Electrochemical Properties of Biologically Active Heterocyclic Naphthoquinones

Abstracts

A series of natural and synthetic heterocyclic naphthoquinones, some of them with anti-plasmodial and trypanocidal activities, were studied by cyclic voltammetry in aprotic media (DMF/TBAP). In this solvent, the voltammograms of the quinones show two pairs of waves, corresponding to reversible or quasi-reversible one-electron transfer processes to form the semiquinone anion radical (Q<FONT FACE=Symbol>·</FONT>)and the dianion (Q2-). Within the studied series, ortho-quinones undergo reduction easier than isomeric para-quinones. However, para-naphthoquinones fused to an aromatic heterocyclic ring are more easily reduced than the corresponding ortho-naphtoquinones with a non aromatic heterocycle. Substituents effects correlated very well with the first reduction potential (Ep c1) and the half wave potential (E1/2). High yield reductive acetylation was achieved by electrolyses in the presence of acetic anhydride. Comparison of electrochemical data with reported antimalarial activities showed no correlation, differently from the already reported trend in relation to trypanocidal activities.

cyclic voltammetry; quinone reduction; heterocyclic naphthoquinones; substituent effects; biological activities

Uma série de naftoquinonas heterocíclicas naturais e sintéticas, algumas delas com atividades anti-plasmódio e tripanosomicida comprovadas, foi estudada através de voltametria cíclica em meio aprótico (DMF/TBAP). Os voltamogramas apresentaram dois pares de ondas, relativos a processos reversíveis ou quase-reversíveis de transferência monoeletrônicos, formando, no ramo catódico, o ânion-radical semiquinônico (Q<FONT FACE=Symbol>·</FONT>) e, em seguida, o diânion (Q2-). Orto-naftoquinonas sofreram redução mais facilmente do que para-naftoquinonas similares. Para-naftoquinonas fundidas a um heterociclo aromático mostraram-se mais facilmente redutíveis do que orto-naftoquinonas ostentando heterociclos não aromáticos. Efeitos dos substituintes correlacionam-se bem com os valores de potencial de redução de primeira onda (Ep c1) e de potencial de meia onda (E1/2). Eletrólises realizadas em presença de anidrido acético forneceram hidroquinonas acetiladas em alto rendimento. Comparação dos dados eletroquímicos com atividades anti-plasmódio evidenciou ausência de correlação, diferentemente do registrado em relação às atividades tripanosomicidas.

Article

Article

Electrochemical Properties of Biologically Active Heterocyclic Naphthoquinones

Josealdo Tonholo ^a,b , Luciano R. Freitas ^a , Fabiane C. de Abreu ^a , Dayse C. Azevedo ^a , Carlos L. Zani ^c , Alaíde B. de Oliveira ^d , and Marília O. F. Goulart ^a*

^aDepartamento de Química, Centro de Ciências Exatas e Naturais, Universidade Federal de Alagoas, 57072-970 Maceió - Al, Brazil;

^bInstituto de Química de São Carlos, Universidade de São Paulo, Brazil;

^cLaboratório de Química de Produtos Naturais - Centro de Pesquisas René Rachou/ FIOCRUZ. 30190-002 Belo Horizonte - MG, Brazil

^dFaculdade de Farmácia da Universidade Federal de Minas Gerais, 30180-112 Belo Horizonte - MG, Brazil

Received: September 7, 1997

Uma série de naftoquinonas heterocíclicas naturais e sintéticas, algumas delas com atividades anti-plasmódio e tripanosomicida comprovadas, foi estudada através de voltametria cíclica em meio aprótico (DMF/TBAP). Os voltamogramas apresentaram dois pares de ondas, relativos a processos reversíveis ou quase-reversíveis de transferência monoeletrônicos, formando, no ramo catódico, o ânion-radical semiquinônico (Q^·) e, em seguida, o diânion (Q^2-). Orto-naftoquinonas sofreram redução mais facilmente do que para-naftoquinonas similares. Para-naftoquinonas fundidas a um heterociclo aromático mostraram-se mais facilmente redutíveis do que orto-naftoquinonas ostentando heterociclos não aromáticos. Efeitos dos substituintes correlacionam-se bem com os valores de potencial de redução de primeira onda (Ep_c1) e de potencial de meia onda (E_1/2). Eletrólises realizadas em presença de anidrido acético forneceram hidroquinonas acetiladas em alto rendimento. Comparação dos dados eletroquímicos com atividades anti-plasmódio evidenciou ausência de correlação, diferentemente do registrado em relação às atividades tripanosomicidas.

