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Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen
Journal of Saudi Chemical Society (2012) xxx, xxx–xxx
King Saud University
Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com
ORIGINAL ARTICLE
Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen Waseem Ahmad, Mohd. Rehan Zaheer, Anamika Gupta *, Jawaid Iqbal Department of Chemistry, Aligarh Muslim University, Aligarh 202002, UP, India Received 19 May 2012; accepted 10 July 2012
KEYWORDS Trimeprazine; Phenothiazine; Singlet oxygen; Phototoxicity
Abstract The antihistaminic drug trimeprazine (1, also known as alimemazine) is photolabile under UV-A light in aerobic conditions. Irradiation of a methanol solution of trimeprazine produces two photoproducts which were isolated as N,N2-trimethyl-3-(10H-phenothiazin-10-yl sulfoxide) propan-1-amine (2) and N,2-dimethyl-3-(10H-phenothiazin-10-yl) propan-1-amine (4). The formation of products was explained by the oxidative photodegradation of trimeprazine in an irreversible trapping of the self-photogenerated 1O2 by the type II photodynamic action of the drug. The generation of singlet oxygen during photolysis of trimeprazine was confirmed by singlet oxygen scavenger 2,5-dimethylfuran (2,5-DMF). ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction Recently, much attention has turned to the problem of biological photosensitization by drugs. Indeed, despite their excellent therapeutic activity, many drugs can induce phototoxic, photoallergic and photomutagenic phenomena, strictly related to the drug’s photochemical reactivity (Sortino et al., 2003) Photosensitization reactions leading to phototoxicity are generally considered as belonging to either the type I (radical mediated) or type II (singlet oxygen mediated) (Cosa, 2004; Ouedraogo and Redmond, 2003). There are photosensitizing drugs of varied structural variety and significant variations in the phototoxic mechanisms must be expected depending on the difference * Corresponding author. Tel.: +91 9058970731. E-mail address: [email protected] (A. Gupta). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
in structural features. The variety and number of phototoxic drugs is large and a relationship between structure and the mechanism of chemical reaction that causes the in vivo phototoxicity is not available (Vargas and Rivas, 1996) and it is therefore necessary to investigate the photochemistry of every photosensitizing drug. Phenothiazine derivatives have found a large variety of applications as dyes, antioxidants, and drugs. Accordingly, the antihistaminic and neuroleptic properties of some phenothiazine derivatives are well-known (Asghar and Khan, 2008; Elisei et al., 2002). Moreover, given the phototoxicity of these drugs (Onoue and Tsuda,2006; Miolo et al., 2006) a large number of investigations on the photochemical properties of these substances have been carried out. Several reports also indicate that irradiation of phenothiazines can produce singlet oxygen (Tranchin et al., 1998) but, surprisingly, very few studies have dealt with the chemical reactivity of 1O2 with the phenothiazines themselves. Trimeprazine (also known as Alimemazine) is a tricyclic Phenothiazine derivative (Lutka and Koziara, 2000). It is in the same class of drugs as chlorpromazine (Thorazine)
1319-6103 ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jscs.2012.07.016
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
2
W. Ahmad et al. Table 1 Effect of triplet energies of different sensitizers on the yields of products.
Scheme 1 trimeprazine.
