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Novel Quinolylnitrones Combining Neuroprotective and Antioxidant Properties Mourad Chioua, Manuel Salgado-Ramos, Daniel Diez-Iriepa, Alejandro Escobar-Peso, Isabel Iriepa, Dimitra Hadjipavlou-Litina, Emma Martínez-Alonso, Alberto Alcazar, and José Marco-Contelles ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.9b00152 • Publication Date (Web): 03 Apr 2019 Downloaded from http://pubs.acs.org on April 4, 2019

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ACS Chemical Neuroscience

Novel Quinolylnitrones Combining Neuroprotective and Antioxidant Properties

Mourad Chioua,† Manuel Salgado-Ramos,†,∫,♯ Daniel Diez-Iriepa,†,♯ Alejandro EscobarPeso,†,∫, ♯ Isabel Iriepa,∞ Dimitra Hadjipavlou-Litina,≠ Emma Martínez-Alonso,∫ Alberto Alcázar,∫,* and José Marco-Contelles†,* † Institute

of General Organic Chemistry (CSIC), Juan de la Cierva 3, Madrid 28006,

Spain ∫ Department of Investigation, Hospital Ramón y Cajal, IRYCIS, Madrid 28034, Spain ≠ Department of Pharmaceutical Chemistry, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece ∞ School of Pharmacy, University of Alcalá, Alcalá de Henares 28871, Spain ♯ These

authors have equally contributed to this work

ABSTRACT: We describe here the preparation, neuroprotective and antioxidant capacity of eleven novel quinolylnitrones (QN). The neuroprotective analysis of QN111 in an OGD model, in primary neuronal cultures, has been determined, allowing us to identify QN6 as a very potent neuroprotective agent, showing significant high value at 0.5 and 10 µM (86.2%), a result in good agreement with the observed strong hydroxyl radical scavenger of QN6.

KEYWORDS: Antioxidants; cerebral ischemia; neuroprotection; quinolylnitrones; synthesis

free

radical

scavengers;

1 ACS Paragon Plus Environment

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Reactive oxygen species (ROS) exert their physical functions at low to moderate concentrations, but at high concentrations they become toxic for the living systems, resulting in oxidative stress (OS).1 Particularly, unsaturated long-chain natural acids react with ROS at allylic positions giving lipid hydroperoxides, which are extremely reactive, and in the presence of Fe salts are transformed into new free radicals affecting membranes, and other biological systems, leading finally to neuronal death.2 Nowadays it is widely accepted that OS is one of the main contributing factors to many pathologies, among others, cerebral ischemia (CI).3 Consequently, current research efforts for CI therapy are targeted to the search for novel, more effective radical trapping and antioxidant agents.2 In this context, in the precedent years, our laboratories have been particularly active in this field, as we have investigated the application of novel nitrones4 for CI therapy.5-7 Among them, of particular interest have been the cholesteronitrones,7 and the quinolylnitrones (QN), such as RP19 (Figure 1), a QN which, alone or in a cocktail of drugs with recombinant plasminogen activator rtPA, has been launched in ongoing project for pre-clinical targeted CI therapy. However, while these developments are still in progress,8 we wanted to confirm that our initial choice for QNs bearing the N-alkyl nitrone motif located at C3, in the ring B, and the chloro atom at C2, such as in RP19, was the correct one in terms of antioxidant and neuroprotective capacities. Although this selection was mainly based on the rich, well known chemistry and commercial availability of the diversely substituted 2-chloroquinoline-3-carbaldehydes, other analogous quinoline carbaldehydes, devoid of chloro atoms at C2, are also similarly available. Thus, here we describe the antioxidantneuroprotection capacities of the eleven QNs 1-11 (Figure 1), designed as the N-methyl


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nitrones bearing the nitrone motif at C2, C3, and C4 (1 [23], 2 [24], 3), the N-t-butyl nitrones bearing the nitrone motif at C2, C3, C4 and C6 (6, 7, 2 [25], 4, 5), and the Nbenzyl nitrones bearing the nitrone motif at C2, C3, C4 and C6 (8-11). From these results we have identified QN6 as a very potent neuroprotective agent, showing significant values at 0.5 and 10 µM, and a quite high ability to scavenge hydroxyl radicals.

O

A

B N

N 3 Cl

RP19

4 N C2: 1 C3: 2 C4: 3

O 3 N Me 2

4

O 3 N

N

2

6 C2: 4 C3: 5 C4: 6 C6: 7

4

O 3 N

N

2

6 C2: 8 C3: 9 C4: 10 C6: 11

Figure 1. Structures of QN RP19, and the QNs 1-11, investigated in this work.