A series of natural and synthetic heterocyclic naphthoquinones, some of them with anti-plasmodial and trypanocidal activities, were studied by cyclic voltammetry in aprotic media (DMF/TBAP). In this solvent, the voltammograms of the quinones show two pairs of waves, corresponding to reversible or quasi-reversible one-electron transfer processes to form the semiquinone anion radical (Q^·)and the dianion (Q^2-). Within the studied series, ortho-quinones undergo reduction easier than isomeric para-quinones. However, para-naphthoquinones fused to an aromatic heterocyclic ring are more easily reduced than the corresponding ortho-naphtoquinones with a non aromatic heterocycle. Substituents effects correlated very well with the first reduction potential (Ep_c1)and the half wave potential (E_1/2). High yield reductive acetylation was achieved by electrolyses in the presence of acetic anhydride. Comparison of electrochemical data with reported antimalarial activities showed no correlation, differently from the already reported trend in relation to trypanocidal activities.

Keywords: cyclic voltammetry, quinone reduction, heterocyclic naphthoquinones, substituent effects, biological activities

Introduction

Several natural and synthetic heterocyclic naphthoquinones have important biological activities such as antitumoral, anti-protozoan and antibiotic^1-9. In cancer chemotherapy, they are considered the second more important group⁸. After an initial bioreduction step, their mode of action normally involves the generation of active oxygen species by redox cycling⁸, intercalation in the DNA double helix¹⁰ or alkylation of biomolecules¹¹. As the bioreduction of quinones is influenced by their redox properties, the understanding of how structural features of the quinones are related to these properties is an important step to comprehend their mechanism of action and predict modifications to improve their biological activity¹².

A plethora of quinones is known, the electrochemistry of which has been widely studied^13,14. There are, however, few reports on electrochemical studies of heterocyclic naphthoquinones^1,13-16. Recently, we observed a contribution of the easiness of reduction on the trypanocidal activity of seventeen synthetic and natural naphthoquinones¹⁷. Correlation between antimalarial activities and redox potential was earlier observed⁹. As the electrochemistry of these quinones have not yet been published, we report here their electrochemical parameters, including Ep_c and E_1/2 values of for their cathodic waves, in aprotic medium, along with results from electrolyses for some of them. We also compare antimalarial activities and electrochemical data. The aprotic medium was chosen because it mimics the hydrophobic cell environment¹⁸.

Experimental

Chemicals

The naphthofuranquinones (NFQ), naphthothiophenquinones (NTQ), naphthodihydropyranquinones (NDQ) used in this work were described elsewhere (1-6¹⁹, 7-12²⁰, 13-14¹⁹ and 15-17^21-22).

Solvents, electrolytes and solutions

N,N-Dimethylformamide (Merck, Uvasol Grade) was treated with cupric sulfate, filtered and distilled at reduced pressure through a glass Vigreux column (12 cm). Tetra-n-butylammonium perchlorate (TBAP) was prepared from the corresponding bromide (Aldrich or Lancaster Synthesis) and perchloric acid 70% (Aldrich). The resulting salt was washed with cold water until neutral pH, recrystallized from ethyl acetate and thoroughly dried before use (2 days, 70 °C, under high vacuum). Test solutions of the quinones (1 mM) were prepared just before electrochemical experiments and the dissolved oxygen eliminated by bubbling the solution with dry nitrogen. During the experiments the cell was covered with aluminum foil to minimize photoreactions.

