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Novel bifunctional synthetic isothiocyanates with high antiproliferative activity

Mateusz Psurski 1,2Łukasz Winiarski 1Marta Piguła 1Joanna 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


Herein, we describe novel class of biologically active compounds containing two distinct chemical moieties - isothiocyano-aralkylphosphonate diphenyl esters. The isothiocyanate moiety is responsible for a fast compound’s accumulation in the cells via  passive diffusion and high reactivity against reduced glutathione which leads to its depletion correlated with several proteins thiocarbamoylation, cell cycle arrest and apoptosis. Numerous studies performed with use of natural isothiocyanates such as benzyl isothiocyanate or sulforaphane strongly suggest that even such simple compounds can be a good candidate for an anticancer drug. Moreover, despite of the high chemical reactivity of the isothiocyanate moiety (this property is often used in organic chemistry), they show remarkable selectivity towards cancer cells. Second moiety – phosphonate diphenyl ester is the transition state analogue for the peptide bond hydrolysis carried out by serine proteases, thus, its responsible for inhibitory activity towards this class of enzymes. Because of the proteases substrate high specificity, both carbon α substitution and phenyl ring substitution allows us to obtain highly active and specific inhibitors. In this presentation, chymotrypsin and elastase-directed compounds will be presented. Both enzymes are an important enzymes in carcinogenesis and metastasis. Chymotrypsin-like proteasome activity, as a part of a large proteasome multicatalytic proteinase complex,  plays an important role in several critical cellular functions including the processing of proteins involved in cell cycle progression and gene expression. It is responsible for a fast degradation of  p53, p27 and cyclin B, and for the activation of the transcription factor NF-κB through the degradation of its regulatory subunit IκBα. Elastase is an enzyme important during the process of metastasis, because of its capability to cleave almost every protein contained within the extracellular matrix (ECM) including, but not limited to, elastin, collagen, fibronectin, laminin, and proteoglycans. Uncontrolled activity and overexpression of elastase allows cancer cells within a tumor to develop and metastasize directly through degradation of ECM.
In this presentation, we present synthetic routes used in order to obtain over 20 compounds, phosphonate analogues of amino acids with unsubstituted phenyl ring. For all of them, the antiproliferative activity against drug-sensitive and drug resistant colon cancer cell line (LoVo and LoVoDX) and the chymotrypsin and elastase enzymes inhibition potency was evaluated. The IC50 for the most active compounds was in range 7-15 µM (determined with SRB method, 72 hour drug treatment) for both cancer cell lines. Simultaneously, the most active chymotrypsin inhibitors demonstrated k2/Ki second order rate constant in range 1 100 - 1 320 [M-1s-1] and elastase inhibitors in range 400 - 505 [M-1s-1]. For the most promising compounds, the molecular mechanism was additionally evaluated. The glutathione reduced depletion (up to 70% depletion after 2 hours of treatment) was observed followed by caspase-3 activation (up to 2,5-fold change compared to control after 24h treatment) and chymotrypsin-like proteasome inhibition (up to 1,7-fold change compared to control).  These results are a good starting point for further development of biologically active compounds based on both isothiocyanates and phosphonate diphenyl esters.  


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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:   2012-03-15 11:41