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Article

Green Synthesis and Electrochemical Properties of Mono- and Dimers Derived from Phenylaminoisoquinolinequinones

by
Juana Andrea Ibacache
1,*,
Jaime A. Valderrama
2,*,
Judith Faúndes
1,
Alex Danimann
1,
Francisco J. Recio
3 and
César A. Zúñiga
3
1
Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, casilla 40, Santiago 9170022, Chile
2
Facultad de Ciencias de la Salud, Universidad Arturo Prat, casilla 121, Iquique 1100000, Chile
3
Facultad de Química y Farmacia, Universidad Católica de Chile, casilla 306, Santiago 7820436, Chile
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(23), 4378; https://doi.org/10.3390/molecules24234378
Submission received: 28 October 2019 / Revised: 25 November 2019 / Accepted: 26 November 2019 / Published: 30 November 2019
(This article belongs to the Section Organic Chemistry)
Browse Figures
Review Reports Versions Notes

Abstract

:
In the search for new quinoid compounds endowed with potential anticancer activity, the synthesis of novel heterodimers containing the cytotoxic 7-phenylaminoisoquinolinequinone and 2-phenylaminonaphthoquinone pharmacophores, connected through methylene and ethylene spacers, is reported. The heterodimers were prepared from their respective isoquinoline and naphthoquinones and 4,4′-diaminodiphenyl alkenes. The access to the target heterodimers and their corresponding monomers was performed both through oxidative amination reactions assisted by ultrasound and CeCl3·7H2O catalysis “in water”. This eco-friendly procedure was successfully extended to the one-pot synthesis of homodimers derived from the 7-phenylaminoisoquinolinequinone pharmacophore. The electrochemical properties of the monomers and dimers were determined by cyclic and square wave voltammetry. The number of electrons transferred during the oxidation process, associated to the redox potential EI1/2, was determined by controlled potential coulometry.

1. Introduction

Quinones are ubiquitous in nature and comprise one of the largest classes of anticancer agents [1,2,3]. Among the broad variety of drugs used clinically in the therapy of solid cancers, mitomycin, mitoxantrone, and saintopin contain the common quinone nucleus into their active pharmacophores. The most remarkable characteristics of these quinoid drugs are their abilities to act as DNA intercalators, reductive alkylators of biomolecules, and/or generators of reactive oxygen species (ROS) such as hydroxyl radical, hydrogen peroxide, superoxide anion, and singlet oxygen [4], which can damage tumor cells [5,6,7,8,9,10,11,12] via oxidative stress [5,13,14]. It is worth to note that in spite of the broad range of effects of quinoid compounds on grown inhibition of diverse cancer cells, the major limitations, in terms of their use as cancer drugs, are their side effects [15].
A common aminoquinoid unit appeared as a key structural scaffold in diverse natural occurring cytotoxic compounds, such as smenospongine [16,17], streptonigrin [18,19,20,21,22,23], mansouramicyn C [24,25] and, synthetic cytotoxic 1,4-benzoquinones, 1,4-naphthoquinones [26,27], and heterocyclic analogs [28,29,30,31,32].
A number of synthetic aminoisoquinolinequinones and polycyclic analogs have been the subject of study for many years due to their in vitro cytotoxic activities on several cancer cell lines [33,34,35,36,37,38,39]. A well-established procedure to prepare alkyl- and arylaminoquinones is based on the oxidative coupling reaction of quinones with alkyl- and arylamines [40,41,42,43,44]. It is widely accepted that the oxidative coupling reaction involves a Michael addition of the nitrogen nucleophiles to the quinones, followed by oxidation of the hydroquinone intermediates [44].
In Figure 1, representative synthetic phenylaminoquinones endowed with in vitro cytotoxic properties against a number of human cancer cell lines are depicted [26,30,31,32]. The common feature of these aminoquinones to target cancer cells has been attributed, in part, to their abilities to produce oxidative stress via generation of reactive oxygen species (ROS) [45,46].
The biological activity of quinones is often related to their electrochemical behavior [47,48,49,50,51,52]. The ability of the quinone nucleus to accept one or two electrons to give the corresponding semiquinone radical anion (Q•−) or hydroquinone dianion (Q2−) species is believed to induce formation of reactive oxygen species (ROS), responsible for the oxidative stress in cells [11,47,53].
Recently, we successfully applied the twin-drug approach [54] to improve the antiproliferative activity and selectivity of the phenylaminoisoquinolinequinone pharmacophore [29,55]. The designed homodimers were prepared through a one-pot procedure from phenylaminoisoquinolinequinones and 4,4′-diaminodiphenylmethane (DDM). It was also reported the selective access to monomers, which are involved in the formation of homodimers [54]. The following Scheme 1 exemplifies the selective access to the corresponding monomer or homodimer employing suitable molar ratio between the quinone and diamine precursors.
The selective access to the monomers and the cytotoxic levels of the monomers and homodimers [54] encourage us to extend our studies to the synthesis of heterodimers constituted by anilinoisoquinolinequinone and 2-anilinonaphthoquinone pharmacophores connected through methylene spacers [26]. Bearing in mind that monomers and dimers exhibit one and two electro-active quinone nucleus, respectively, we were also interested to get insight into their electrochemical properties. Herein we report results on the eco-friendly access to monomers, heterodimers, and homodimers derived from isoquinolinequinones, naphthoquinones, and 4,4′-diamino diphenyl alkanes. The new synthesized monomers and dimers were subject to electrochemical studies by cyclic voltammetry, square wave voltammetry, and controlled potential coulometry.