Oxidative
Photodegradation
products
Sensitizer
Triplet energy (kcal /mole)
Yields of product (%) (2 + 4)
Methylene blue Rose bengal Riboflavin Benzophenone
33.5–34.0 39.2–42.2 57.8 68.6–69.1
60.9 59.5 50.4 49.1
(34.3 + 26.6) (32.3 + 27.2) (26.5 + 23.9) (25.1 + 24.0)
of
and trifluoperazine (Stelazine); however, unlike the other drugs in this class, trimeprazine is not used clinically as an anti-psychotic. It acts as anti-histamine, a sedative, and an anti-emetic (anti-nausea) (Bello, 2011). Interest in the photo reactivity of trimeprazine arises from the clinical and pharmacological reports of phototoxic effects demonstrated by this drug (Mio et al., 1999; Quintero and Miranda, 2000). In pursuance of our interest in the photochemical reactions involved in the phototoxicity of the photosensitizing drugs and their mechanisms, herein we have examined the photo behaviour of the antihistaminic drug trimeprazine (a phenothiazine derivative) under aerobic condition. Photolysis of trimeprazine (1) in the presence of oxygen resulted in the formation of two photodegradation products, identified as 2 and 4 from their spectral (IR, 1H NMR, 13C NMR, mass spectra) properties (Scheme 1). The products are formed by oxidative photodegradation of trimeprazine in an irreversible trapping of the self-photogenerated 1O2 in the type II photodynamic action of the drug. 2. Experimental 2.1. Apparatus and chemicals All chemicals used were of analytical grade. Pure Trimeprazine was obtained from Sigma Aldrich (India), IR spectra were recorded as KBr discs on a Perkin Elmer model spectrum RXI. 1 H NMR and 13C NMR Spectra were recorded on a Bruker Avance-DRX-300 Spectrometer using TMS as internal standard and CD3OD as solvent. High resolution mass spectra were determined with a VG-ZAB-BEQ9 spectrometer at 70 eV ionization voltage. Merck silica gel 60 F254 plates were used for analytical TLC; column chromatography was performed on Merck silica gel 60 (60–120 mesh). 2.2. Photoirradiation procedure A solution of Trimeprazine (275 mg, 0.7 mM) in methanol (400 ml) under aerobic condition was irradiated for 1 h in a Rayonet photochemical reactor (The Southern New England Ultraviolet Co; Model RPR-208 equipped with four RUL350 nm fluorescence lamps) for the complete conversion of reactant. Progress of the reaction was monitored by thin layer chromatography (chloroform–methanol, 98:2). At the end of the reaction formation of two major photoproducts were indicated on TLC and photoproducts were isolated by eluting with dichloromethane–ethyl ether (1:1, v/v) on a silica column. The photoproducts were identified as, N,N2-trimethyl-3-(10Hphenothiazin-10-yl sulfoxide) propan-1-amine (2) and N,2-di-
methyl-3-(10H-phenothiazin-10-yl) propan-1-amine ( 4) from the following spectral properties: 2.3. N,N2-trimethyl-3-(10H-phenothiazin-10-yl sulfoxide) propan-1-amine (2) Yield: 95 mg (34.5%); HRMS calcd. for (M+) C18H22N2OS 314.1453. Found 314.1448; IR (KBr, cm 1): 3416, 2965, 1388, 1301, 1270, 1209, 1055 (SO), 978, 763. 1H NMR (CD3OD, 300 MHz): d 7.12–6.9 (m, 8 H, arom), 4.60 (d, J = 7.3 Hz, 2 H, H-15), 2.32 (s, 6 H, H-19, H-20), 2.27 (d, J = 7.4 Hz, 2 H, H-17), 2.13 (m, 1 H, H-16), 1.02 (d, J = 6.0 Hz, 3 H, H-21) ppm. 13C NMR (CD3OD, 300 MHz): 145.1, 131.0, 128.6, 119.3, 118.2, 62.2, 55.3, 36.1, 32.1 16.0 ppm. MS: m/z: 314 (M+), 298 (M+ 16), 214 (M+ 100). 2.4. N,2-dimethyl-3-(10H-phenothiazin-10-yl) propan-1-amine (4) Yield: 75 mg (27.2%); HRMS calcd. for (M+) C17H20N2S 284.4191. Found 284.4185; IR (KBr, cm 1): 1388, 1301, 1270, 1209, 978, 763. 1H NMR (CD3OD, 300 MHz): d 7.12–6.9 (m, 8H, arom), 4.50 (d, J = 7.3 Hz, 2 H, H-15), 2.38 (s, 3 H, H19), 2.26 (d, J = 7.4 Hz, 2 H, H-17), 2.14 (m, 1 H, H-16), 1.02 (d, J = 6.0 Hz, 3 H, H-20) ppm. 13C NMR (CD3OD, 300 MHz): d 145.2, 131.1, 128.7, 119.4, 118.3, 62.3, 55.4, 36.2, 32.2, 15.9 ppm. MS: m/z: 284 (M+), 198 (M+ 86). 2.5. Singlet oxygen detection In order to confirm the role of singlet oxygen 1O2 as a trigger of trimeprazine (TMPZ) photodecomposition, photolysis was performed under the same experimental condition but now in the presence of 2,5-dimethylfuran (2,5-DMF) which is normally used as a trap for singlet oxygen (1O2) (Gollnick and Griesbeck, 1983). Similar experiment was also carried out by using different sensitizers such as methylene blue, rose bengal, riboflavin, and benzophenone to study the effect of triplet energy of sensitizer on the percentage yields of products (Table 1).
