Coumarins from Creston Apple Seeds: Isolation, Chemical Modification, and Cytotoxicity Study

Yasser Fakri Mustafa; Moath Abdulla Najem; Zena Sideek Tawffiq

doi:10.7324/JAPS.2018.8808

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Abstract

In the present work, preliminary phytochemical screening tests were performed on extracts of Creston apple seeds. Extraction was performed using two methods, which are serial Soxhlet extraction and kinetic maceration utilizing water, methanol, chloroform, and n-hexane as extraction solvents. Three coumarin derivatives acquired from chloroform extract in the order of increasing polarity were isolated via column chromatography and one of them was chemically modified by esterification, Fries rearrangement, and methylation afforded three semisynthetic derivatives. Detection of physicochemical properties and analysis of FTIR, 1H-NMR and 13C-NMR spectra of the natural and semisynthetic coumarins were used to identify their structures. In vitro cytotoxic activity of the aforementioned coumarin derivatives was studied on three cancer cell lines, which are MCF-7, AMN3, and HeLa using MTT assay. The results indicated that compounds N3, S4, S5 and S6 have IC50 values lower than that of 5- fluorouracil against MCF-7 cell line and all compounds have higher IC50 values than that of 5-fluorouracil against AMN3 and HeLa cell lines.

Keyword: Creston apple phytochemical coumarinderivative cytotoxicity.

Citation:

Mustafa YF, Najem MA, Tawffiq ZS. Coumarins from Creston Apple Seeds: Isolation, Chemical Modification, and Cytotoxicity Study. J App Pharm Sci, 2018; 8(08): 049-056.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