2. Results

2.1. Chemistry

The strategy to construct the heterodimers, where the phenylamino groups of the selected quinoid pharmacophores are connected through methylene spacers, is based on oxidative monoamination reactions of the parent isoquinolinquinones 1 and 2 with the 4,4′-diamino diphenyl alkanes 3 and 4 followed by amination reactions of the resulting monomers with naphthoquinones 8 and 9 (Figure 2).
The access to the designed heterodimers 10, 11, and 12 was planned through the aminoisoquinolinequinone monomers 5, 6, and 7 resulting from the reaction between the quinones 1/2 and symmetrical diamines 3/4. The synthetic approach to heterodimer 10 was firstly examined from isoquinolinequinone 1, naphthoquinone 8, and diamine 3. The required monomer precursor 5 was synthesized in 74% yield, according to our previously reported procedure [54], by reaction of the quinone 1 with diamine 3 in a 1:2 mole ratio, catalytic amounts of CeCl3·7H2O in ethanol at room temperature [29]. Further reaction assays of 5 with naphthoquinone 9 in a 1:2 ratio under the above-mentioned conditions, performed at room temperature and, in refluxing ethanol, produced heterodimer 10 albeit in low yields (22% and 28%, respectively). The heterodimer 10 was isolated as a purple solid, m.p. 186 °C (d). The IR spectrum reveals the presence of N–H and C=O bands at v/cm−1: 3337, 1720, 1666, and 1673, respectively. The 1H-NMR spectrum shows the signals of two vinylic protons at δ 7.54 and 7.67 ppm and the amino proton signals at δ 7.54 and 7.67 ppm. In the aromatic proton region, the proton signals of the naphthoquinone fragment, at δ: 7.67, 7.76 and 8.11, were observed and those of the protons of the phenyl groups of the linker that appeared as a multiplet at δ 7.21 ppm. The methylene protons of the spacer are observed at 4.00 ppm. The 13C-NMR spectrum displays signals of three carbonyl groups at δ: 181.5, 181.1, 180.4, and the mass spectrum shows the molecular ion [M+] peak at m/z 598.1971.
Interestingly, when a water suspension containing compounds 5 and 9 (1:2 mole ratio) and CeCl3·7H2O were ultrasound-irradiated [56] for 6 h, heterodimer 10 was generated and isolated in 88% yield (Scheme 2). Based on this excellent outcome, we decided to extend this green procedure to the synthesis of monomers 5–7 and heterodimers 11 and 12. The reactions that were conducted under irradiation period of 1.5–7 h, produced the respective monomers 5–7 in excellent yields (94–98%), and compounds 11 and 12 in moderate yield (48% and 50%) (Scheme 2). The lower yields formation of heterodimers 11 and 12 compared to that of dimer 10 could be attributed to steric hindrance interactions involved in the addition of the nitrogen nucleophiles 11 and 12 across the disubstituted electrophilic quinone double bond of 9.
The one-pot access to homodimers 13–15 from their respective isoquinolinquinones 1 and 2 and their symmetrical diamines 3 and 4 were also carried out under ultrasound irradiation, catalyzed with CeCl3·7H2O in water. Under these conditions, the respective homodimers 13–15 were isolated in good yields (65–75%) (Scheme 2).
The structures of the new compounds 6, 7, 10–12, 14, and 15 were established by infrared spectroscopy (IR), 1H- and 13C-nuclear magnetic resonance (NMR), bidimensional nuclear magnetic resonance (2D-NMR), and high-resolution mass spectroscopy (HRMS).

