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Journal of Chemical Sciences

, 131:107 | Cite as

Design and synthesis of sulfur-containing butylated hydroxytoluene: antioxidant potency and selective anticancer agent

  • Mohd H Ahmad
  • Noorsaadah Abd Rahman
  • Farkaad A Kadir
  • Lina A Al-Ani
  • Najihah M Hashim
  • Wageeh A YehyeEmail author
Regular Article
  • 17 Downloads

Abstract

In the present study, a series of multipotent antioxidants (MPAOs), namely sulfur-containing BHT (S-BHT), derivatives were rationally designed and synthesized, and their inhibitory activities against free radicals and human cancer cell lines, HT29 (colon cancer) and MCF7 (breast cancer) were further evaluated. The experimental results showed that the Six out-of-eight S-BHT compounds had excellent antioxidant activity against DPPH radical with major enhancement compared to BHT. Among them, compounds 2b, 2a and 3b attained over 45% lower IC50 values than BHT. In vitro cytotoxicity, MTT assay was carried out using two human cancer cell lines, HT29 (colon cancer) and MCF7 (breast cancer) in addition to their non-tumorigenic counterparts to explore selectivity. In line with antioxidant activity, compounds 2a and 2b displayed the highest cytotoxicity effect on both cancer types. Interestingly, 2b not only exhibited superior cancer inhibition but also scored high selectivity index (SI = 5.2, 12.5) in colon and breast tissues, respectively, exceeding that of the standard chemotherapeutic drugs used 5-Fluorouracil (5-FU) and Tamoxifen (Tmx), with lower IC50 values. The results indicated that the symmetric S-BHT derivatives were significantly enhanced by the antioxidant potency and their ability as useful and promising selective anticancer agents.

Graphic abstract

A series of sulfur-containing phenols (S-BHT) as multipotent antioxidants structure have been rationally designed and synthesized by the combination of the antiradical activity of the most well-known phenol moiety, butylated hydroxytoluene (BHT, primary antioxidant) with the antiperoxide (secondary antioxidant) and anti-proliferative fragments, sulfur-containing groups into one structure aiming to enhance scavenging ability and antiproliferative activity of the radicals. Accordingly, the bioactivity of S-BHT was analysed by antioxidant and anticancer in vitro studies and demonstrated remarkable cancer inhibition rates along with significant cytotoxicity and selectivity against HT29 and MCF7 cancer cell lines. This work efficiently sets the ground for eminent sulfur-containing phenols developed based on a well-known standard antioxidant BHT, with features superior to common drawbacks faced in cancer therapeutic approaches, in addition to the great potential holding as selective and biocompatible agent for cancer applications.

Keywords

Antioxidant anticancer sulfur-containing BHT HT29 MCF7 

Notes

Acknowledgements

The authors wish to acknowledge the grant from the University of Malaya - Postgraduate Research Grant RP044C-17AET and PPP-2015B to conduct this study.

Supplementary material

12039_2019_1682_MOESM1_ESM.pdf (1.8 mb)
Supplementary material 1 (PDF 1788 kb)