Al-Shammari AM, Salman MI, Saihood YD, Yaseen NY, Raed K, Shaker HK, Ahmed A, Khalid A, Duiach A. In vitro synergistic enhancement of newcastle disease virus to 5-Fluorouracil cytotoxicity against tumor cells. Biomedicines, 2016; 4. https://doi.org/10.3390/ biomedicines4010003.
Anbu Jeba Sunilson J, Anita Gnana Kumari AV, Khan A, Anandarajagopal K. Effects of Malus domestica fruit extracts against clinically isolated dental pathogens. Eur J Dent Med, 2016; 8:12-16. http:// dx.doi.org/10.3923/ejdm.2016.12.16. https://doi.org/10.3923/ejdm.2016.12.16
Appendino G, Cravotto G, Giovenzana GB, Palmisano G. A Straightforward Entry into Polyketide Monoprenylated Furanocoumarins and Pyranocoumarins. J Nat Prod, 1999; 62:1627-1631. https://doi.org/10.1021/np990241o
Apu AS, Liza MS, Jamaluddin AT, Howlader MA, Saha RK, Rizwan F, Nasrin N. Phytochemical screening and in vitro bioactivities of the extracts of aerial part of Boerhavia diffusa Linn. Asian Pac J Trop Biomed, 2012; 2:673-678. https://doi.org/10.1016/S2221-1691(12)60208-1
Atanasov AG, Waltenberger B, Pferschy-Wenzig E, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol Adv, 2015; 33:1582-1614. https://doi.org/10.1016/j.biotechadv.2015.08.001
Attar R, Cincin ZB, Bireller ES, Cakmakoglu B. Apoptotic and genomic effects of corilagin on SKOV3 ovarian cancer cell line. Onco Targets Ther, 2017; 10:1941-1946. https://doi.org/10.2147/OTT.S135315
Bernini R, Crisante F, Ginnasi MC. A convenient and safe O-methylation of flavonoids with dimethyl carbonate (DMC). Molecules, 2011; 16:1418-1425. https://doi.org/10.3390/molecules16021418. https://doi.org/10.3390/molecules16021418
Bonvin Y, Callens E, Larrosa I, Henderson DA, Oldham J, Burton AJ, et al. Bismuth-catalyzed benzylic oxidations with tert-butyl hydroperoxide. Org. Lett., 2005; 7:4549-4552. https://doi.org/10.1021/ol051765k
Crane EA, Gademann K. Capturing biological activity in natural product fragments by chemical synthesis. Angew Chem Int Ed Engl, 2016; 55:3882-3902. https://doi.org/10.1002/anie.201505863
Ghanbari K, Aghajani H, Golbabaee M, Khah EN, Nabavi SH, Koohian A. Column chromatography: A facile and inexpensive procedure to purify the red dopant DCJ applied for OLEDs. Adv Mat Phy Chem, 2011; 1:91-93. http://dx.doi.org/10.4236/ampc.2011.13015. https://doi.org/10.4236/ampc.2011.13015
Habibi D, Rahmani P, Akbaripanah Z. Acetylation of phenols, anilines, and thiols using silica sulfuric acid under solvent-free conditions. J Chem, 2013; 2013. http://dx.doi.org/10.1155/2013/268654. https://doi.org/10.1155/2013/268654
Harborne JB, 1998. Phytochemical methods: A guide to modern techniques of plant analysis. Second ed. London: Chapmann and Hall Publishers.
Hrdlovic P, Donovalova J, Stankovicova H, Gaplovsky A. Influence of polarity of solvents on the spectral properties of bichromophoric coumarins. Molecules, 2010; 15:8915-8932. http://dx.doi:10.3390/ molecules15128915.
Jelodarian S, Haghir Ebrahimabadi A, Khalighi A, Batooli H. Evaluation of antioxidant activity of Malus domestica fruit extract from Kashan area. Avicenna J Phytomed, 2012; 2:139-145.
Karteek SD, Rao MVB, Yeggoni DP, Adeppa K, Darla SS, Manidhar DM. Design, synthesis and molecular docking of 2-iso propyl amino derivatives of 7-methoxy coumarin as potent acetylcholinesterase inhibitors. Der Pharma Chemica, 2015; 7:255-272. https://www. researchgate.net/publication/281717418.
Kok TM, Breda SG, Briede JJ. Genomics-based identification of molecular mechanisms behind the cancer preventive action of phytochemicals: potential and challenges. Curr Pharm Biotechnol, 2012; 13:255-264. https://doi.org/10.2174/138920112798868601
Konarska A. The structure of the fruit peel in two varieties of Malus domestica Borkh. (Rosaceae) before and after storage. Protoplasma, 2013; 250:701-714. https://doi.org/10.1007/s00709-012-0454-y
Lamoureux G, Agüero C. A comparison of several modern alkylating agents. ARKIVOC, 2009; 2009:251-264. http://dx.doi. org/10.3998/ark.5550190.0010.108.
Liaudanskas M, Viskelis P, Raudonis R, Kviklys D, Uselis N, Janulis V. Phenolic composition and antioxidant activity of Malus domestica leaves. Sci World J, 2014; 2014. http://dx.doi.org/10.1155/2014/306217. https://doi.org/10.1155/2014/306217
Li-Weber M. Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer, 2015; 137:1791-1799. https://doi.org/10.1002/ijc.29013
Lopez-Castillo NN, Rojas-Rodriguez AD, Porta1 BM, Cruz- Gomez MJ. Process for the obtention of coumaric acid from coumarin: Analysis of the reaction conditions. Adv Chem Eng Sci, 2013; 3:195-201. http://dx.doi.org/10.4236/aces.2013.33025. https://doi.org/10.4236/aces.2013.33025
Mahlo SM, Chauke HR, McGaw L, Eloff J. Antioxidant and antifungal activity of selected medicinal plant extracts against phytopathogenic fungi. Afr J Tradit Complement Altern Med, 2016; 13:216-222. https://doi.org/10.21010/ajtcam.v13i4.28
