Available online at Bioorganic & Medicinal Chemistry Letters 17 (2007) 6439–6443 Synthesis and anti-inflammatory/antioxidant activities of some new ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives and of their Asuncio´n Burguete,a Eleni Pontiki,b Dimitra Hadjipavlou-Litina,b,* Raquel Villar,a Esther Vicente,a Beatriz Solano,a Saioa Ancizu,a Silvia Pe´rez-Silanes,a aUnidad de Investigacio´n y Desarrollo de Medicamentos, Centro de Investigacio´n en Farmacobiologı´a Aplicada (CIFA), Universidad de Navarra, c/Irunlarrea s/n, 31080 Pamplona, Spain bDepartment of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece Received 7 September 2007; revised 1 October 2007; accepted 1 October 2007 Abstract—We report the synthesis, anti-inflammatory and antioxidant activities of novel ring substituted 3-phenyl-1-(1,4-di-N-oxidequinoxalin-2-yl)-2-propen-1-one derivatives and of their 4,5-dihydro-(1H)-pyrazole analogues. The tested compounds inhibit thecarrageenin-induced rat paw edema (4.5–56.1%) and present important scavenging activities. Compound 2a is the most potent(56.1%) in the in vivo experiment and exhibits promising in vitro inhibition of soybean lipoxygenase (IC50 < 1 lM).
Ó 2007 Elsevier Ltd. All rights reserved.
Quinoxalines, including their fused-ring derivatives, dis- Systemic hypoxia increases reactive oxygen species gen- play diverse pharmacological activities (antiviral, anti- eration and promotes leukocyte-endothelial adherence cancer, and antibacterial).Scientists in Belgium and via reactive oxidant generation. Thus, antioxidants pre- the United Kingdom have found that quinoxaline is a vent the increase in leukocyte-endothelial adhesive inter- potential treatment for HIV infection, and works well actions observed in hypoxia.Bioreductive drugs have with lamivudine, abacavir, and efavirenz.Oxidation been designed to take advantage of the particular meta- of both nitrogens of the quinoxaline ring dramatically bolic characteristics of hypoxic cells.
increased the diversity of certain biological properties,such as antibacterial activitand hypoxia-selective The formation of reactive oxygen species (ROS) is char- anticancer activityMonge et are involved in the acteristic of aerobic organisms that normally defend synthesis and biological evaluation of new agents de- themselves against these highly reactive species using en- rived from quinoxaline 1,4-di-N-oxide and related com- zymes, like superoxide dismutase and glutathione perox- pounds that have proved to be efficient cytotoxic agents idase and naturally occurring antioxidantsROS, like for hypoxic cells in solid tumors. The poor tumor vascu- superoxide radical anion, hydrogen peroxide, and hy- lar structure, the inefficient blood supply along with a droxyl radical, are produced during the inflammation high interstitial pressure generate a variable proportion process by phagocytic leukocytes (e.g., neutrophils, of viable hypoxic cells in solid tumors which is one of monocytes, macrophages, eosinophils) that invade the the causes of cell resistance to anticancer treatments.
tissue. Moreover, these reactive species are involved inthe biosynthesis of prostaglandins and in the cycloxy-genase- and lipoxygenase-mediated conversion of ara- Keywords: Quinoxaline 1,4-di-N-oxide; a,b-Unsaturated ketone; 4,5- chidonic acid into proinflammatory intermedi Persistently high levels of ROS may involve pathological * Corresponding author. Tel.: +30 2310997627; fax: +30 2310997679; conditions, as the active species can modify essentially 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.002 A. Burguete et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6439–6443 biological molecules, such as lipids, proteins, and DNA.
measure of the overall lipophilic/hydrophilic balance It is therefore evident that the treatment of the above- of these molecules. We could attribute this to the differ- mentioned pathophysiological conditions could benefit ent nature of the hydrophilic and lipophilic phases in the from the use of drugs that combine antioxidant and two systems and to the presence of basic nitrogen atoms anti-inflammatory activity, as has already been proven in the examined compounds, which could disturb the for a number of commercially available non-steroidal anti-inflammatory drugs (NSAIDs), for example, tolfe-namic acid which simultaneously possess radical scav- In acute toxicity experiments, the studied compounds did not present in vivo toxic effects at doses up to0.5 mmol/ml/kg body weight. The in vivo anti-inflam- There is increasing evidence from animal models and matory effects of the tested compounds were assessed by using the functional model of carrageenin-induced (LOX) and their products may play a role in tumor for- rat paw edemaand are presented in as per- mation and cancer metastasis.Recently the concept centage inhibition of weight increase at the right hind has been put forward that LOX activation may be in- paw in comparison to the uninjected left hind paw volved in both pro- and anti-tumorigenic effects.Ara- chidonate lipoxygenase pathway appears to play a rolein brain tumor growth as well as inhibition of apoptosis All the tested compounds (dose ip 0.01 mmol/ml/kg in in vitro studies. Emerging reports now indicate alter- body weight), after 3.5 induced protection (ran- ations of arachidonic acid metabolism related to carci- ged from 4.5% to 56.1%) against carrageenin induced nogenesis and many anti-inflammatory drugs are being paw edema while the reference drug indomethacin investigated as potential anticancer drugs.
