as antiproliferative agents in three human tumor cell lines and on normal fibroblasts. The most remarkable difference was observed for compounds 5 and 6, differing in the length of the linker (n:1 vs. n:3), as while compound 5 was the most active compound in this study, compound 6 was inactive. On the other hand, the tumor cell selectivity of the compounds 7 and 8 is very interesting.

Acknowledgments

Financial support of FONDECYT Project 11100046 is gratefully acknowledged.

Author Contributions

Mariano Walter Pertino was co-responsible for the synthesis and wrote the manuscript; Valery Verdugo was co-responsible for the synthesis; Cristina Theoduloz executed the experiments and Guillermo Schmeda-Hirschmann contributed with valuable discussions and revised the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 116 are available from the authors.
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