2.2. Electrochemistry

The monomers 5–7 and dimers 10–12, 14, and 15 were evaluated for their half-wave potentials (EI1/2 and EII1/2). For all the compounds, the first faradaic process (EI1/2) presents a reversible behavior, and the second process is quasi-reversible. In Table 1, the electrochemical parameters determined in this study are summarized. The net charge consumption was used to calculate the number of electrons for each compound. In the monomers (5–7), the values of charge are close to 10 mC, which indicate a one-electron transfer during the faradaic process. However, for the heterodimers and homodimers it is close to 20 mC under the studied conditions, which implies 2-electrons. These transferred electron values were corroborated by the following equation: | E pc − ( E pc 2 ) | = 90.6 n for an ideal reversible peak (EI1/2), where EPc is the cathodic peak potential and Epc/2 is potential at half-width of the cathodic peak for all the studied molecules [57,58,59].
The first potential for compounds 5–7 (via one-electron), and, for dimers 10, 11, 12, 14–15 (vía two-electrons) produce the corresponding semiquinone radical anion(s) [6,13,14]. The first and second reduction potential of monomer 5 correspond to the monoelectronic transfer processes: EI: Q + e− = semiquinone radical anion (Q•−) and EII: Q•− + e− = quinone dianion (Q2−) [60,61]. It is important to note that in the case of dimers 10, 11, 12, 14, and 15, a broad faradaic process associated to the overlap between EI1/2 and EII1/2 is detected due to the conjugate nature of the benzene ring groups together with the fast-kinetic reaction of the carbonyl groups [62,63].
Figure 3 shows the voltammograms for monomer 5–7 and homo- and heterodimer 10–12, 14–15 (Supplementary Figures S1–S8, Cyclic voltammetry and square wave voltammetry (SWV)).
The electrochemical parameters presented in Table 1 indicate that monomers 5–7 exhibited a relative closeness in the values of the potential EI1/2 and EII1/2 and widening of the faradic signal associated with both processes. These facts could be attributed to the electronic nature of the substituents of the compounds [46]. In the case of heterodimers 10 and its chlorine analog 11, the shift to more positive values of EI1/2 and EII1/2 of the later with respect to 10 could be attributed to the electron-withdrawing effect of the chlorine atom. Similarly, the shift to more positive values of EI1/2 of monomer 6 compared to 7, and homodimer 14 compared to 15 could be explained by the stronger electron-withdrawing ability of the methoxycarbonyl group in 14 than the acetyl group in 15. These results agree with precedents on the influence of electron-withdrawing substituents in aminoquinones groups, on their oxidant properties [64,65,66,67].
The data analysis led us also to found differences between the potential EI1/2 and EII1/2 of dimers and monomers containing the 4,4′-diaminodiphenylalkane fragment in terms of the nature of the alkane spacers. The comparison of the monomers 5 and 6, which differ in the chain length of the alkane spacers, shows that the formal potentials of the ethylene-containing monomer 6 appeared at more positive values than its methylene-containing analog 5. Additional examples are required to establish the influence of the chain length on the potential EI1/2 and EII1/2.