3. Results and discussion The two major photoproducts, N,N2-trimethyl-3-(10H-phenothiazin-10-yl sulfoxide) propan-1-amine (2) and N,2-dimethyl3-(10H-phenothiazin-10-yl) propan-1-amine (4), which were obtained on irradiation of trimeprazine in methanol under oxygen atmosphere, are depicted in Scheme 1.
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
Photodegradation of trimeprazine triggeredby self-photogenerated singlet molecular oxygen
Scheme 2
3
Mechanistic pathway of oxidative photodegradation of trimeprazine.
Their formation has been rationalized in the photosensitized generation of singlet oxygen by the type II photodynamic action of the drug and subsequent quenching of the generated singlet oxygen by the drug as proposed in Scheme 2. Photoproduct 2 is formed by simple sulfoxidation of parent compound and photoproduct 4 is formed through a mechanism in which a charge transfer complex is formed involving the N-dimethyl amino nitrogen of trimeprazine and 1O2. This complex, in addition to intersystem crossing process, undergoes a-hydrogen abstraction to form a transient a-amino carbon radical (3) and peroxy radical (HO2 ). Both of these radicals can then undergo electron transfer to produce an iminium cation leading to the Ndemethylation product 4. This mechanism is in agreement with the photodegradation pathway proposed for N-demethylation of trialkylamines (Baciocchi et al.,2004, 2006a,b). When trimeprazine was irradiated with singlet oxygen scavenger 2,5dimethylfuran (2,5 DMF) it competes with the drug for singlet oxygen (1O2), and decreased availability of singlet oxygen (1O2) therefore slowed down the rate of photodegradation. In order to further ascertain the oxidative photodegradation of trimeprazine by its quenching of the self-generated singlet oxygen, the drug was photolysed under the same experimental condition, in the presence of a well known photosensitized singlet oxygen generator, where same photoproducts were obtained in different yields. Rose bengal and methylene blue were much more efficient than riboflavin and benzophe-
none in the photosensitized decomposition of 1 (Table 1). This may be due to the fact that rose bengal and methylene blue, with lower triplet energies, produce singlet oxygen in large amounts (Tuite and Kelly, 1993; Roul and Cadet, 1996) by type II mechanism (Foote, 1991). On the other hand riboflavin and benzophenone (higher triplet energies) act mainly by type I photosensitized photooxidation, do not produce significant amount of 1O2 (Wondrak et al., 2006). The result indicates that these photoproducts are formed by irreversible trapping of self-photogenerated singlet molecular oxygen. The formation of photoproduct through oxygenation is relevant to understand the mechanism of photobiological effect of trimeprazine. Usually, the self-sensitized drug photooxidation (or singlet oxygen physical quenching) is barely considered, although it would be important because if 1O2 is quenched, it will not be available to react with other biologically relevant substrates. References Asghar, M.N., Khan, I.U., 2008. Measurement of antioxidant activity with trifluoperazine dihydrochloride radical cation. Braz. J. Med. Biol. Res. 41, 455–461. Baciocchi, E., Giacco, T.D., Lapi, A., 2004. Oxygenation of benzyldimethylamine by singlet oxygen. Products and mechanism. Org. Lett. 6, 4791–4794.