References

  1. 1.
    May M 2014 Attacking an epidemic Nature 509 S50–S51PubMedGoogle Scholar
  2. 2.
    DeSantis C, Ma J, Bryan L and Jemal A 2014 Breast cancer statistics, 2013 CA Cancer J. Clin. 64 52Google Scholar
  3. 3.
    Kanchana A and Balakrishnan M 2011 Anti-cancer effect of saponins isolated from solanum trilobatum leaf extract and induction of apoptosis in human larynx cancer cell lines Int. J. Pharm. Pharm. Sci. 3 356Google Scholar
  4. 4.
    Ariffin A, Rahman N A, Yehye W A, Alhadi A A and Kadir F A 2014 PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives Eur. J. Med. Chem. 87 564Google Scholar
  5. 5.
    Conner E M and Grisham M B 1996 Inflammation, free radicals, and antioxidants Nutrition 12 274PubMedPubMedCentralGoogle Scholar
  6. 6.
    Schoneich C 1999 Reactive oxygen species and biological aging: A mechanistic approach Exp. Gerontol. 34 19Google Scholar
  7. 7.
    Sahinoglu T, Stevens C R, Bhatt B and Blake D R 1996 The role of reactive oxygen species in inflammatory disease: Evaluation of methodology Methods 9 628PubMedGoogle Scholar
  8. 8.
    Mills R and Wu G Z 2004 Synthesis and evaluation of novel prodrugs of foscarnet and dideoxycytidine with a universal carrier compound comprising a chemiluminescent and a photochromic conjugate J. Pharm. Sci. 93 1320PubMedGoogle Scholar
  9. 9.
    Ames B N, Gold L S and Willett W C 1995 The causes and prevention of cancer Proc. Natl. Acad. Sci. USA 92 5258Google Scholar
  10. 10.
    Rajeshkumar S 2016 Anticancer activity of eco-friendly gold nanoparticles against lung and liver cancer cells Genet. Eng. Biotechnol. J. 14 195Google Scholar
  11. 11.
    Solomon V R, Hu C and Lee H 2010 Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach Bioorg. Med. Chem. 18 1563Google Scholar
  12. 12.
    Chinery R, Brockman J A, Peeler M O, Shyr Y, Beauchamp R D and Coffey R J 1997 Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta Nat. Med. 3 1233Google Scholar
  13. 13.
    Lobo V, Patil A, Phatak A and Chandra N 2010 Free radicals, antioxidants and functional foods: Impact on human health Pharmacogn. Rev. 4 118Google Scholar
  14. 14.
    Stillson G H 1947 Alkylation of phenols U.S. Patent 2428745 AGoogle Scholar
  15. 15.
    Hilton J W 1989 Antioxidants: Function, types and necessity of inclusion in pet foods Can. Vet. J. 30 682Google Scholar
  16. 16.
    Botterweck A A M, Verhagen H, Goldbohm R A, Kleinjans J and van den Brandt P A 2000 Intake of butylated hydroxyanisole and butylated hydroxytoluene and stomach cancer risk: Results from analyses in the Netherlands cohort study Food Chem. Toxicol. 38 599Google Scholar
  17. 17.
    Yehye W A, Rahman N A, Alhadi A A, Khaledi H, Ng S W and Ariffin A 2012 Butylated hydroxytoluene analogs: Synthesis and evaluation of their multipotent antioxidant activities Molecules 17 7645PubMedPubMedCentralGoogle Scholar
  18. 18.
    Barclay L R C, Vinqvist M R, Mukai K, Goto H, Hashimoto Y, Tokunaga A and Uno H 2000 On the antioxidant mechanism of curcumin: Classical methods are needed to determine antioxidant mechanism and activity Org. Lett. 2 2841Google Scholar
  19. 19.
    Erik K, Vladimír L and Cibulkova Z 2005 On the energetics of phenol antioxidants activity Pet. 47 33Google Scholar
  20. 20.
    Fukumoto L R and Mazza G 2000 Assessing antioxidant and prooxidant activities of phenolic compounds J. Agric. Food Chem. 48 3597PubMedGoogle Scholar
  21. 21.
    Bondet V, BrandWilliams W and Berset C 1997 Kinetics and mechanisms of antioxidant activity using the DPPH* free radical method Lebensm. Wiss. Technol. 30 609Google Scholar
