Synthetic Tigliane Intermediates Engage Thiols to Induce Potent Cell Line Selective Anti‐Cancer Activity

• Published in: Chemistry : a European journal 2020-10, Vol.26 (59), p.13372-13377
• Main Authors: Chow, Sharon, Krainz, Tanja, Bettencourt, Christian J., Broit, Natasa, Ferguson, Blake, Zhu, Mingzhao, Hull, Kenneth G., Pierens, Gregory K., Bernhardt, Paul V., Parsons, Peter G., Romo, Daniel, Boyle, Glen M., Williams, Craig M.
• Format: Article
• Language: English
• Subjects: Biological activity; Biological effects; Biotechnology; Cancer; Cell activation; Cell Line; Chemical synthesis; Chemistry; Cycloaddition; D-rings; Derivatives; Esters; Glutathione; Humans; Intermediates; Interrogation; Michael addition; Mode of action; Neoplasms; Phorbol esters; Phorbols; Protein Kinase C - chemistry; Rhodium; Sulfhydryl Compounds - chemistry; synthetic methods; Thiols; tiglianes; Tumor cell lines; Tumors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202003221

The tigliane ring system, which encompasses iconic members such as phorbol and TPA, is widely renowned due to numerous observations of displaying potent biological activity, and subsequent use as mainstream biochemical tools. Traditionally, naturally occurring phorboids are regarded as tumor promotors through PKC activation, although in recent times more highly oxidized natural derivatives have been identified as anti‐tumor agents. In the view that only limited synthetic investigations toward skeletal stereochemical modification have been undertaken, non‐natural systems could be useful for a better understanding of the tigliane pharmacophore via interrogation of cellular sensitivity. In this context the concise construction of a number of highly functionalized non‐natural D‐ring inverted phorbol esters were synthesized, via a rhodium‐catalyzed [4+3] cycloaddition, and biologically evaluated using a range of cancer cell lines. The biological results highlight the notion that subtle changes in structure have dramatic effects on potency. Furthermore, although the non‐natural derivatives did not outcompete the natural systems in the PKC‐activation sensitive MCF7 cancer cell line, they outperformed in other cancer cell lines (MM96L and CAL27). This observation strongly suggested an alternate mode of action not involving activation of PKC, but instead involves thiol addition as indicated by glutathione addition and NF‐κB reporter activity. Advanced synthetic intermediates en route to D‐ring inverted non‐natural tiglianes display higher potency (e.g. MM96L and CAL27) as compared to natural tigliane esters, especially when moving away from PKC‐activation sensitive cancer cell lines (e.g. MCF7).