(Z)-QNs 1–11 were synthesized according to the procedures used in our laboratory, starting from the commercial and appropriate quinoline carbaldehyde with the respective N-alkyl hydroxylamine.5,6 Spectroscopic and analytical values are those expected according to the previously described for QN1,9 QN2,10 and QN411 (see Supporting Information). The neuroprotective effect of the standard compounds and QNs 1-11 was evaluated in primary neuronal cultures by a cell viability test, adding the compounds at the start of the reoxygenation period at term of oxygen-glucose deprivation (OGD) 3 ACS Paragon Plus Environment


conditions, and determined by the MTT assay. Exposure of neuronal cultures to 4 h OGD (OGD 4h) induced a significant decrease in cell viability (65.4%), which was partially reversed after 24 h-long recovery period (reoxygenation, R24h, 77.5%, p < 0.0001, by t test), but without reaching the 100%. Citicoline,12 PBN and RP19,6 were used as reference compounds. Citicoline was assayed at 10 and 100 µM, showing higher cell viability values than R24h group. Therefore, neuroprotective effect (79.9 and 82.3%, respectively). In contrast, PBN proved not to be neuroprotective in the range 0.1-10 mM, whereas RP19 significantly increased cell viability values when added at 10 and 50 µM (89.8 and 90.1%, respectively).

100

**

* *

+ Cell viability (MTT %)

75

50

25

0 Con OG trol D R244h h 10 100 100 50 1000 50 0 10000 00 10 50 0.5 1.0 10 100 250 0.5 1.0 10 100 250 500 0.5 1.0 10 100 250 500 0.3 1.0 10 100 250 0.3 1.0 10 100 250 500 0.1 0.5 1.0 10 100 250 1.0 5.0 1 100 0 250 500 100 0 0.3 1.0 10 100 250 0.3 1.0 10 100 250 0.3 1.0 10 100 250 0.5 1.0 1 100 0 250 500

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Citicoline PBN

RP19

1

2

3

4

5

6

7

8

9

10

11

Figure 2. Neuroprotective effect of QNs 1-11 on neuronal cultures after experimental ischemia. Primary neuronal cultures were exposed to oxygen−glucose deprivation (OGD) for 4 h to induce experimental ischemia and after recovered in normoxic conditions and then treated with different concentrations (M) of citicoline, PBN, RP19 or QNs 1-11. Cell viability (%) was performed at 24 h of recovery after OGD and the results showed in the bar chart. Data are expressed in percentage with respect to the control cell value (1.895  0.09 AU), which was considered as 100%. The values are the mean of four to eight independent experiments; error bars representing the SE. *p < 0.05, and **p < 0.01 compared with untreated cell (R24h) (red line) by Dunnett’s post-test after ANOVA, when it was significant. +p < 0.05 citicoline value (black line) compared with R24h by Dunnett’s test. Statistical significances below R24h value were not shown.


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Based on previous experience by our group QNs 1-11 were added at doses from 0.1 µM to 500 µM. As can be seen in Figure 2, higher cell viability than for the untreated R24h group was afforded in several cases, even though only a few of them reach or exceed the value obtained for the reference compound citicoline (grey bar, black line) at specific concentrations. Also, some of the nitrones tested showed low cell viabilities, sometimes lower than the OGD4h at certain concentrations, usually when it was higher than 250 µM. This toxic effect is also observed for QNs 1, 9 and 10 for the whole range tested and therefore, they were not considered for further studies. Similarly, QNs 2, 8 and 11, only showed higher cell viabilities than R24h group for a small range of concentrations, with comparable values to citicoline; therefore, less interesting for neuroprotection. For those QNs showing better cell viability results for wider intervals of concentration, only QNs 3-6 afforded higher cell viability than citicoline at some of the concentrations tested. Among them, QNs 3 and 6 exert remarkably high neuroprotective effect. For QN3, its best neuroprotection value was 10 μM (86.1%) but it did not achieve statistical significance with the experiments performed. However, QN6 had a neuroprotective range of 0.5 to 10 μM, being the neuroprotection significant at 0.5 and 10 μM (87.4 and 86.2%, respectively). Regarding the QNs tested for their neuroprotection, the most potent neuroprotective QN6 bears a N-t-butyl motif in a nitrone located at position C4 at the quinoline ring. Next, and based on these results, we tested the antioxidant potential of QN6 in order to find an explanation and possible correlation between its neuroprotection capacity and its presumed ability to scavenge ROS and which type of them.13



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Table 1. Antioxidant activity of QNs 1-11, and standards Trolox and NDGA. QNs/ Stand.

