In recent years many efforts have been made1 to define innovative strategies for the identification of biological targets of calixarene derivatives.2,3 MS-based chemical proteomics4 has had a significant impact on discovery of novel biomolecular target for potential drug candidates. Recently we have introduced, for the first time, a chemical proteomics approach based on mass spectrometry to identify biomolecular target of a given calixarene derivative.5 We have showed that the simply calixarene derivatives bearing acetamido groups at the exo rim (pAC 1) was able to recognize the protein disulfide isomerase (PDI), which was fished in a crude extract of HeLa cells. Western blot and surface plasmon resonance (SPR) studies indicated the direct interaction between the PDI protein and the pAC derivative. Literature data evidenced that increased PDI levels have been documented in a variety of human cancers, suggesting that PDI is a promising druggable target. Thus, biological tests showed that pAC 1was cytotoxic and cytostatic toward CAL-27 (oral adenosquamous carcinoma cell line) and PC-3 (human prostate cancer cell line) in vitro. Finally, docking studies showed that both H-bonding and hydrophobic interactions seem to be the main driving forces for the stabilization of the PDI/calixarene 1 complexes.
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