3. Materials and Methods

3.1. General

All solvents, reagents, and precursors such as quinones 8 and 9 were purchased from different companies such as Aldrich (St. Louis, MO, USA) and Merck (Darmstadt, Germany) and were used as supplied. Melting points were determined on a Stuart Scientific SMP3 (Bibby Sterilin Ltd., Staffordshire, UK) apparatus and are uncorrected. The IR spectra were recorded on an FT IR Bruker spectrophotometer; (model Vector 22 Bruker, Rheinstetten, Germany), using KBr disks, and the wave numbers are given in cm−1. 1H- and 13C-NMR spectra were recorded on a Bruker Avance-400 instrument (Bruker, Ettlingen, Germany) in CDCl3 at 400 and 100 MHz, respectively. Chemical shifts are expressed in ppm downfield relative to tetramethylsilane and the coupling constants (J) are reported in hertz. Data for 1H-NMR spectra are reported as follows: s = singlet, br s = broad singlet, d = doublet, m = multiplet, and the coupling constants (J) in Hz. Bidimensional NMR techniques were used for signal assignments. HRMS-ESI were carried out on a Thermo Scientific Exactive Plus Orbitrap spectrometer (Thermo Fisher, Bremen, Germany) with a constant nebulizer temperature of 250 °C. The experiments were performed in positive ion mode, with a scan range of m/z 100–300. All fragment ions were assigned by accurate mass measurements at high resolution (resolving power: 140,000 FWHM). The samples were infused directly into the electrospray ionization source (ESI) using a syringe pump at flow rates of 5 μL min−1. Silica gel Merck 60 (70–230 mesh, from Merck, Darmstadt, Germany) was used for preparative column chromatography and TLC aluminum foil 60F254 for analytical thin-layer chromatography (TLC). Isoquinolinequinones 1–2 were prepared by previously reported procedures [40].
The ultrasound-promoted reactions were carried out in standard oven-dried glassware in a Branson sonicator cup horn working at 19.7–20.0 kHz (75 W).

3.2. Chemistry

3.2.1. Preparation of Monoamination Compounds 5–7. General Procedure

Suspensions of quinones 1–2 (1 mmol) and corresponding diamine (2 equiv), CeCl3·7H2O (5 mmol %), and water (20 mL) were left with ultrasonic irradiation after completion of the reaction as indicated by TLC. The reaction mixture was partitioned between chloroform and water, the organic extract was washed with water (2 × 15 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was column chromatographed over silica gel (95:5 CH2Cl2/EtOAc) to yield the corresponding pure monoamination compounds 5–7.

3.2.2. Preparation of Heterodimers 10–12. General Procedure

Suspensions of compounds 5–7 (2 mmol), naphthoquinone 8/9 (1 mmol), CeCl3·7H2O (5 mmol %), and water (20 mL) were left with stirring under ultrasonic irradiation after completion of the reaction as indicated by TLC. The reaction mixture was partitioned between chloroform and water, the organic extract was washed with water (2 × 15 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was column chromatographed over silica gel (95:5 CH2Cl2/EtOAc) to yield the corresponding pure heterodimers 10–12.