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
4 Baciocchi, E., Giacco, T.D., Lapi, A., 2006a. Quenching of singlet oxygen by tertiary aliphatic amines. Structural effects on rates and products. Helv. Chim. Acta 89, 2273–2280. Baciocchi, E., Giacco, T.D., Lapi, A., 2006b. Dual pathways for the desilylation of silylamines by singlet oxygen. Org. Lett. 8, 1783– 1786. Bello, L.L., 2011. Factors affecting efficacy of oral trimeprazine sedation for dental procedures in children: a retrospective study. SDJ 23, 87–90. Cosa, G., 2004. Photodegradation and photosensitization in pharmaceutical products: assessing drug phototoxicity. Pure Appl. Chem. 76, 263–275. Elisei, F., Latterini, L., Aloisi, G.G., Mazzucato, U., Viola, G., Miolo, G., Vedaldi, D., Dall’Acqua, F., 2002. Excited-state properties and in vitro phototoxicity studies of three phenothiazine derivatives. Photochem. Photobiol. 75, 11–21. Foote, C.S., 1991. Definition of type I and type II photosensitized oxidation. Photochem. Photobiol. 54, 659–660. Gollnick, K., Griesbeck, A., 1983. [4+2]-Cycloaddition of singlet oxygen to 2,5 dimethylfuran: isolation and reactions of the monomeric and dimeric endoperoxides. Angew. Chem., Int. Ed. Engl. 22, 726–727. Lutka, A., Koziara, J., 2000. Interaction of trimeprazine with cyclodextrins in aqueous solution. Acta Pol. Pharm., Drug Res. 573, 369–374. Mio, M., Yabuta, M., Kamei, C., 1999. Ultraviolet B (UVB) lightinduced histamine release from rat peritoneal mast cells and its augmentation by certain phenothiazine compounds. Immunopharmacology 415, 55–63. Miolo, G., Levorato, L., Galloccho, F., Caffieri, S., Bastianon, C., Zanoni, R., Reddi, E., 2006. In vitro phototoxicity of phenothi-
W. Ahmad et al. azines: involvement of stable UVA photolysis products formed in aqueous medium. Chem. Res. Toxicol. 19, 156–163. Onoue, S., Tsuda, Y., 2006. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharm. Res. 23, 156–164. Ouedraogo, G.D., Redmond, R.W., 2003. Secondary reactive oxygen species extend the range of photosensitization effects in cells: DNA damage produced via initial membrane photosensitization. Photochem. Photobiol. 77, 192–203. Quintero, B., Miranda, M.A., 2000. Mechanisms of photosensitization induced by drugs: a general survey. Ars Pharm. 41, 27–46. Roul, S., Cadet, J., 1996. Photosensitized reaction of 8-oxo-7, 8dihydro-2¢-deoxyguanosine: identification of 1-(2-deoxy-aˆ-d-erythro-pentofuranosyl) cyanuric acid as the major singlet oxygen oxidation product. J. Am. Chem. Soc. 118, 1892–1898. Sortino, S., Petralia, S., Darcy, R., Donohue, R., Mazzaglia, A., 2003. Photochemical outcome modification of diflunisal by a novel cationic amphiphilic cyclodextrin. New J. Chem. 27, 602–608. Tranchin, M., Callegarin, F., Elisei, F., Mazzucato, U., Reddi, E., Jori, G., 1998. Drugs: Photochemistry and Photostability. Royal Society of Chemistry, London. Tuite, E.M., Kelly, J.M., 1993. Photochemical interactions of methylene blue and analogues with DNA and other biological substrates. J. Photochem. Photobiol. B: Biol. 21, 103–124. Vargas, F., Rivas, C., 1996. Mechanistic Studies on the Photochemistry and Phototoxicity of Diuretic Drugs. CRC Press, New York. Wondrak, G.T., Jacobson, M.K., Jacobson, E.L., 2006. Endogenous UVA-photosensitizers: mediators of skin photodamage and novel targets for skin photoprotection. Photochem. Photobiol. Sci. 5, 215–237.