  22. 22.
    De Gianni E and Fimognari C 2015 Anticancer mechanism of sulfur-containing compounds Enzymes 37 167PubMedGoogle Scholar
  23. 23.
    Cerella C, Dicato M, Jacob C and Diederich M 2011 Chemical properties and mechanisms determining the anti-cancer action of garlic-derived organic sulfur compounds Anticancer Agents Med. Chem. 11 267Google Scholar
  24. 24.
    Hong-Yu Z 2005 Structure-activity relationships and rational design strategies for radical-scavenging antioxidants Curr. Comput. Aided Drug Des. 1 257Google Scholar
  25. 25.
    Rzeski W, Matysiak J and Kandefer-Szerszen M 2007 Anticancer, neuroprotective activities and computational studies of 2-amino-1,3,4-thiadiazole based compound Bioorg. Med. Chem. 15 3201Google Scholar
  26. 26.
    Abdel-Rahman, T M 2006 Synthesis, reactions, and anticancer activity of some 1,3,4-thiadiazole/thiadiazine derivatives of carbazole Phosphorus Sulfur Silicon Relat. Elem. 181 1737Google Scholar
  27. 27.
    Vasoya S L, Paghdar D J, Chovatia P T and Joshi H S 2005 Synthesis of some new thiosemicarbazide and 1,3,4-thiadiazole heterocycles bearing benzo[b]thiophene nucleus as a potent antitubercular and antimicrobial agents J. Sci. I. R. Iran 16 33Google Scholar
  28. 28.
    Dawood K M and Gomha S M 2015 Synthesis and anti-cancer activity of 1,3,4-thiadiazole and 1,3-thiazole derivatives having 1,3,4-oxadiazole moiety J. Heterocycl. Chem. 52 1400Google Scholar
  29. 29.
    Aliabadi A, Eghbalian E and Kiani A 2013 Synthesis and evaluation of the cytotoxicity of a series of 1,3,4-thiadiazole based compounds as anticancer agents Iran. J. Basic Med. Sci. 16 1133Google Scholar
  30. 30.
    Gorinstein S, Martin-Belloso O, Katrich E, Lojek A, Ciz M, Gligelmo-Miguel N, Haruenkit R, Park Y S, Jung S T and Trakhtenberg S 2003 Comparison of the contents of the main biochemical compounds and the antioxidant activity of some Spanish olive oils as determined by four different radical scavenging tests J. Nutr. Biochem. 14 154PubMedGoogle Scholar
  31. 31.
    Mosmann T 1983 Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays J. Immunol. Met. 65 55Google Scholar
  32. 32.
    Badisa R B, Darling-Reed S F, Joseph P, Cooperwood J S, Latinwo L M and Goodman C B 2009 Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells Anticancer Res. 29 2993Google Scholar
  33. 33.
    Yehye W A, Rahman N A, Ariffin A, Hamid S B A, Alhadi A A, Kadir F A and Yaeghoobi M 2015 Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review Eur. J. Med. Chem. 101 295Google Scholar
  34. 34.
    Wright J S, Johnson E R and DiLabio G A 2001 Predicting the activity of phenolic antioxidants: Theoretical method, analysis of substituent effects, and application to major families of antioxidants J. Am. Chem. Soc. 123 1173PubMedGoogle Scholar
  35. 35.
    Zhang H Y, Yang D P and Tang G Y 2006 Multipotent antioxidants: From screening to design Drug Discov. Today 11 749Google Scholar
  36. 36.
    Lucarini M, Pedulli G F and Cipollone M 1994 Bond-dissociation enthalpy of alpha-tocopherol and other phenolic antioxidants J. Org. Chem. 59 5063Google Scholar
  37. 37.
    Lim Y Y, Lim T T and Tee J J 2007 Antioxidant properties of several tropical fruits: A comparative study Food Chem. 103 1003Google Scholar
  38. 38.
    Henriquez C Bueno C Lissi E A and Encinas M V 2003 Thiols as chain transfer agents in free radical polymerization in aqueous solution Polymer 44 5559Google Scholar
  39. 39.
    Bordwell F G, Zhang X M, Satish A V and Cheng J P 1994 Assessment of the importance of changes in ground-state energies on the bond-dissociation enthalpies of the O-H bonds in phenols and the S-H Bonds in thiophenols J. Am. Chem. Soc. 116 6605Google Scholar
  40. 40.
    Wardman P and Vonsonntag C 1995 Kinetic factors that control the fate of thiyl radicals in cells Biothiols. Pt. A 251 31Google Scholar
  41. 41.
    Hermann R, Dey G R, Naumov S and Brede O 2000 Thiol radical cations and thiyl radicals as direct products of the free electron transfer from aromatic thiols to n-butyl chloride radical cations Phys. Chem. Chem. Phys. 2 1213Google Scholar
  42. 42.
    Eklund P C, Langvik O K, Warna J P, Salmi T O, Willfor S M and Sjoholm R E 2005 Chemical studies on antioxidant mechanisms and free radical scavenging properties of lignans Org. Biomol. Chem. 3 3336Google Scholar
  43. 43.
    Sharma O P and Bhat T K 2009 DPPH antioxidant assay revisited Food Chem. 113 1202Google Scholar
  44. 44.
    Ohkatsu Y, Haruna T and Osa T 1977 Kinetic evaluation of reactivity of phenolic derivatives as antioxidants for polypropylene J. Macromol. Sc. A 11 1975Google Scholar
  45. 45.
    Fujisawa S, Kadoma Y and Yokoe I 2004 Radical-scavenging activity of butylated hydroxytoluene (BHT) and its metabolites Chem. Phys. Lipids 130 189Google Scholar
  46. 46.
    Demirayak S, Benkli K and Guven K 2000 Synthesis and antimicrobial activities of some 3-arylamino-5-[2-(substituted 1-imidazolyl)ethyl]-1,2,4-triazole derivatives Eur. J. Med. Chem. 35 1037Google Scholar
  47. 47.
    Saito M, Sakagami H and Fujisawa S 2003 Cytotoxicity and apoptosis induction by butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) Anticancer Res. 23 4693Google Scholar
  48. 48.
    Abu N, Akhtar M N, Ho W Y, Yeap S K and Alitheen N B 2013 3-Bromo-1-hydroxy-9,10-anthraquinone (BHAQ) inhibits growth and migration of the human breast cancer cell lines MCF-7 and MDA-MB231 Molecules 18 10367Google Scholar
  49. 49.
    Yaacob N S, Kamal N N N M and Norazmi M N 2014 Synergistic anticancer effects of a bioactive subfraction of strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231 human breast cancer cell lines BMC Complement. Altern. Med. 14 252Google Scholar
  50. 50.
    Etti I, Abdullah R, Hashim N M, Kadir A, Abdul A B, Etti C, Malami I, Waziri P and How C W 2016 Artonin E and structural analogs from artocarpus species abrogates estrogen receptor signaling in breast cancer Molecules 21 839PubMedCentralGoogle Scholar
  51. 51.
    Anand M, Selvaraj V and Alagar M 2014 Synthesis, characterization and evaluation of antioxidant and anticancer activities of novel benzisoxazole-substituted-allyl derivatives Korean J. Chem. Eng. 31 659Google Scholar
  52. 52.
    Kan W L T, Yin C, Xu H X, Xu G, To K K W, Cho C H, Rudd J A and Lin G 2013 Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1-mediated G0/G1 cell cycle arrest and apoptosis Int. J. Cancer 132 707Google Scholar

Copyright information

© Indian Academy of Sciences 2019

Authors and Affiliations

  • Mohd H Ahmad
    • 1
  • Noorsaadah Abd Rahman
    • 2
  • Farkaad A Kadir
    • 3
  • Lina A Al-Ani
    • 1
  • Najihah M Hashim
    • 4
  • Wageeh A Yehye
    • 1
    Email author
  1. 1.Nanotechnology and Catalysis Research Centre (NANOCAT), Block 3A, Institute of Graduate Studies BuildingUniversity of MalayaKuala LumpurMalaysia
  2. 2.Department of Chemistry, Faculty of ScienceUniversity of MalayaKuala LumpurMalaysia
  3. 3.Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, School of Medical SciencesUniversity of AucklandAucklandNew Zealand
  4. 4.Department of Pharmacy, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia

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