3.2.3. Preparation of Homodimers 13–15. General Procedure

Suspensions of quinones 1/2 (4 mmol) and corresponding diamine 3/4 (1 equiv), CeCl3·7H2O (5 mmol %), and water (20 mL) were left with stirring under ultrasonic irradiation after completion of the reaction. The reaction mixture was partitioned between chloroform and water, the organic extract was washed with water (2 × 15 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was column chromatographed over silica gel (95:5 CH2Cl2/EtOAc) to yield the corresponding pure homodimers 13–15.
Methyl-7-(4-(4-aminobenzyl)phenyl)amino)-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate (5). m.p. 149–150 °C; IR (KBr) v/cm−1: 3423 (N-H), 3305, and 3251 (NH2), 1734 (C=O ester), 1668 (C=O quinone). 1H-NMR (400 MHz, CDCl3) δ 2.61 (s, 3H, 3-Me), 2.99 (s, 3H, 1-Me), 3.60 (s, 2H, NH2), 3.88 (s, 2H, CH2), 4.00 (s, 3H, CO2Me), 6.30 (s, 1H, 6-H), 6,62 (dd, J = 8.3 Hz, 12.8 Hz, 2H), 6.96 (t, J = 6.8 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.68 (s, 1H, N-H). 13C-NMR (100 MHz, CDCl3) δ 182.1, 181.7, 169.6, 161.6, 161.3, 146.0, 145.1, 142.7, 140.8, 138.3, 130.9, 130.5, 125.5, 123.4, 120.3, 115.8, 115.7, 102.5, 53.4, 40.9, 26.5, 23.3. HRMS [M + H]+: calculated for C26H23N3O4: 442.1762; found: 442.1761.
Methyl 7-(4-(4-aminophenethyl)phenylamino)-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4 carboxylate (6). m.p. 212–213 °C; IR (KBr) v/cm−1: 3465 (NH), 3368, and 3312 (NH2) 1723 (C=O ester), 1665 (C=O quinone). 1H-NMR (400 MHz, CDCl3) δ 2.64 (s, 3H, 3-Me), 2.87 (m, 4H, CH2CH2), 3.01 (s, 3H, 1-Me), 3.67 (s, 2H, NH2), 4.03 (s, 3H, CO2Me), 6.32 (s, 1H, 6-H), 6.64 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 7.18 (dd, J = 23.1, 8.4 Hz, 4H), 7.28 (s, 1H, NH). 13C-NMR (100 MHz, CDCl3) δ 181.7, 181.4, 169.2, 161.2, 161.0, 145.6, 144.4, 140.5, 137.8, 134.5, 131.3, 129.9, 129.3, 125.1, 122.9, 119.9, 115.3, 102.1, 53.0, 37.7, 36.9, 26.1, 22.9. HRMS [M + H]+: calculated for C27H25N3O4: 456.19181; found: 456.1913.
4-acetyl-7-(4-(4-aminophenethyl)phenylamino)-1,3-dimethylisoquinoline-5,8-dione (7). m.p. 224–225 °C; IR (KBr) v/cm−1: 3339 (NH), 3224, and 3183 (NH2), 1671 (C=O acetyl) and 1612 (C=O quinone), 1H-NMR (400 MHz, CDCl3) δ 2.53 (s, 3H, COMe), 2.56 (s, 3H, 3-Me), 2.85 (m, 4H, CH2CH2), 2.98 (s, 3H, 1-Me), 3.60 (s, 2H, NH2), 6.28 (s, 1H, 6-H), 6.62 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 7.16 (dd, J = 23.8, 8.4 Hz, 4H), 7.72 (s, 1H, NH). 13C-NMR (100 MHz, CDCl3) δ 22.9, 25.9, 31.1, 36.9, 37.7, 101.7, 115.3, 120.0, 123.0, 129.3, 129.9, 131.2, 133.5, 134.4, 137.9, 140.6, 144.5, 145.9, 159.8, 160.4, 181.7, 182.3, 203.8. HRMS [M + H]+: calcd for C27H25N3O3: 440.19689; found:440.1966.
Methyl 7-(4-(4-(1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)benzyl)phenylamino)-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate (10). m.p. 186 °C; IR (KBr) v/cm−1: 3337 (NH), 1720 (C=O ester), 1673 and 1666 (C=O quinone). 1H-NMR (400 MHz, CDCl3) δ 2.61 (s, 3H, 3-Me), 2.99 (s, 3H, 1-Me), 4.00 (s, 5H, CO2Me, CH2), 6.32 (s, 1H, CH), 6.38 (s, 1H, CH), 7.21 (m, 8H, arom), 7.54 (s, 1H, NH), 7.67 (m, 3H, NH, CH), 7.76 (t, J = 8.3 Hz, 1H, CH), 8.11 (t, J = 6.7 Hz, 1H, CH). 13C-NMR (100 MHz, CDCl3) δ 181.5, 181.1, 180.4, 177.0, 173.2, 169.3, 161.7, 162.1, 144.8, 141.3, 139.2, 138.8, 137.1, 135.5, 134.8, 133.3, 132.9, 131.3, 130.7, 130.4, 129.0, 127.7, 127.0, 124.1, 123.4, 102.5, 67.5, 53.3, 39.1, 32.7, 22.1. HRMS [M + H]+: calculated for C36H27N3O6: 598.19729; found: 598.1971.