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
King Saud University
Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com
ORIGINAL ARTICLE
Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen Waseem Ahmad, Mohd. Rehan Zaheer, Anamika Gupta *, Jawaid Iqbal Department of Chemistry, Aligarh Muslim University, Aligarh 202002, UP, India Received 19 May 2012; accepted 10 July 2012
KEYWORDS Trimeprazine; Phenothiazine; Singlet oxygen; Phototoxicity
Abstract The antihistaminic drug trimeprazine (1, also known as alimemazine) is photolabile under UV-A light in aerobic conditions. Irradiation of a methanol solution of trimeprazine produces two photoproducts which were isolated as N,N2-trimethyl-3-(10H-phenothiazin-10-yl sulfoxide) propan-1-amine (2) and N,2-dimethyl-3-(10H-phenothiazin-10-yl) propan-1-amine (4). The formation of products was explained by the oxidative photodegradation of trimeprazine in an irreversible trapping of the self-photogenerated 1O2 by the type II photodynamic action of the drug. The generation of singlet oxygen during photolysis of trimeprazine was confirmed by singlet oxygen scavenger 2,5-dimethylfuran (2,5-DMF). ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction Recently, much attention has turned to the problem of biological photosensitization by drugs. Indeed, despite their excellent therapeutic activity, many drugs can induce phototoxic, photoallergic and photomutagenic phenomena, strictly related to the drug’s photochemical reactivity (Sortino et al., 2003) Photosensitization reactions leading to phototoxicity are generally considered as belonging to either the type I (radical mediated) or type II (singlet oxygen mediated) (Cosa, 2004; Ouedraogo and Redmond, 2003). There are photosensitizing drugs of varied structural variety and significant variations in the phototoxic mechanisms must be expected depending on the difference * Corresponding author. Tel.: +91 9058970731. E-mail address: [email protected] (A. Gupta). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
in structural features. The variety and number of phototoxic drugs is large and a relationship between structure and the mechanism of chemical reaction that causes the in vivo phototoxicity is not available (Vargas and Rivas, 1996) and it is therefore necessary to investigate the photochemistry of every photosensitizing drug. Phenothiazine derivatives have found a large variety of applications as dyes, antioxidants, and drugs. Accordingly, the antihistaminic and neuroleptic properties of some phenothiazine derivatives are well-known (Asghar and Khan, 2008; Elisei et al., 2002). Moreover, given the phototoxicity of these drugs (Onoue and Tsuda,2006; Miolo et al., 2006) a large number of investigations on the photochemical properties of these substances have been carried out. Several reports also indicate that irradiation of phenothiazines can produce singlet oxygen (Tranchin et al., 1998) but, surprisingly, very few studies have dealt with the chemical reactivity of 1O2 with the phenothiazines themselves. Trimeprazine (also known as Alimemazine) is a tricyclic Phenothiazine derivative (Lutka and Koziara, 2000). It is in the same class of drugs as chlorpromazine (Thorazine)
1319-6103 ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jscs.2012.07.016
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
2
W. Ahmad et al. Table 1 Effect of triplet energies of different sensitizers on the yields of products.
Scheme 1 trimeprazine.