Naviglio D, Formato A, Vitulano M, Cozzolino I, Ferrara L, Zanoelo EF, Gallo M. Comparison between the kinetics of conventional maceration and a cyclic pressurization extraction process for the production of lemon liqueur using a numerical model. J Food Process Eng, 2016; 40. http://dx.doi.org/10.1111/jfpe.12350. https://doi.org/10.1111/jfpe.12350
Nelson LS, Shih RD, Balick MJ. 2007. Handbook of poisonous and injurious plants. 2nd ed. Springer, New York, pp. 211-212. ISBN 978-0- 387-33817-0. Retrieved 9 February 2018. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod, 2016; 79:629-661.
Perel'son ME, Sheinker YN, Syrova GP, Turchin KF. NMR spectra of natural coumarins. Translated from Khimiya Prirodnykh Soedinenii, 1970; 6:6-14.
Quamme HA, Lapins KO, Schmidt H, MacDonald RA, Lane WD, Hampson CR. Creston apple. Can J Plant Sci, 1999; 79:291-294. https://doi.org/10.4141/P98-083. https://doi.org/10.4141/P98-083
Ramesh P, Das AT, Mohandass P, Nagasathya R. The structure of Hantzsch coumarin. Indian J Chem, 2008; 47B:1447-1450.
Rosselli S, Maggio AM, Faraone N, Spadaro V, Morris-Natschke SL, Bastow KF, Lee KH, Bruno M. The cytotoxic properties of natural coumarins isolated from roots of Ferulago campestris (Apiaceae) and of synthetic ester derivatives of aegelinol. Nat Prod Commun, 2009; 4:1701- 1706.
Sandhya B, Mathew V, Lohitha P, Ashwini T, Shravani A. Synthesis, characterization and pharmacological activities of coumarin derivatives. Int J Chem Pharm Sci, 2010; 1:16-25.
Sanjeewa KKA, Kim EA, Son KT, Jeon YJ. Bioactive properties and potentials cosmeceutical applications of phlorotannins isolated from brown seaweeds: A review. J Photochem Photobiol B, 2016; 162:100-105. https://doi.org/10.1016/j.jphotobiol.2016.06.027
Selva M, Perosa A. Green chemistry metrics: a comparative evaluation of dimethyl carbonate, methyl iodide, dimethyl sulfate and methanol as methylating agents. Green Chem, 2008; 10:457-464. https://doi.org/10.1039/B713985C. https://doi.org/10.1039/b713985c
Shahneh FZ, Valiyari S, Azadmehr A, Hajiaghaee R, Yaripour S, Bandehagh A, Baradaran B. Inhibition of growth and induction of apoptosis in fibrosarcoma cell lines by Echinophora platyloba DC: In vitro analysis. Adv Phar Sci, 2013. http://dx.doi.org/10.1155/2013/512931. https://doi.org/10.1155/2013/512931
Shullts ES, Petrova TN, Shakirov MM, Chernyak EI, Pokrovskiy LM, Nekhoroshev SA, Tolstikov GA.Coumarin compounds from Root of Peucedanum (Peucedanum morisonii Bess.). Chem Sust Dev, 2003; 11:649-654.
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA. Cancer J Clin, 2018; 68:7-30. https://doi.org/10.3322/caac.21442
Sowa A, Zgorka G, Szykula A, Franiczek R, Zbikowska B, Gamian A, Sroka Z. Analysis of polyphenolic compounds in extracts from leaves of some Malus domestica cultivars: Antiradical and antimicrobial analysis of these extracts. Biomed Res Int, 2016; 2016. http://dx.doi. org/10.1155/2016/6705431.
Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Coumarin: A natural, privileged and versatile scaffold for bioactive compounds. Molecules, 2018; 23. https://doi.org/10.3390/molecules23020250. https://doi.org/10.3390/molecules23020250
Swayam SS, Smita S, Subhangankar N, Himanshu BS. Synthesis of novel coumarin derivatives and its biological evaluations. Euro J Exp Bio, 2012; 2:899-908.
Traven VF, Podhaluzina NY, Vasilyev AV, Manaev AV. Unusual Fries rearrangement of 7-acyloxyquinolin-2-ones– A new way to linear and angular furoquinolin-2-ones. ARKIVOC, 2000; 6:931-938. http://dx.doi. org/10.3998/ark.5550190.0001.611. https://doi.org/10.3998/ark.5550190.0001.611
Traven VF. New synthetic routes to furocoumarins and their analogs: A review. Molecules, 2004; 9:50-66. http://dx.doi. org/10.3390/90300050. https://doi.org/10.3390/90300050
Tsuchiya H. Membrane interactions of phytochemicals as their molecular mechanism applicable to the discovery of drug leads from plants. Molecules, 2015; 20:18923-18966. https://doi.org/10.3390/molecules201018923
Venugopala KN, Rashmi V, Odhav B. Review on natural coumarin lead compounds for their pharmacological activity. Biomed Res Int, 2013; 2013. http://dx.doi.org/10.1155/2013/963248. https://doi.org/10.1155/2013/963248
Vineetha VP, Girija S, Soumya RS, Raghu KG. Polyphenol-rich apple (Malus domestica L.) peel extract attenuates arsenic trioxide induced cardiotoxicity in H9c2 cells via its antioxidant activity. Food Funct, 2014; 5:502-511. https://doi.org/10.1039/c3fo60470e
White BA, Horwath CC, Conner TS. Many apples a day keep the blues away--daily experiences of negative and positive affect and food consumption in young adults. Br J Health Psychol, 2013; 18:782-798. https://doi.org/10.1111/bjhp.12021. https://doi.org/10.1111/bjhp.12021