Methyl 7-(4-(4-(3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)benzyl)phenylamino)-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate (11). m.p. 268–270 °C; IR (KBr) v/cm−1: 3323 (NH), 1719 (C=O ester), 1681 and 1678(C=O quinone), 721 (C-Cl). 1H-NMR (400 MHz, CDCl3) δ 2.61 (s, 3H, 3-Me), 2.99 (s, 3H, 1-Me), 4.00 (s, 3H, CO2Me), 4.01 (m, 2H, CH2), 6.32 (s, 1H, 6-H), 7.03 (d, J = 8.3 Hz, 2H), 7.17 (m, 4H, arom), 7.24 (m, 2H, arom), 7.69 (m, 3H, NH, CH), 7.76 (m, 1H, CH), 8.12 (d, J = 7.5 Hz, 1H, CH), 8.19 (d, J = 7.6 Hz, 1H, CH). 13C-NMR (100 MHz, CDCl3) δ 181.8, 181.5, 180.7, 177.6, 173.7, 169.3, 161.4, 161.1, 145.7, 141.7, 139.3, 138.2, 137.9, 135.9, 135.2, 133.1, 132.8, 131.0, 130.4, 130.0, 129.0, 127.3, 127.2, 124.7, 123.3, 102.4, 66.9, 53.2, 38.9, 32.1, 22,8. HRMS [M + H]+: calculated for C36H26ClN3O6: 632.15831; found:632.1582.
Methyl 7-(4-(4-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)phenethyl)phenylamino)-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate (12). m.p. 263–265 °C; IR (KBr) v/cm−1: 3307 (NH), 1722 (C=O ester), 1679, and 1675 (C=O quinone), 720 (C-Cl). 1H-NMR (400 MHz, CDCl3) δ 2.61 (s, 3H, 3-Me), 2.95 (s, 4H, CH2CH2), 2.99 (s, 3H, 1-Me), 4.00 (s, 3H, CO2Me), 6.29 (s, 1H, 6-H), 7.05 (dd, J = 41.2, 8 Hz, 4H, arom), 7.16 (q, J = 8.5 Hz, 4H, arom), 7.69 (m, 3H, CH, NH), 7.76 (t, J = 7.5 Hz, 1H, CH), 8.11 (d, J = 7.6 Hz, 1H, CH), 8.19 (d, J = 7.6 Hz, 1H, CH). 13C-NMR (100 MHz, CDCl3) δ 181.6, 181.4, 180.6, 177.5, 169.2, 161.2, 160.9, 145.6, 141.2, 139.7, 138.9, 137.8, 135.5, 135.0, 134.8, 132.9, 132.7, 129.9, 129.8, 128.5, 127.1, 126.9, 125.1, 124.5, 123.0, 119.9, 117.2, 114.4, 102.2, 23.0, 26.1, 29.7, 37.2. HRMS [M + H]+: calculated for C37H28ClN3O6: 646.17396; found: 646.1796.
Dimethyl-7,7′-(4,4′-methylenebis(4,1-phenylene)bis(azanediyl)bis(1,3-dimethyl-5,8-dioxo-5,8- dihydroisoquinoline-4-carboxylate) (13). m.p. 199–200 °C; IR (KBr): ν/cm−1: 3446 (NH), 1736 (C=O ester), 1652 and 1647 (C=O quinone). 1H-NMR (CDCl3) δ 2.64 (s, 6H, 3-Me), 3.02 (s, 6H, 1-Me), 4.03 (s, 8H, CH2 and CO2Me), 6.34 (s, 1H, 6-H), 7.26 (m, 8H, arom.), 7.73 (s, 2H, NH). 13C-NMR (100 MHz, CDCl3) δ 181.6, 181.4, 169.1, 161.3, 160.9, 145.5, 138.8, 137.8, 135.2, 130.2, 125.1, 123.2, 119.9, 102.3, 53.0, 40.8, 26.1, 22.93. HRMS [M + H]+: calculated for C39H32N4O8: 685.2293; found: 685.2208.
Dimethyl7,7′-(4,4′-(ethane-1,2-diyl)bis(4,1-phenylene))bis(azanediyl)bis(1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxilate) (14). m.p. 290–293 °C; IR (KBr) v/cm−1: 3315 (NH), 1730 (C=O ester), 1650 and 1649 (C=O quinone). 1H-NMR (400 MHz, CDCl3) δ 2.53 (s, 6H, 3-Me), 2.56 (s, 6H, 1-Me), 2.96 (s, 4H, CH2CH2), 2,99 (s, 6H, CO2Me), 6.28 (s, 2H, 6-H), 7.18 (q, J = 8.5 Hz, 8H, arom), 7.73 (s, 2H, NH). 13C-NMR (100 MHz, CDCl3) δ 203.8, 182.7, 182.1, 160.8, 160.2, 146.4, 140.0, 138.2, 135.3, 133.9, 130.3, 123.6, 120.4, 102.3, 37.4, 31.3, 26.2, 23.2. HRMS [M + H]+: calculated for C40H34N4O8: 699.24496; found: 699.2449.
7,7′-(4,4′-(ethane-1,2-diyl)bis(4,1-phenylene))bis(azanediyl)bis(4-acetyl-1,3-dimethylisoquinoline-5,8-dione) (15). m.p. 245–246 °C; IR (KBr) v/cm−1 3163 (NH), 1693 (C=O acetyl). 1H-NMR (400 MHz, CDCl3) δ 2.52 (s, 6H, COMe), 2.56 (s, 6H, 3-Me), 2.96 (s, 4H, CH2CH2), 2.99 (s, 6H, 1-Me), 6.27 (s, 2H, 6-H), 7.18 (q, J = 8.6 Hz, 8H, arom), 7.74 (s, 2H, NH). 13C-NMR (100 MHz, CDCl3) δ 203.8, 182.3, 181.6, 160.5, 159.8, 145.9, 139.6, 137.8, 134.6, 133.3, 130.0, 123.2, 101.8, 60.4, 37.1, 31.1, 26.0, 23.0. HRMS [M + H]+: calculated for C40H34N4O6: 667.25513; found: 667.2570.