Oxidative
Photodegradation
products
Sensitizer
Triplet energy (kcal /mole)
Yields of product (%) (2 + 4)
Methylene blue Rose bengal Riboflavin Benzophenone
33.5–34.0 39.2–42.2 57.8 68.6–69.1
60.9 59.5 50.4 49.1
(34.3 + 26.6) (32.3 + 27.2) (26.5 + 23.9) (25.1 + 24.0)
of
and trifluoperazine (Stelazine); however, unlike the other drugs in this class, trimeprazine is not used clinically as an anti-psychotic. It acts as anti-histamine, a sedative, and an anti-emetic (anti-nausea) (Bello, 2011). Interest in the photo reactivity of trimeprazine arises from the clinical and pharmacological reports of phototoxic effects demonstrated by this drug (Mio et al., 1999; Quintero and Miranda, 2000). In pursuance of our interest in the photochemical reactions involved in the phototoxicity of the photosensitizing drugs and their mechanisms, herein we have examined the photo behaviour of the antihistaminic drug trimeprazine (a phenothiazine derivative) under aerobic condition. Photolysis of trimeprazine (1) in the presence of oxygen resulted in the formation of two photodegradation products, identified as 2 and 4 from their spectral (IR, 1H NMR, 13C NMR, mass spectra) properties (Scheme 1). The products are formed by oxidative photodegradation of trimeprazine in an irreversible trapping of the self-photogenerated 1O2 in the type II photodynamic action of the drug. 2. Experimental 2.1. Apparatus and chemicals All chemicals used were of analytical grade. Pure Trimeprazine was obtained from Sigma Aldrich (India), IR spectra were recorded as KBr discs on a Perkin Elmer model spectrum RXI. 1 H NMR and 13C NMR Spectra were recorded on a Bruker Avance-DRX-300 Spectrometer using TMS as internal standard and CD3OD as solvent. High resolution mass spectra were determined with a VG-ZAB-BEQ9 spectrometer at 70 eV ionization voltage. Merck silica gel 60 F254 plates were used for analytical TLC; column chromatography was performed on Merck silica gel 60 (60–120 mesh). 2.2. Photoirradiation procedure A solution of Trimeprazine (275 mg, 0.7 mM) in methanol (400 ml) under aerobic condition was irradiated for 1 h in a Rayonet photochemical reactor (The Southern New England Ultraviolet Co; Model RPR-208 equipped with four RUL350 nm fluorescence lamps) for the complete conversion of reactant. Progress of the reaction was monitored by thin layer chromatography (chloroform–methanol, 98:2). At the end of the reaction formation of two major photoproducts were indicated on TLC and photoproducts were isolated by eluting with dichloromethane–ethyl ether (1:1, v/v) on a silica column. The photoproducts were identified as, N,N2-trimethyl-3-(10Hphenothiazin-10-yl sulfoxide) propan-1-amine (2) and N,2-di-
methyl-3-(10H-phenothiazin-10-yl) propan-1-amine ( 4) from the following spectral properties: 2.3. N,N2-trimethyl-3-(10H-phenothiazin-10-yl sulfoxide) propan-1-amine (2) Yield: 95 mg (34.5%); HRMS calcd. for (M+) C18H22N2OS 314.1453. Found 314.1448; IR (KBr, cm 1): 3416, 2965, 1388, 1301, 1270, 1209, 1055 (SO), 978, 763. 1H NMR (CD3OD, 300 MHz): d 7.12–6.9 (m, 8 H, arom), 4.60 (d, J = 7.3 Hz, 2 H, H-15), 2.32 (s, 6 H, H-19, H-20), 2.27 (d, J = 7.4 Hz, 2 H, H-17), 2.13 (m, 1 H, H-16), 1.02 (d, J = 6.0 Hz, 3 H, H-21) ppm. 13C NMR (CD3OD, 300 MHz): 145.1, 131.0, 128.6, 119.3, 118.2, 62.2, 55.3, 36.1, 32.1 16.0 ppm. MS: m/z: 314 (M+), 298 (M+ 16), 214 (M+ 100). 2.4. N,2-dimethyl-3-(10H-phenothiazin-10-yl) propan-1-amine (4) Yield: 75 mg (27.2%); HRMS calcd. for (M+) C17H20N2S 284.4191. Found 284.4185; IR (KBr, cm 1): 1388, 1301, 1270, 1209, 978, 763. 1H NMR (CD3OD, 300 MHz): d 7.12–6.9 (m, 8H, arom), 4.50 (d, J = 7.3 Hz, 2 H, H-15), 2.38 (s, 3 H, H19), 2.26 (d, J = 7.4 Hz, 2 H, H-17), 2.14 (m, 1 H, H-16), 1.02 (d, J = 6.0 Hz, 3 H, H-20) ppm. 13C NMR (CD3OD, 300 MHz): d 145.2, 131.1, 128.7, 119.4, 118.3, 62.3, 55.4, 36.2, 32.2, 15.9 ppm. MS: m/z: 284 (M+), 198 (M+ 86). 2.5. Singlet oxygen detection In order to confirm the role of singlet oxygen 1O2 as a trigger of trimeprazine (TMPZ) photodecomposition, photolysis was performed under the same experimental condition but now in the presence of 2,5-dimethylfuran (2,5-DMF) which is normally used as a trap for singlet oxygen (1O2) (Gollnick and Griesbeck, 1983). Similar experiment was also carried out by using different sensitizers such as methylene blue, rose bengal, riboflavin, and benzophenone to study the effect of triplet energy of sensitizer on the percentage yields of products (Table 1).
3. Results and discussion The two major photoproducts, N,N2-trimethyl-3-(10H-phenothiazin-10-yl sulfoxide) propan-1-amine (2) and N,2-dimethyl3-(10H-phenothiazin-10-yl) propan-1-amine (4), which were obtained on irradiation of trimeprazine in methanol under oxygen atmosphere, are depicted in Scheme 1.
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
Photodegradation of trimeprazine triggeredby self-photogenerated singlet molecular oxygen
Scheme 2
3
Mechanistic pathway of oxidative photodegradation of trimeprazine.
Their formation has been rationalized in the photosensitized generation of singlet oxygen by the type II photodynamic action of the drug and subsequent quenching of the generated singlet oxygen by the drug as proposed in Scheme 2. Photoproduct 2 is formed by simple sulfoxidation of parent compound and photoproduct 4 is formed through a mechanism in which a charge transfer complex is formed involving the N-dimethyl amino nitrogen of trimeprazine and 1O2. This complex, in addition to intersystem crossing process, undergoes a-hydrogen abstraction to form a transient a-amino carbon radical (3) and peroxy radical (HO2 ). Both of these radicals can then undergo electron transfer to produce an iminium cation leading to the Ndemethylation product 4. This mechanism is in agreement with the photodegradation pathway proposed for N-demethylation of trialkylamines (Baciocchi et al.,2004, 2006a,b). When trimeprazine was irradiated with singlet oxygen scavenger 2,5dimethylfuran (2,5 DMF) it competes with the drug for singlet oxygen (1O2), and decreased availability of singlet oxygen (1O2) therefore slowed down the rate of photodegradation. In order to further ascertain the oxidative photodegradation of trimeprazine by its quenching of the self-generated singlet oxygen, the drug was photolysed under the same experimental condition, in the presence of a well known photosensitized singlet oxygen generator, where same photoproducts were obtained in different yields. Rose bengal and methylene blue were much more efficient than riboflavin and benzophe-
none in the photosensitized decomposition of 1 (Table 1). This may be due to the fact that rose bengal and methylene blue, with lower triplet energies, produce singlet oxygen in large amounts (Tuite and Kelly, 1993; Roul and Cadet, 1996) by type II mechanism (Foote, 1991). On the other hand riboflavin and benzophenone (higher triplet energies) act mainly by type I photosensitized photooxidation, do not produce significant amount of 1O2 (Wondrak et al., 2006). The result indicates that these photoproducts are formed by irreversible trapping of self-photogenerated singlet molecular oxygen. The formation of photoproduct through oxygenation is relevant to understand the mechanism of photobiological effect of trimeprazine. Usually, the self-sensitized drug photooxidation (or singlet oxygen physical quenching) is barely considered, although it would be important because if 1O2 is quenched, it will not be available to react with other biologically relevant substrates. References Asghar, M.N., Khan, I.U., 2008. Measurement of antioxidant activity with trifluoperazine dihydrochloride radical cation. Braz. J. Med. Biol. Res. 41, 455–461. Baciocchi, E., Giacco, T.D., Lapi, A., 2004. Oxygenation of benzyldimethylamine by singlet oxygen. Products and mechanism. Org. Lett. 6, 4791–4794.
Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016
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Please cite this article in press as: Ahmad, W. et al., Photodegradation of trimeprazine triggered by self-photogenerated singlet molecular oxygen. Journal of Saudi Chemical Society (2012), http://dx.doi.org/10.1016/j.jscs.2012.07.016