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Al-Shammari AM, Salman MI, Saihood YD, Yaseen NY, Raed K, Shaker HK, Ahmed A, Khalid A, Duiach A. In vitro synergistic enhancement of newcastle disease virus to 5-Fluorouracil cytotoxicity against tumor cells. Biomedicines, 2016; 4. https://doi.org/10.3390/ biomedicines4010003.

Anbu Jeba Sunilson J, Anita Gnana Kumari AV, Khan A, Anandarajagopal K. Effects of Malus domestica fruit extracts against clinically isolated dental pathogens. Eur J Dent Med, 2016; 8:12-16. http:// dx.doi.org/10.3923/ejdm.2016.12.16. https://doi.org/10.3923/ejdm.2016.12.16

Appendino G, Cravotto G, Giovenzana GB, Palmisano G. A Straightforward Entry into Polyketide Monoprenylated Furanocoumarins and Pyranocoumarins. J Nat Prod, 1999; 62:1627-1631. https://doi.org/10.1021/np990241o

Apu AS, Liza MS, Jamaluddin AT, Howlader MA, Saha RK, Rizwan F, Nasrin N. Phytochemical screening and in vitro bioactivities of the extracts of aerial part of Boerhavia diffusa Linn. Asian Pac J Trop Biomed, 2012; 2:673-678. https://doi.org/10.1016/S2221-1691(12)60208-1

Atanasov AG, Waltenberger B, Pferschy-Wenzig E, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol Adv, 2015; 33:1582-1614. https://doi.org/10.1016/j.biotechadv.2015.08.001

Attar R, Cincin ZB, Bireller ES, Cakmakoglu B. Apoptotic and genomic effects of corilagin on SKOV3 ovarian cancer cell line. Onco Targets Ther, 2017; 10:1941-1946. https://doi.org/10.2147/OTT.S135315

Bernini R, Crisante F, Ginnasi MC. A convenient and safe O-methylation of flavonoids with dimethyl carbonate (DMC). Molecules, 2011; 16:1418-1425. https://doi.org/10.3390/molecules16021418. https://doi.org/10.3390/molecules16021418

Bonvin Y, Callens E, Larrosa I, Henderson DA, Oldham J, Burton AJ, et al. Bismuth-catalyzed benzylic oxidations with tert-butyl hydroperoxide. Org. Lett., 2005; 7:4549-4552. https://doi.org/10.1021/ol051765k

Crane EA, Gademann K. Capturing biological activity in natural product fragments by chemical synthesis. Angew Chem Int Ed Engl, 2016; 55:3882-3902. https://doi.org/10.1002/anie.201505863

Ghanbari K, Aghajani H, Golbabaee M, Khah EN, Nabavi SH, Koohian A. Column chromatography: A facile and inexpensive procedure to purify the red dopant DCJ applied for OLEDs. Adv Mat Phy Chem, 2011; 1:91-93. http://dx.doi.org/10.4236/ampc.2011.13015. https://doi.org/10.4236/ampc.2011.13015

Habibi D, Rahmani P, Akbaripanah Z. Acetylation of phenols, anilines, and thiols using silica sulfuric acid under solvent-free conditions. J Chem, 2013; 2013. http://dx.doi.org/10.1155/2013/268654. https://doi.org/10.1155/2013/268654

Harborne JB, 1998. Phytochemical methods: A guide to modern techniques of plant analysis. Second ed. London: Chapmann and Hall Publishers.

