ICI00005: Doxorubicin is part of the anthracycline class of chemotherapeutics. Their main mechanism of action was considered to be DNA double-strand breakage, leading to cell death. Recent experiments with GFP-tagged histones have shown that these compounds are able to kick out histones (including their post-translational modifications). For aclarubicin, this is the actual dominant mechanism instead. An array of (oligo)-saccharides related to doxorubicin and aclarubicin will be synthesized through a shuffleable building-block approach. Combined with a cell-biology and bio-informatics pipeline, these compounds will be tested for their effectiveness and side-effects, as well as their potential as epigenetic modifiers.
ICI00020: My previous work with the ICI on anti-cancer anthracyclines yielded a vast library of doxorubicin and aclarubicin variants. Out of these, N,N-dimethyldoxorubicin was identified as a potent, and most notably, non-cardiotoxic analogue. Current and future efforts are aimed at large scale bio- and organosynthetic production of the above compound for (pre-)clinical testing and traceable variants thereof, as well as the generation of more variants in search of better anthracyclines.
This work is being executed in collaboration with Sabina van der Zanden and Floor van Haften (LUMC, cell biology) and Thadee Grocholski (UTU Finland, biosynthesis).