Electrochemical Measurements

Cyclic voltammetry (CV) was performed using a PAR model 273 A/PAR EG & G potentiostat/galvanostat equipped with an HP 7090A measuring plotter system. The whole system was controlled by a 386 SX/Microtec compatible PC. A SMDE 303 A/EG & G PARC hanging mercury electrode (area 0.009664 cm²) was used as the working electrode, together with a platinum counter-electrode and a home-built Ag/AgCl/NaCl (0.1 M) Luggin reference electrode, isolated from the solution by a Vycor rod. The scan rate was in the range 0.035 - 35 V s^-1.

Reduction

2, 3, 7 and 14, were electrolyzed at a potentiostat-galvanostat 371/PAR EG&G. The current was integrated electronically. Conventional glass cells were used with the anode and cathode compartments separated by medium porosity sintered glass. The electrolyte was pre-electrolyzed at -2.0 V until the background current reached a low steady value.

The following description is typical for electrolyses procedures and methods for work-up and isolation of products. 2-Methylfuran-para-naphthoquinone, 2 (0.0175 g, 0.08 mmol), dissolved in 40 mL of DMF/TBAP (0.1M) was electrolyzed at an Hg pool cathode held at -0.9 V. After consumption of 1 F/mol, the cell current reached residual current. The potential was then increased to the potential of the second wave (-1.6 V). After uptake of an additional 1 F/mol, the cell current was still 50% of the initial one. The decrease of the current turned very slow, and the electrolysis was finished. Addition of water, followed by ether extraction furnished a colorless compound that immediately suffered air oxidation to give back the original quinone. The electrolysis was then, carried out, using quinones 3 (0. O146 g, 0.065 mmol)/7 (0.0216 g, 0.101 mmol) and 14 (0.0205 g, 0.086 mmol) in the presence of freshly distilled acetic anhydride (5 mL) as an electrophile, close to the potential of the second wave (-1.7 V). After reaching the residual current, with exact consumption of 2 F/mol, the acetylated compounds 18, 19 and 20 were obtained, with yields of 100%, 82%, and 94%, respectively.

4,9-Diacetoxy-2-ethylnaphtho[2,3-b]furan ( 18 )

Colorless crystals, m.p. 165-167 °C (CHCl₃); IR KBr/max^(cm-1):1762 (nCO), 1600 (n arom. ring), 1366 (dOCOC),1203, 1164, 1042 (dCO), 765, 735 (n furan). ¹H-NMR (CDCl₃, 400 MHz, d): 1.36 (t, J = 7.5 Hz, 3H, CH₂CH₃), 2.52 (s, 3H, COCH₃), 2.57 (s, 3H, COCH₃), 2.82 (dq, J = 7.5 Hz, J = 1.0 Hz, 2 H, CH₂CH₃), 6.38 (t, J = 1.0 Hz, 1H, furan ring), 7.42-7.52 (m, 2 H, arom. ring) 7.90-7.95 (m, 2H, arom. ring).

¹³C-NMR (CDCl₃, d): 11.3 (Me), 20.6 (Me), 20.8 (Me), 22.0 (CH₂), 98.6 (CH), 120.9 (CH), 121.0 (CH), 123.5 (Cq), 123.6 (Cq), 124.4 (Cq), 124.7 (CH), 125.3 (CH), 126.2 (Cq), 134.5 (Cq), 144.3 (Cq), 164.4 (Cq), 168.3 (CO), 168.8 (CO).

4,9-Diacetoxynaphtho[2,3-b]thiophen ( 19 )

Colorless crystals, m.p. 237 °C IR KBr/max^(cm-1):1752, 1365, 1206, 1163, 1069, 1014, 758. ¹H-NMR (CDCl₃, 400 MHz, d): 2.56 (s, 6H, COCH₃), 7.28 (bs, 1H, thiophen ring), 7.46 (bs, 1H, thiophen ring), 7.52-7.55 (m, 2H, arom. ring), 7.85-7.89 (m, 1H, arom. ring), 7.93-7.97 (m, 1H, arom. ring).¹³C-NMR (CDCl₃, d): 20.7 (Me), 20.7 (Me), 120.2 (CH), 120.6 (CH), 121.6 (CH), 124.5 (Cq), 124.8 (Cq), 125.9 (CH), 126.2 (CH), 128.8 (CH), 130.9 (Cq), 131.9 Cq), 138.4 (Cq), 138.6 (Cq), 168.2 (CO), 169.0 (CO).