Hrdlovic P, Donovalova J, Stankovicova H, Gaplovsky A. Influence of polarity of solvents on the spectral properties of bichromophoric coumarins. Molecules, 2010; 15:8915-8932. http://dx.doi:10.3390/ molecules15128915.

Jelodarian S, Haghir Ebrahimabadi A, Khalighi A, Batooli H. Evaluation of antioxidant activity of Malus domestica fruit extract from Kashan area. Avicenna J Phytomed, 2012; 2:139-145.

Karteek SD, Rao MVB, Yeggoni DP, Adeppa K, Darla SS, Manidhar DM. Design, synthesis and molecular docking of 2-iso propyl amino derivatives of 7-methoxy coumarin as potent acetylcholinesterase inhibitors. Der Pharma Chemica, 2015; 7:255-272. https://www. researchgate.net/publication/281717418.

Kok TM, Breda SG, Briede JJ. Genomics-based identification of molecular mechanisms behind the cancer preventive action of phytochemicals: potential and challenges. Curr Pharm Biotechnol, 2012; 13:255-264. https://doi.org/10.2174/138920112798868601

Konarska A. The structure of the fruit peel in two varieties of Malus domestica Borkh. (Rosaceae) before and after storage. Protoplasma, 2013; 250:701-714. https://doi.org/10.1007/s00709-012-0454-y

Lamoureux G, Agüero C. A comparison of several modern alkylating agents. ARKIVOC, 2009; 2009:251-264. http://dx.doi. org/10.3998/ark.5550190.0010.108.

Liaudanskas M, Viskelis P, Raudonis R, Kviklys D, Uselis N, Janulis V. Phenolic composition and antioxidant activity of Malus domestica leaves. Sci World J, 2014; 2014. http://dx.doi.org/10.1155/2014/306217. https://doi.org/10.1155/2014/306217

Li-Weber M. Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer, 2015; 137:1791-1799. https://doi.org/10.1002/ijc.29013

Lopez-Castillo NN, Rojas-Rodriguez AD, Porta1 BM, Cruz- Gomez MJ. Process for the obtention of coumaric acid from coumarin: Analysis of the reaction conditions. Adv Chem Eng Sci, 2013; 3:195-201. http://dx.doi.org/10.4236/aces.2013.33025. https://doi.org/10.4236/aces.2013.33025

Mahlo SM, Chauke HR, McGaw L, Eloff J. Antioxidant and antifungal activity of selected medicinal plant extracts against phytopathogenic fungi. Afr J Tradit Complement Altern Med, 2016; 13:216-222. https://doi.org/10.21010/ajtcam.v13i4.28

Naviglio D, Formato A, Vitulano M, Cozzolino I, Ferrara L, Zanoelo EF, Gallo M. Comparison between the kinetics of conventional maceration and a cyclic pressurization extraction process for the production of lemon liqueur using a numerical model. J Food Process Eng, 2016; 40. http://dx.doi.org/10.1111/jfpe.12350. https://doi.org/10.1111/jfpe.12350

Nelson LS, Shih RD, Balick MJ. 2007. Handbook of poisonous and injurious plants. 2nd ed. Springer, New York, pp. 211-212. ISBN 978-0- 387-33817-0. Retrieved 9 February 2018. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod, 2016; 79:629-661.

Perel'son ME, Sheinker YN, Syrova GP, Turchin KF. NMR spectra of natural coumarins. Translated from Khimiya Prirodnykh Soedinenii, 1970; 6:6-14.

Quamme HA, Lapins KO, Schmidt H, MacDonald RA, Lane WD, Hampson CR. Creston apple. Can J Plant Sci, 1999; 79:291-294. https://doi.org/10.4141/P98-083. https://doi.org/10.4141/P98-083

Ramesh P, Das AT, Mohandass P, Nagasathya R. The structure of Hantzsch coumarin. Indian J Chem, 2008; 47B:1447-1450.

Rosselli S, Maggio AM, Faraone N, Spadaro V, Morris-Natschke SL, Bastow KF, Lee KH, Bruno M. The cytotoxic properties of natural coumarins isolated from roots of Ferulago campestris (Apiaceae) and of synthetic ester derivatives of aegelinol. Nat Prod Commun, 2009; 4:1701- 1706.

