Doxorubicin is one of the Topoisomerase II inhibitors that are used for the treatment of various types of cancer, including leukaemia and non-Hodgkin lymphoma. According to its typical mechanism of action, intercalation occurs into the DNA, their target topoisomerase is trapped, thereby generating DNA double-strand breaks and ultimately cell death. As effective and popular as this drug is, its usage is hugely limited by the cumulative cardiotoxicity it brings along. It was recently shown that these anthracyclines are able to induce histone eviction from chromatin . Amongst the consequences are a marked delay in DNA repair and diverse epigenetic changes. This additional activity of the anthracyclines may explain the difference in potency and side-effects between these drugs and structurally different Topo II inhibitors. We have developed a flexible methodology that allows for the preparation of mono-, di- and trisaccharide analogues of doxorubicin and aclarubicin (a related anthracycline trisaccharide). Structural variation in the target compounds has been achieved by swapping and shuffling of the sugar sequence and varying the alkylation pattern on the amine functionality. The saccharides can be assembled by iterative stereoselective couplings using thiophenyl donors, which can then be coupled to the desired aglycon using Yu’s ortho-alkynyl benzoate donor methodology . A combined cell-biology and bio-informatic pipeline allows us to gain more insight in the biological and cytotoxic properties of the designer antracyclines, in search of better chemotherapeutic agents with diminished side-effects. This has so far led to the discovery of a doxorubicin-aclarubicin hybrid structure that lacks the classical DSB mechanism, yet maintains its histone evicting property and cytotoxicity. Moreover, its cardiotoxic property has shown to be abolished in vivo in mice. Efficacy studies on human AML xenografts in mice are currently ongoing with the hope of ultimately providing non-cardiotoxic anthracycline anti-cancer treatment for humans.
Pang, B.; Qiao, X.; Janssen, L.; Velds, A.; Groothuis, T.; Kerkhoven, R.; Nieuwland, M.; Ovaa, H.; Rottenberg, S.; van Tellingen, O.; Janssen, J.; