Antioxidant and cytotoxic properties of novel spirocyclic benzothiazolines

Abstract

In this work, we report the synthesis, structural characterization

and evaluation of in vitro antioxidant and cytotoxic properties

of novel spirobenzothiazolines (1a-e, 2a-e). 5-nonsubstituted

spirobenzothiazolines (1a-e) demonstrated notable inhibitory

capacity on lipid peroxidation (LPO), reducing power and

scavinging effects on diphenylpicryl hydrazine (DPPH˙)

and 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid

(ABTS˙+) radicals, that were similar to that of α-tocopherol.

The most potent antioxidant was compound 1a (incorporating

an ethyl group on the cyclohexane ring) with an anti-LPO

activity 2-fold higher than that of α-tocopherol. Compound

1a exhibited anti-LPO and DPPH˙ scavenging activities at

concentrations lower than those cytotoxic for mouse normal

fibroblast (NIH/3T3) cells and was also found to be slightly

more selective for cancer cells (human prostat adenocarcinoma

cell/PC-3) than normal mammalian cells.

Keywords

• Benzothiazole; spiroheterocycle; antioxidant activity; cytotoxic activity

References

1. 1. Glasauer A, Chandel NS. Targeting antioxidants for cancer therapy. Biochem Pharm 2014; 92: 90-101. 2. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82: 47-95. 3. Ostrovidov S, Franck P, Joseph D, Martarello L, Kirsch G, Belleville F, Nabet P, Dousset B. Screening of new antioxidant molecules using flow cytometry. J Med Chem 2000; 43:1762-9. 4. Fuchs-Tarlovsky V. Role of antioxidants in cancer therapy. Nutrition 2013; 29:15-21. 5. Özben T. Antioxidant supplementation on cancer risk and during cancer therapy: an update. Curr Top Med Chem 2015; 15: 170-8. 6. Menon S, Lu C, Menon R, Schwartz J, Guan Y. Effects of antioxidants in human cancers: Differential effects on noncoding intronic RNA expression. Antioxidants 2016; 5: 1-17. 7. Yasueda A, Urushima H, Ito T. Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment. Integr Cancer Ther 2016; 15: 17-39. 8. Goodman M, Bostick RM, Kucuk O, Jones DP. Clinical trials of antioxidants as cancer prevention agents: Past, present, and future. Free Radic Biol Med 2011; 51: 1068-84. 9. Le Gal K, Ibrahim MX, Wiel C, Sayın VI, Akula MK, Karlsson C, Dalin MG, Akyurek LM, Lindahl P, Nilsson J, Bergo MO. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 2015; 7: 308re8. 10. Roche SP, Porco JA. Dearomatization strategies in the synthesis of complex natural products. Angew Chem Int Ed 2011; 50: 4068-93. 11. Purkayastha RP. Progress in phytoalexin research during the past 50 years. In: Daniel P, Purkayastha RP. (Eds). Handbook of Phytoalexin Metabolism and Action. Marcel Dekker, Inc., New York, 1995, pp.1-40. 12. Mehta RG, Liu J, Constantinou A, Thomas CF, Hawthorne M, You M, Gerhäuser C, Pezzuto JM, Moon RC, Moriarty RM. Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage. Carcinogenesis 1995; 16: 399–404. 13. Sabol M, Kutschy P, Siegfried L, Mirossay A, Suchy M, Hrbkova H, Dzurilla M, Maruskova R, Starkova J, Paulikova E. Cytotoxic effect of cruciferous phytoalexins against murine L1210 leukemia and B16 melanoma. Biologia 2000; 55: 701–7. 14. Pilátová M, Sarisský M, Kutschy P, Mirossay A, Mezencev R, Curillová Z, Suchý M, Monde K, Mirossay L, Mojzis J. Cruciferous phytoalexins: antiproliferative effects in T-Jurkat leukemic cells. Leuk Res 2005; 29: 415-21. 15. Chripkova M, Zigo F, Mojzis J. Antiproliferative effect of indole phytoalexins. Molecules 2016; 21: 1626-41. 16. Karalı N, Güzel Ö, Özsoy N, Özbey S, Salman A. Synthesis of new spiroindolinones incorporating a benzothiazole moiety as antioxidant agents. Eur J Med Chem 2010; 45:1068-77. 17. Ermut G, Karalı N, Özsoy N, Can A. New spiroindolinones bearing 5-chlorobenzothiazole moiety. J Enzyme Inhib Med Chem 2014; 29: 457-68. 18. Panteleon V, Marakos P, Pouli N, Mikros E, Andreadou I. Synthesis, conformational analysis and free radical scavenging activity of some new spiropyranoquinolinones. Chem Pharm Bull 2003; 51: 522-9. 19. Youssef MM, Amin MA. Microwave assisted synthesis of some new heterocyclic spiro-derivatives with potential antimicrobial and antioxidant activity. Molecules 2010; 15: 8827-40. 20. Dandia A, Saini D, Bhaskaran S, Saini DK. Ultrasound promoted green synthesis of spiro[pyrano[2,3-c]pyrazoles] as antioxidant agents. Med Chem Res 2014; 23: 725-34. 21. Shrestha R, Sharma K, Lee YR, Wee YJ. Cerium oxide-catalyzed multicomponent condensation approach to spirooxindoles in water. Mol Divers 2016; 20: 847-58. 22. Coudert P, Couquelet J, Sudre O, Bastide J. Synthesis and analgesic activity of new spiro-derivatives of benzothiazoline. J Pharm Belg1988; 43: 258-62. 23. Akkurt M, Cihan-Üstündağ G, Çapan G, Türktekin-Çelikesir S, Tahir MN. 5-Chloro-4′-ethyl-3H-spiro[ 1,3-benzothiazole- 2,1′-cyclohexane]. Acta Crystallogr Sect E. 2012; 68(5): o1466. 24. Akkurt M, Cihan-Üstündağ G, Çapan G, Dağdemir Y, Tahir N. 4′-tert-Butyl-5-chloro-3H-spiro[ 1,3-benzothiazole- 2,1′- cyclohexane]. Acta Crystallogr Sect E 2012; 68: o1542. 25. Duh PD, Tu YY, Yen GC. Antioxidant activity of water extract of Harng Jyur (Chrysanthemum morifolium Ramat). Food Sci Technol-LEB 1999; 32: 269-77. 26. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978; 52: 302-10. 27. Brand-Williams W, Cuvelier ME, Berset C. Use of a free radical method to evaluate antioxidant activity. Food Sci Technol- LEB 1995; 28: 25-30. 28. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice- Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 1999; 26: 1231-7. 29. Benzie IFF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Anal Biochem 1996; 239; 70-6. 30. van Meerloo J, Kaspers GJ, Cloos J. Cell sensitivity assays: the MTT assay. Methods Mol Biol 2011; 731: 237-45.