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Naturally occurring hydroxyalkyl isothiocyanates and isothiocyanatoalkyl benzoates - structure-activity and structure-mechanism of action relationship studies.

Mateusz Psurski 1,2Joanna Wietrzyk 2Józef Oleksyszyn 1

1. Wroclaw University of Technology, Division of Medicinal Chemistry and Microbiology (PWR), Wybrzeże Wyspiańskiego 27, Wrocław 50-370, Poland
2. Polish Academy of Sciences, Institute of Immunology and Experimental Therapy (IITD), Rudolfa Weigla 12, Wrocław 53-114, Poland


Isothiocyanates are among most extensively studied natural compounds as a potential anticancer drugs present in a cruciferous vegetables in high amounts and variety. Numerous studies showed that benzyl isothiocyanate or sulphoraphane are capable to induce cell cycle arrest and apoptosis in a variety of cancer cell lines in vitro and in vivo. However, only a few most abundant representatives of this large and diversified group were extensively studied so far.Herein, we describes studies over the structure-activity relationship for previously never tested representatives of natural isothiocyanates - hydroxyalkyl isothiocyanates and isothiocyanatoalkyl benzoates. Both groups showed high antiproliferative activity against several cancer cell lines including lung, breast, drug-sensitive and drug-resistant colon cancer. This activity was comparable to the activity of extensively studied benzyl, phenylethyl isothiocyanate and suforaphane, e.g. IC50 values measured for drug-sensitive colon cancer cell line (LoVo) were in range 3 – 13 µM and only slight activity decrease was observed when drug-resistant subline (LoVoDX) was used (IC50 in range 6 – 18 µM). The length of the alkyl chain connecting the hydroxyl moiety with isothiocyanate moiety had a direct impact on this activity – the most active compounds were those with the longest alkyl chain - 6-isothicyanohexan-1-ol and 6-isothiocyanatohexyl benzoate.
Isothiocyanates mechanism of action is based on fast accumulation in cells via passive diffusion followed by the reaction with glutathione reduced and protein's thiocarbamoylation which leads to a number of changes in cell's metabolism and signaling routes. At least 30 proteins were recognized as  isothiocyanates molecular targets so far, thus, studies over the structure-mechanism of action relationship are difficult. However, several parental molecular targets can be set and the most important target for almost all isothiocyanates appears  to be glutathione,  main redox status guardian present in high amounts within cells.  Because mitochondria of most cancer cells do not functioning properly, they produce high amounts of reactive oxygen species and to counteract this phenomenon the biosynthesis of glutathione route is highly active and overexpressed. Based on this observations we evaluated the structure-mechanism of action relationship for tested isothiocyanates using glutathione level, ROS level, caspase-3 activity and cell cycle distribution as markers to asses this correlation. Generally, we have found that hydrophobic representatives like 6-isothicyanohexan-1-ol caused high glutathione depletion and caspase-3 activation correlated with high ROS production level. Hydrophilic compounds like 3-isothicyanopropan-1-ol caused only a moderate glutathione depletion without significant caspase-3 activation, but a cell cycle arrest was observed in G2/M or in G0/G1 phase.


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Related papers

Presentation: Poster at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Mateusz Psurski
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-03-05 09:39
Revised:   2012-03-16 07:00