(IMA) induced 47% protection at an equivalent dose.Compounds 2a and 4a were the most potent (56.1% and So, on the basis of these results, it seemed interesting to 55.4%, and presented almost equipotent effect.
synthesize some novel ring substituted 3-phenyl-1-(1,4- Among derivatives 2a, 2b, and 2c, compound 2a was di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives found to be the most potent followed by 2b and 2c and their 4,5-dihydro-(1H)-pyrazole analogues. Repre- (2b > 2c). The existence of the pyrazolyl ring decreases sentative compounds have been tested, in order to study the biological response (compounds 5a and 5b) whereas their scavenging activities, their role in inflammation, the condensed ring –OCH2O– (compound 3a) is corre- and their inhibition of LOX since LOX inhibitors are lated with a very significant loss in inhibition.
able to induce the anti-carcinogenic and/or to inhibitthe pro-carcinogenic enzymes responsible for polyunsat- Compounds 2a and 4a, the most potent in vivo, as well as compounds 2b, 2c, 3a, 5a, and 5b were further evalu-ated for inhibition of soybean lipoxygenase LOX by the Synthesis of the derivatives 2a–c, 3a–c, and 4a–c () was carried out by a base-catalyzed Clais- oxidize certain fatty acids at specific positions to hydro- en–Schmidt condenestablishing a required peroxides that are the precursors of leukotrienes, which temperature of À10 °C. The synthesis of compounds contain a conjugated triene structure. It is known that 5a–c was carried out by dissolution of derivatives 4a–c soybean lipoxygenase, which converts linoleic to 13- in absolute ethanol and subsequent addition of hydra- hydroperoxylinoleic acid, is inhibited by NSAIDs in a zine hydrate.The starting reagents used (1a–c) were qualitatively similar way to that of the rat mast cell lipoxygenase and may be used in a reliable screen forsuch activity. Perusal of % inhibition values or IC50 val- All the synthesized compoundswere characterized by ues () shows that compound 2a (IC50 < 1 lM) is infrared, proton nuclear magnetic resonance, elemental the most active, within the set, followed by compounds analysis of C, H, and N, and melting point.
Non-steroidal anti-inflammatory drugs (NSAIDs) are Most of the LOX inhibitors are antioxidants or free rad- widely used for the treatment of pain, fever, and inflam- ical scavengers, since lipoxygenation occurs via a carbon- mation. All of the NSAIDs are approximately equiva- centered radical. Although lipophilicity is referredto lent in terms of anti-inflammatory efficacy but also as an important physicochemical property for LOX cause untoward side effects (such as gastrointestinal inhibitors, all the above tested derivatives do not follow ulcers, hemorrhages) in a significant fraction of treated patients and this fact frequently limits therapy. The vari-ations in both efficacy and their tolerability are partly Many non-steroidal anti-inflammatory drugs have been due to differences in their physicochemical properties, reported to act either as inhibitors of free radical pro- which determine their distribution in the body and their duction or as radical scavengers. Compounds with anti- ability to pass through and to enter cells.Thus par- oxidant properties could be expected to offer protection tition coefficients such as RM values are determined in rheumatoid arthritis and inflammation and to lead to experimentallyand compared with the corresponding potentially effective drugs. Thus, we tested the new theoretically calculated clog P in n-octanol-buf- derivatives with regard to their antioxidant ability and fer. From our results () it can be concluded that in comparison to well-known antioxidant agents, for RM values could not be used as a successful relative example, nordihydriguaiaretic acid (NDGA), trolox, A. Burguete et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6439–6443 1b: R7=F
1c: R7=CH O
2c: R7=CH O
4c: R7=CH O
3c: R7=CH O
5a: R7=H
5b: R7=F
5c: R7=CH O
Scheme 1. Reagents and conditions: (a) 3-methoxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde, 3% NaOH/methanol, À10 °C; HCl 35%; (b)benzo[1,3]dioxole-5-carbaldehyde, 3% NaOH/methanol, À10 °C; (c) 3,4,5-trimethoxy-benzaldehyde, 3% NaOH/methanol, À10 °C; (d) NH2NH2,ethanol, rt.