4,5-Diacetoxynaphtho[1,2-b]furan ( 20 )

Colorless crystals, m.p. 134-136 °C. IR KBr/max^(cm-1): 1766, 1369, 1206, 1042, 1010, 764, 721. ¹H-NMR (CDCl₃, 400 MHz, d): 1.39 (d, J = 7.1 Hz, 6H, CH(CH₃)₂), 2.41 (s, 3H, COCH₃), 2.46 (s, 3H, COCH₃), 3.17(m, 1H, CHCH₃)₂), 6.38 (s, 1H, furan ring), 7.4-7.51 (m, 1H, arom. ring), 7.53-7.59 51 (m, 1H, arom. ring), 7.84 (d, J = 8.1 Hz, 1H, arom. ring), 8.26 (d, J = 8.1 Hz, 1H, arom. ring). ¹³C-NMR (CDCl₃, d): 20.4 (Me), 20.6 (Me), 21.0 (2 x Me), 28.4 (CH), 98.9 (CH), 119.3 (Cq), 119.8 (Cq), 120.2 (CH), 121.9 (CH), 124.4 (CH), 125.5 (CH), 126.3 (CH), 132.8 (Cq), 133.3 (Cq), 148.2 (Cq), 165.0 (Cq), 167.9 (CO), 168.6 (CO).

Results and Discussions

The cyclic voltammograms of the naphthoquinones in DMF showed two typical waves corresponding to two sequential reversible or quasi-reversible one-electron transfer processes^13,14. The first wave was related to the redox couple quinone (Q) / semiquinone anion radical (Q^·) and the second wave due to the semiquinone anion radical (Q^·) / quinone dianion (Q^2-).

The electrochemical parameters (Ep_c1 and Ep_c2, Ep_a1 and Ep_a2, E_(1/2)1 and E_(1/2)2, DEp_c, for both waves, and Ep_c2-Ep_c1), for seventeen heterocyclic naphthoquinones (Fig. 1) were measured from cyclic voltammograms registered with a scan rate of 0.100 V s^-1. These data are listed in Table 1.

The Ep_c1 of the para-naphthoquinone derivatives 1-12 is in the range -0.76 V 0.87 V while Ep_c2 varies from -1.40 V to -1.48 V (Fig. 2). In the case of the aromatic heterocyclic ortho-naphthoquinones 13 and 14, Ep_c1 and Ep_c2 vary from -0.66 V to -0.71 V and from -1.21 V to -1.29 V, respectively (Fig. 3). The ortho-naphthoquinones with a non aromatic heterocyclic ring (16 and 17) showed their Ep_c1 (-0.80 V and 0.81 V) and Ep_c2 (-1.32 V to -1.38 V)close to those of para-naphthoquinone derivatives. The Ep_c1 and Ep_c2 of the para-derivative 15, -0.90 V and -1.50 V, respectively, are the more negatives among the investigated quinones.

The peak current of the first (Ip_c1) and second reduction waves (Ip_c2) of the studied naphthoquinones are proportional to the square root of the scan rate, indicating diffusion controlled processes. In relation to the first cathodic wave, compounds 2, 3, 5, 8-11, 16 and 17 displayed an almost ideal electrochemical behavior: the separation between anodic and cathodic peak potentials (DEp) is close to that expected for a reversible one electron transfer (59 mV); the peak current ratio (Ip_a1/ Ip_c1) is close to unity and Ep_c1 and E_1/2 are independent of scan rates. These data and the one Faraday/mol consumption measured from electrolysis with quinone 2 (see experimental) are compatible with a reversible monoelectronic reduction wave (Figs. 2 and 3). The other quinones (1, 4, 6, 7, 12-15) showed a slight deviation from the ideal behavior: the DEp values varies from 70 mV to 80 mV and the Ep_c1 and E_a1 are constant only at low scan rates (£ 2.0 V s^-1), changing slightly with the increase of scan rate, as expected for a quasi-reversible process.