ClogP

AAPH inhibition (%) ± SD*

LOX inhibition (% or IC50 [μM]) ± SD*

Scav. activity for •OH (%) ± SD*

1

0.45

100 ± 2.3

72.5 ± 1.7

No

2

0.78

55 ± 0.4

44 ± 0.2

No

3

0.78

52 ± 0.8

100 ± 1.6

No

4

2.36

77 ± 1.8

35.5 ± 0.8

No

5

2.01

48 ± 0.6

100 ± 2.3

No

6

2.01

55 ± 1.1

100 ± 1.8

62 ± 1.5

7

1.79

45 ± 0.6

100 ± 0.6

No

8

2.90

41 ± 0.8

24% #

No

9

2.55

59 ± 0.2

38% #

97 ± 2.8

10

2.55

64 ± 1.0

100 ± 0.8

No

11

2.32

51 ± 0.6

No

62 ± 0.9

NDGA

Nd

Nd

0.5 ± 0.1 (93%)

Nd

Trolox

nd

88 ± 1.8

Nd

73 ± 0.7

* Values represent the average of three to four experiments. Nd: Not determined. No: no activity. #, for these compounds the IC50 values were not possible to be determined. Nitrones tested at 100 μM. NDGA, nordihydroguaiaretic acid. These

assays

comprised

the

use

of

2,2′-azobis(2-amidinopropane)

dihydrochloride (AAPH) as lipid peroxidation promotor,14 lipoxygenase (LOX), as the key enzyme in leukotriene biosynthesis,15 and the hydroxyl radical (•OH) test.5 Thus, we examined the effect of QN6 at 100 M concentration on lipid peroxidation induced by the water soluble azo compound AAPH, using Trolox as standard (88%), showing a 55% value (Table 1). As shown, the significant ClogP value determined for QN6 (2.01, Table 1) support its good anti-lipid peroxidation activity. Lipoxygenase (LOX) is the key enzyme in leukotriene biosynthesis.15 Test of LOX inhibition was carried out by the 6 ACS Paragon Plus Environment

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UV absorbance-based enzyme assay,5 at a dose of 100 μM, QN6 showed inhibition (IC50 value, Table 1) although far from NDGA value. Finally, in the •OH free radical QN6 showed 62% activity at 100 μM, comparing very well with the value shown for Trolox (73%, Table 1). To sum up, from the antioxidant analysis results, we conclude that QN6 was particularly active in the hydroxyl and peroxyl radical scavenging, preventing lipid peroxidation, thus the high neuroprotective capacity of QN6 could be presumably linked to its demonstrated capacity to scavenge this type of ROS. Similar antioxidant protocols have been investigated for QNs 1-5, 7-11. As shown in Table 1, among the QNs 1–5, 7-11, values ranging from 41% to 100% have been measured (Table 1), the highest anti-lipid peroxidation were presented by QN1 (100%) and QN4 (77%), followed by nitrones 10 (64%) and 9 (59%). QNs 4, 9 and 10 with the higher lipophilicity values as ClogP exhibit higher anti-lipid peroxidation activities within the series. At 100 μM dose QNs 8 and 9 showed poor inhibition expressed as % (24 and 38) compared with NDGA (93%) used as standard. However, nitrones QN4 (IC50 = 35.5 M), QN2 (IC50 = 44 M), and QN1 (IC50 = 72.5 M) are the most potent, followed by QNs 3, 5, 7 and 10 which present equipotent inhibition values IC50 = 100 µM (Table 1). Most of the LOX inhibitors are antioxidants or free radical scavengers, since lipoxygenation occurs via a carbon-centered radical. Thus, herein, it seems that the lipoxygenase inhibition is correlated to the antioxidant activity of the tested nitrones. In the •OH free radical experiment, the majority of the tested QNs showed no activity at 100 μM. However, QNs 9, and 11 gave 97%, and 62% values, respectively; hence QN9 was more potent than Trolox (73%) (Table 1). To sum up, from the antioxidant analysis results, we can conclude that: (a) QNs 1-5, 7-11 showed from moderate to high (45-100%) radical scavenging activity in the AAPH test. The 7 ACS Paragon Plus Environment


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most potent were QNs 4 (77%), 10 (64%), and 9 (59%), showing lower values than Trolox (88%). (b) QNs 1-5, 7-11 showed from poor to significant activity as LOX inhibitors; the most potent was QN4 (35.5 M), showing a value lower than NDGA (0.5 M). (c) Most of the QNs 1-5, 7-11 showed no radical scavenging activity in the hydroxyl radical test; the most potent was QN9 (97%).

O N

t-Bu N O

H

OH N

O NH

4 N QN6

ROS

N ROS I

N ROS

N ROS II

Scheme 1. One of the tentative reaction paths of ROS with QN6.