Sandhya B, Mathew V, Lohitha P, Ashwini T, Shravani A. Synthesis, characterization and pharmacological activities of coumarin derivatives. Int J Chem Pharm Sci, 2010; 1:16-25.

Sanjeewa KKA, Kim EA, Son KT, Jeon YJ. Bioactive properties and potentials cosmeceutical applications of phlorotannins isolated from brown seaweeds: A review. J Photochem Photobiol B, 2016; 162:100-105. https://doi.org/10.1016/j.jphotobiol.2016.06.027

Selva M, Perosa A. Green chemistry metrics: a comparative evaluation of dimethyl carbonate, methyl iodide, dimethyl sulfate and methanol as methylating agents. Green Chem, 2008; 10:457-464. https://doi.org/10.1039/B713985C. https://doi.org/10.1039/b713985c

Shahneh FZ, Valiyari S, Azadmehr A, Hajiaghaee R, Yaripour S, Bandehagh A, Baradaran B. Inhibition of growth and induction of apoptosis in fibrosarcoma cell lines by Echinophora platyloba DC: In vitro analysis. Adv Phar Sci, 2013. http://dx.doi.org/10.1155/2013/512931. https://doi.org/10.1155/2013/512931

Shullts ES, Petrova TN, Shakirov MM, Chernyak EI, Pokrovskiy LM, Nekhoroshev SA, Tolstikov GA.Coumarin compounds from Root of Peucedanum (Peucedanum morisonii Bess.). Chem Sust Dev, 2003; 11:649-654.

Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA. Cancer J Clin, 2018; 68:7-30. https://doi.org/10.3322/caac.21442

Sowa A, Zgorka G, Szykula A, Franiczek R, Zbikowska B, Gamian A, Sroka Z. Analysis of polyphenolic compounds in extracts from leaves of some Malus domestica cultivars: Antiradical and antimicrobial analysis of these extracts. Biomed Res Int, 2016; 2016. http://dx.doi. org/10.1155/2016/6705431.

Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Coumarin: A natural, privileged and versatile scaffold for bioactive compounds. Molecules, 2018; 23. https://doi.org/10.3390/molecules23020250. https://doi.org/10.3390/molecules23020250

Swayam SS, Smita S, Subhangankar N, Himanshu BS. Synthesis of novel coumarin derivatives and its biological evaluations. Euro J Exp Bio, 2012; 2:899-908.

Traven VF, Podhaluzina NY, Vasilyev AV, Manaev AV. Unusual Fries rearrangement of 7-acyloxyquinolin-2-ones– A new way to linear and angular furoquinolin-2-ones. ARKIVOC, 2000; 6:931-938. http://dx.doi. org/10.3998/ark.5550190.0001.611. https://doi.org/10.3998/ark.5550190.0001.611

Traven VF. New synthetic routes to furocoumarins and their analogs: A review. Molecules, 2004; 9:50-66. http://dx.doi. org/10.3390/90300050. https://doi.org/10.3390/90300050

Tsuchiya H. Membrane interactions of phytochemicals as their molecular mechanism applicable to the discovery of drug leads from plants. Molecules, 2015; 20:18923-18966. https://doi.org/10.3390/molecules201018923

Venugopala KN, Rashmi V, Odhav B. Review on natural coumarin lead compounds for their pharmacological activity. Biomed Res Int, 2013; 2013. http://dx.doi.org/10.1155/2013/963248. https://doi.org/10.1155/2013/963248

Vineetha VP, Girija S, Soumya RS, Raghu KG. Polyphenol-rich apple (Malus domestica L.) peel extract attenuates arsenic trioxide induced cardiotoxicity in H9c2 cells via its antioxidant activity. Food Funct, 2014; 5:502-511. https://doi.org/10.1039/c3fo60470e

White BA, Horwath CC, Conner TS. Many apples a day keep the blues away--daily experiences of negative and positive affect and food consumption in young adults. Br J Health Psychol, 2013; 18:782-798. https://doi.org/10.1111/bjhp.12021. https://doi.org/10.1111/bjhp.12021