Except for 2, 3 and 6, the profiles of the second reduction wave show characteristics of a less reversible monoelectronic processes: besides appearing broader and smaller than the first wave, their current ratios (Ip_a2/Ip_c2) deviated significantly from unity. This fact is more evident for the ortho derivatives, 13 (Fig. 3), 16 and 17, where the corresponding anodic waves are not discernible. This fact is indicative of kinetic or other complications. It is possible that the residual water present in the solvent and reagents could catalyze the disproportionation of the radical anion (Q^·) or be reduced by the electrogenerated dianion (Q^2-)²³.This quasi-reversible character of the second reduction process and the positive shift in Ep_c2 could also be due to ion-pairing stabilization of the quinone dianion (Q^2-) by the tetra-n-butylammonium cation¹⁵.

Except for 6 (DE = 0.588 V), the difference between the two cathodic peaks (Ep_c2-Ep_c1, Table 1) is consistently smaller for the ortho-quinone derivatives (13, 14, 16 and 17) than for the para-quinones. As reported for aromatic dianions²⁴,charges dispersed over a large molecular framework are usually less affected or unaffected by counter ions. On the other hand, the proximity of the two charges in the ortho-naphthoquinone dianions could be more efficiently stabilized by counter-ions (n-Bu₄N⁺Q^2-), causing a positive shift in the second wave. The vicinity of a charge and the nonbonding electrons of the peri-OMe substituent could have a similar effect and explain the intermediate values of Ep_c2-Ep_c1 for the para-quinones 5, 8, 10-12.

Using the Ep_c1 values measured from CV recorded with n = 0.100 V s^-1, the seventeen quinones investigated can be arranged in the following order of easiness of reduction: 13 > 14 > 1 > 2 = 3 > 4 > 7 > 16 = 17 > 6 = 9 > 5 > 8 > 10 > 11 > 12 > 15.

In spite of the possibility of comparison only on a qualitative basis, regular Ep_c1 changes with the constant s of the tethered substituent²⁵ were verified, always with the expected trend²⁶. Thus, the introduction of a methoxy group at C₅ position (peri) of the para-NFQ skeleton (1 ® 5) provoked an Ep_c1 shift of -0.066 V. The same substitution causes a less intense effect (-0.039 V) on the NTQ (7 ® 8), indicating an influence of the heteroatom. Interestingly, a methoxy group at the C₈ (peri) position of NTQ (7® 10) induces a higher shift (-0.054 V). As expected on the basis of substituent constants for methoxy groups (s_p-X = -0.12, s_m-X = 0.10 and s_o-X = -0.39) ²⁵, their attachment to the C₆ position of para-NTQ (7 ® 9) have a smaller influence on the Ep_c1, making the reduction only 0.024 V more negative. This reflects the dominant electrodonating mesomeric effect of the lone electron pair of the methoxy group. Although not additive, possibly due to changes in the molecule’s planarity caused by the steric congestion²⁶, the introduction of a second methoxy group, as in (7 ® 11) and (7 ® 12), does lead to shifts of -0.062 V and -0.078 V, respectively. The location of the methoxy group on the benzenoid ring (C₅vs. C₈, C₆vs. C₇) and different heteroatoms in the attached ring (S or O) seems to influence the naphthoquinone carbonyls and thus Ep_c1, fact already demonstrated by ¹³C-NMR data analysis^19,27.

Introduction of methyl, ethyl and isopropyl groups at C₂ of the para-NFQ skeleton (2 and 3) promoted small cathodic shifts of ca 0.025 V. All the negative increments are consistent with the increase of the negative charge at the reduction site²⁶.