In order to explain the QN6 behaviour, something special and particular should take place in QN6 rendering it the most interesting nitrone, and comparatively better than the other QNs described here as well as our previously reported hit-nitrone RP19. Indeed, as shown in scheme 1, we can hypothesize that in QN6 should take place an irreversible Michael type addition of ROS to N1 leading to a very stable quinonoid-type nitroxide radical I, that would possible evolve to radical species II, by elimination of isobutene. In fact, among the most interesting QNs investigated here, 4, 6, 9, 10 and 11, in two of them, QNs 6 and 10, the nitrone is located at C4, bearing a t-Bu and Bn groups, respectively, at the nitrogen on the nitrone. QN4 bears the nitrone motif at C2, where a similar mechanism as the one depicted for QN6 can take place in scheme 1, but involving a more sterically hindered radical nucleophilic attack, and affording a nonquinonoid-type radical intermediate shown for QN6. Finally, the easy and favored 1,5H radical migration in QN6, compared with the similar 1,4-H radical migration in 8 ACS Paragon Plus Environment

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QN10, would explain the observed results, and account for the better neuroprotective effect of QN6. We assume that this is a very simple approach to explain a very complex reactivity, and therefore deeper studies are required. These, along with new efforts to design and synthesize new QNs showing new antioxidant and biological properties, widening the current approach, coupled to computational chemistry analysis, are being pursued in our laboratory to achieve these goals. To sum up, QNs 1-11, bearing diverse N-alkyl groups at the nitrone motif, such as methyl, t-butyl and benzyl, at different positions in the quinoline ring, from C2, C3, C4 and C6, have been submitted to three different antioxidant tests to analyze their radical scavenging radical activity, concluding that only QNs 4 (APPH, LOX inhibition), 6 (•OH radical trap), 9 (APPH, •OH radical trap), 10 (APPH), and 11 (•OH radical trap), showed significant activity in some tests. Regarding QNs 4 and 9 they were active in two of those tests, which means from the antioxidant point of view the Nt-butyl and N-benzyl motifs are preferred in nitrones to be located at positions C2 or C3 of the quinoline ring. Finally, when comparing the entire set of evaluated compounds, QN6 was the only that showed scavenging activity against all the studied radicals, although with moderate LOX value, together with a good lipophilicity (ClogP, 2.01). Therefore, we conclude that our original choice for RP19 was correct. Among the new QNs 1-11, QN6, bearing a N-t-butyl group at the nitrone located at C4 at the quinoline ring, is a new promising hit-QN for further investigation looking for more efficient stroke therapy.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the



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ACS Publications website at DOI: Synthesis of nitrones QNs 1-11; NMR spectra of nitrones QNs 1-11; neuroprotection and antioxidant activity tests methods AUTHOR INFORMATION Corresponding Authors Alberto Alcázar Dept. Investigation, IRYCIS, Hospital Ramón y Cajal, Ctra. Colmenar km 9.1, Madrid 28034, Spain. E-mail: [email protected] José Marco-Contelles Institute of General Organic Chemistry (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain. E-mail: [email protected] ORCID Alberto Alcázar 0000-0002-7904-481X José Marco-Contelles 0000-0003-0690-0328 Author Contributions M.C, M.S.-R., D.D.-I., A.E.-P. and I.I. carried out the synthesis of the QNs; D. H.-L. performed the antioxidant tests; E. M.-A., M.S.-R and A.E-P. performed the neuroprotection analysis; A, A. and J. M.-C. coordinated the project, wrote and corrected the manuscript.

Acknowledgements This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65586-R) to J.M.C., and the Instituto de Salud Carlos III and cofinancing by the European Development Regional Fund (FEDER) (PI14/00705, PI18/0255 and RETICS RD16/0019/0006) to A.A., who thanks M. Gómez-Calcerrada for technical assistance. Notes The authors declare no competing financial interest. ABBREVIATIONS USED AAPH, 2,2′-azobis(2-amidinopropane) dihydrochloride; BBB, blood−brain barrier; LOX, lipoxygenase; LP, lipid peroxidation; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide; NDGA, Nordihydroguaiaretic acid; OGD, oxygen glucose deprivation.

REFERENCES 10 ACS Paragon Plus Environment

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Graphical Abstract

O

N RP19

N

N

O

N

Cl

QN 6

QN 6 is a very potent neuroprotective agent, showing significant value at 10 µM (86.2%), data which compare very well for the obtained for our standard compound RP19 (89.8%), a trend that has its support in the quite high ability of QN6 to scavenge OH radicals (62%).


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