3.3. Electrochemical Measurement

The electrochemical measurements were performed in an electrochemical three electrodes cell. Calomel saturated electrode (SCEsat.) and platinum wire were used as a reference (implementing a Luggin capillary system) and as a counter electrode, respectively. Glassy carbon electrode was used as a working electrode (area: 0.196 cm2, Pine Instrument). The measurements were performed using a bipotentiostat (CH Instrument, CH1720E) in acetonitrile containing 0.1 M tetrabutylammonium perchlorate (TBAP) at room temperature. Before the measurements, the solution was deoxygenated using N2 as purging gas for 15 min.
The half-wave potential (E1/2) of the quinone compounds were characterized by cyclic voltammetry in a potential range from −1.9 or −1.5 to 0.5 V at a scan rate of 0.1 V s−1. The E1/2 was calculated as the average between the anodic and cathodic peak ((Epa+Epc)/2) [59]. In addition, square wave voltammetry (SWV) was carried out (from −1.5 to −0.5 V vs SCE) to corroborate the half-wave potential, using acetonitrile containing 0.1 M tetrabutylammonium perchlorate (TBAP) at room temperature and purging with N2 gas for 15 min (Supplementary Figures S1–S8, Cyclic voltammetry and square wave voltammetry (SWV)).
The number of electrons transferred in the faradaic process (Epa or Epc) was determined by coulometric measurements. The tests were performed at a fixed potential 0.1 V higher than the highest anodic peak determined by cyclic voltammetry for two hours. The number of electrons was calculated considering the total charge (Qnet) and using the Faraday equation that relates the charge to each mole of quinone studied. (Qnet = nFz,) [59] where, n = number of moles of the compound, F = Faraday constant (96.487 C mol−1) and z = number of transferred electrons [59]. The concentration of the compounds was 1 × 10−5 M in a total volume of 10 mL.

4. Conclusions

In conclusion, we have synthesized a series of novel heterodimers containing the cytotoxic 7-phenylaminoisoquinolinequinone and 2-phenylaminonaphthoquinone pharmacophores connected through methylene and ethylene spacers. The access to the target heterodimers and their corresponding monomers was performed both through oxidative amination reactions assisted by ultrasound and CeCl3·7H2O catalysis “in water”. This eco-friendly procedure was successfully extended to the one-pot synthesis of homodimers derived of the 7-phenylaminoisoquinolinequinone pharmacophore. For the mono and dimeric compounds, it was determined that the corresponding first potentials (EI1/2) are reversible while the second potentials (EII1/2) are quasi reversible (∆EII1/2). Furthermore, it was also established that during the oxidation process associated with the potential EI1/2, the net charge consumption for the monomers is close to 10 mC, while for the heterodimers and homodimers is nearly 20 mC. These facts indicate that in the case of homo- and heterodimers two semiquinone anion radical species are simultaneously generated in the same molecule at similar formal EI1/2 potentials (via two-electron).

Supplementary Materials

Supplementary materials are available online. The Cyclic voltammetry and square wave voltammetry (SWV) of compounds 5–7 and 10–12, 14, 15 are available as supporting data.

Author Contributions

J.A.I. proposed the subject and designed the study, J.F. and A.D. carried out the chemical experiments, F.J.R. and C.A.Z. performed electrochemical data analysis, and J.A.V. wrote the article.