Within the quinones investigated, the ortho-quinones were shown to be more easily reduced than the similar para-quinones, corroborating previous observations with other classes of quinones¹³, in spite of the small number of systematic electrochemical studies comparing ortho- and para- pair of compounds²⁸. By comparing the Ep_c1 and Ep_c2 values of 13 vs. 1, 14 vs. 4, and 16 vs. 15, one observes that the differences are almost constant, around 100 mV and > 140 mV more negative, respectively, for para- derivatives. The larger difference on Ep_c2 is related to higher ortho-Q^2- stability, as already reported. Very recently, Stoppani and coworkers²⁹ concluded, based on the calculated LUMO atomic charges, that electronic asymmetry and polarity of C=O bond are higher in ortho-naphthoquinones than in para-naphthoquinones. These aspects make the carbonyl carbon atom of ortho compounds more electron deficient and, hence, easier to reduce than those in symmetric para-naphthoquinone derivatives. They also observed that in tetrahydronaphthoquinones the eletrophilicity of the carbonyl oxygen was lowered²⁹.Indeed, within the quinones investigated in the present study, the ortho-naphthodihydropyranquinones (16, 17) are more difficult to reduce than para-naphthothiophenquinones and para-naphthofuranquinones, probably due to a smaller ability to stabilize the electrogenerated semiquinone (Q^·) and dianion (Q^2-) via conjugation.

Electrolyses of quinones, in the absence of electrophiles (acetic anhydride), lead, quite regularly to the starting material, by air oxidation. In our case, quinone 2 was recovered, after cathodic reduction, almost quantitatively. In the presence of acetic anhydride, all the reactions occurred smoothly, with exact consumption of 2 F/mol and with high yields, reproducing earlier results³⁰.

It was shown recently that the trypanocidal activity was higher among quinones with more positive reduction potentials¹⁷. Earlier studies suggested a correlation between redox potentials and antimalarial activities⁹. It was also suggested that oxidative stress plays important role in malaria, being both beneficial and pathological³¹. Using the results published in the literature reporting the antiplasmodial activity assays for some of these quinones^5,19 we could see no apparent correlation, ortho- and para-quinones being equally active. This suggests that a different mechanism of drug action³¹, independent of bioreduction is operating, as is the case for chloroquine and other alkaloids³². Among other possible mechanisms, the significant and similar antimalarial activity of ortho- and para-heterocyclic quinones could involve iron chelation³¹.

Conclusions

Ortho-naphthoquinones are always easier to reduce than their para- isomers, reflecting the enhanced electrophylic character of the vicinal carbonyls in the former group. The Q^2- species generated by the reduction of ortho-quinones or peri-OMe substituted para-quinones are better stabilized by cations of the supporting electrolytes. This stabilization results in a positive shift of Ep_c2, turning DEp_c smaller than 0.600 V for these compounds. The heteroatoms (O and S) of heterocyclic naphthoquinones exert different effects over their carbonyl groups and, as consequence, over the carbons in the benzenoid ring. This fact causes different shifts in the reduction potential of quinones depending on the position of the substituent. The positions ortho, meta and para can not be considered similar and the effect is more pronounced when substituents are placed in the peri- position. Electrochemical reductive transformations of quinones in the presence of electrophiles are easily performed and may be useful for synthesis of several quinone derivatives or to protect the reactive carbonyl groups.

No correlation was evidenced between electrochemical parameters of quinones and published antiplasmodial activities. This finding suggests that, at least for the quinones evaluated, redox potential are not related to this biological activity.

Acknowledgments

The authors wish to thank Prof. Délio S. Raslan, Prof. Mariano A. Pereira and Prof. Antônio Ventura for kind gifts of quinones. We acknowledge CNPq, PADCT, FAPEAL, FAPEMIG and CAPES for fellowships and financial support to this work. We also thank Prof. José Dias S. Filho (Department of Chemistry, Universidade Federal de Minas Gerais) for running NMR spectra.

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Publication Dates

• Publication in this collection
  12 Dec 2005
• Date of issue
  Apr 1998