Table 1. Experimentally determined R values and theoretically and caffeic acid. The interaction of the examined com- calculated clog P17 values; inhibition% of induced carrageenin rat paw pounds with the stable free radical DPPH was studied edema (CPE%) at 0.01 mmol/ml/kg; in vitro inhibition of soybean by the use of the stable 1,1-diphenyl-2-picrylhydrazyl radical DPPH at 0.05 and 0.1 mM after 20 and 60 min ). This interaction indicates their radical scav- enging ability in an iron-free system. Compounds 2b and 2c interact with DPPH in a concentration and timedependent manner, whereas compounds 2a, 3a, and 4a do not present any interaction at 0.05 mM. Slight differ- ences are observed between the compounds 2c and 5b with the time and the concentration whereas compound 2a presents reducing ability at 0.1 mM. The presence of the condensed ring –OCH2O– (compound 3a) dimin- ishes the reducing activity. Preliminary QSAstudies on the values of DPPH interaction have shown that the molar refractivity (MR) of substituents R7 plays a sig- nificant role. Molar refractivity (MR) is related not only to the volume of the substituents but also to the London dispersive forces. Thus, high molar refractivity values of substituent R7– (MR for R7–OCH3 = 0.78, MR for R7– RM values are the average of at least 10 measurements; each experi- H = 0.103, and MR for R7–F = 0.092) affect the reduc- ment was performed at least in triplicate and the standard deviation ing ability. No role for lipophilicity is defined.
of absorbance was less than 10% of the mean.
b Theoretically calculated values of lipophilicity.
c Statistical studies were done with Student’s t-test, *p < 0.01, The insertion of a pyrazolyl ring (compounds 5a and 5b) increases the reducing ability. The R7 = –F substitution A. Burguete et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6439–6443 Table 2. Interaction % with DPPH at 0.05 mM and at 0.1 mM Competition % with DMSO for hydroxyl radical (HOÅ %); superoxide radical scavenging activity (PMS %).
No, no result under the experimental conditions; NDGA, nordihydroguaiaretic acid; CA acid, caffeic acid; each experiment was performed at least intriplicate and the standard deviation of absorbance was less than 10% of the mean.
in compound 5b is correlated with an increase compared Further investigation is in progress to delineate the to compound 5a. Further investigations are in progress physicochemical properties implicated in the in vivo re- in order to have a detailed structure–activity relation- sponse. Regression analysis was performed to discover ship study on their interaction with DPPH.
whether any correlation existed between anti-inflamma-tory activity and several physicochemical parameters It is consistent that rates of reactive oxygen species (lipophilicity, steric and electronic variables). Unfortu- nately the confidence limits were found to be poor.
mainly due to their transformation into ÅOH, reactive For the in vivo results the following equation was radical metal complexes, and 1O2. During the inflamma- tory process, phagocytes generate the superoxide anion log %ðCPEÞ ¼ À1:312ðÆ0:797ÞclogP þ 1:902ðÆ0:367Þ radical at the inflamed site and this is connected to otheroxidizing species as ÅOH. Hydroxyl radicals are among the most reactive oxygen species and are considered to be responsible for some of the tissue damage occurring in inflammation. It has been claimed that hydroxyl rad-ical scavengers could serve as protectors, thus increasing Hydrophilicity (lipophilicity with negative sign) is the most significant parameter. Compound 5b, the morelipophilic, is not included in the regression. This fact The competition of compounds with dimethylsulfoxide proceeds in parallel to the observation that low lipophil- (DMSO) for OH radicals,generated by the Fe3+/ icity is highly involved to the biological response. At- ascorbic acid system, expressed as the inhibition of tempts to correlate the in vivo/in vitro expressions of formaldehyde production, was used for the evaluation of their hydroxyl radical scavenging activity. All the M values in a linear or non-linear regres- sion analysis gave statistically non-significant correla- tested derivatives show high inhibition of DMSO tions. Unfortunately the number of compounds is not (33 mM) oxidation at 0.1 mM Lipophilicity enough to calculate a combination of all the effects.
is not well correlated with the results. Antioxidantsof hydrophilic or lipophilic character are both neededto act as radical scavengers in the aqueous phase The authors are grateful to Drs. C. Hansch and A. Leoand to Biobyte Corp. for the free access to the C-QSAR Non-enzymatic superoxide anion radicals were gener- program. A. Burguete was awarded a Ph.D. fellowship The superoxide producing system was set up by supported by the ‘‘Gobierno de Navarra’’.
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