Funding

The authors thank Vicerrectoría de Investigación, Desarrollo e Innovación, Universidad de Santiago de Chile. DICYT Project No. 021841IR.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

DDM4:4′-Diaminodiphenylmethane
IRInfrared
2D-NMRBidimensional Nuclear Magnetic Resonance
HRMSHigh Resolution Mass Spectroscopy
SCECalomel Saturated Electrode
TBAPTetrabutylammonium perchlorate
MICMinimal Inhibitory Concentration

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Sample Availability: Samples of the synthesized compounds 5, 6, 13 and 15 are available from the corresponding authors.
Molecules 24 04378 g001 550
Figure 1. Structure of biological active phenylaminoquinones.
Figure 1. Structure of biological active phenylaminoquinones.
Molecules 24 04378 g001
Molecules 24 04378 sch001 550
Scheme 1. Selective access to a monomer and its homodimer containing the nitrogen pharmacophore.
Scheme 1. Selective access to a monomer and its homodimer containing the nitrogen pharmacophore.
Molecules 24 04378 sch001
Molecules 24 04378 g002 550
Figure 2. Precursor of phenylaminoisoquinolinquinone-containing monomers and heterodimers.
Figure 2. Precursor of phenylaminoisoquinolinquinone-containing monomers and heterodimers.
Molecules 24 04378 g002
Molecules 24 04378 sch002 550
Scheme 2. Preparation of hetero- and homodimers from quinones 1, 2, 8, 9 and diamines 3 and 4.
Scheme 2. Preparation of hetero- and homodimers from quinones 1, 2, 8, 9 and diamines 3 and 4.
Molecules 24 04378 sch002
Molecules 24 04378 g003 550
Figure 3. Cyclic voltammetry 100 mV s−1 of (a) monomers 5, 6, 7; (b) heterodimers 10–12; (c) homodimers 14, 15; with a concentration of 0.1 M of the molecules studied in 0.1 M tetrabutylammonium perchlorate (TBAP) in acetonitrile and saturated N2 atmosphere.
Figure 3. Cyclic voltammetry 100 mV s−1 of (a) monomers 5, 6, 7; (b) heterodimers 10–12; (c) homodimers 14, 15; with a concentration of 0.1 M of the molecules studied in 0.1 M tetrabutylammonium perchlorate (TBAP) in acetonitrile and saturated N2 atmosphere.
Molecules 24 04378 g003
Table
Table 1. Electrochemical parameters of compounds 5–7, 10–12, and 14–15.
Table 1. Electrochemical parameters of compounds 5–7, 10–12, and 14–15.
Compound N°Structure−EI1/2 (mV) a−EII1/2 (mV) an b
5 Molecules 24 04378 i00169713181.1
6 Molecules 24 04378 i0026818971.2
7 Molecules 24 04378 i00368811741.2
10 Molecules 24 04378 i004661-2.0
11 Molecules 24 04378 i005580-1.7
12 Molecules 24 04378 i006667-1.9
14 Molecules 24 04378 i007652-1.8
15 Molecules 24 04378 i008689-1.9
a The formal potentials were obtained as E1/2= (EIpa + EIpc)/2. b Number of electrons transferred calculated for the first formal potential (EI1/2).

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Ibacache, J.A.; Valderrama, J.A.; Faúndes, J.; Danimann, A.; Recio, F.J.; Zúñiga, C.A. Green Synthesis and Electrochemical Properties of Mono- and Dimers Derived from Phenylaminoisoquinolinequinones. Molecules 2019, 24, 4378. https://doi.org/10.3390/molecules24234378

AMA Style

Ibacache JA, Valderrama JA, Faúndes J, Danimann A, Recio FJ, Zúñiga CA. Green Synthesis and Electrochemical Properties of Mono- and Dimers Derived from Phenylaminoisoquinolinequinones. Molecules. 2019; 24(23):4378. https://doi.org/10.3390/molecules24234378

Chicago/Turabian Style

Ibacache, Juana Andrea, Jaime A. Valderrama, Judith Faúndes, Alex Danimann, Francisco J. Recio, and César A. Zúñiga. 2019. "Green Synthesis and Electrochemical Properties of Mono- and Dimers Derived from Phenylaminoisoquinolinequinones" Molecules 24, no. 23: 4378. https://doi.org/10.3390/molecules24234378

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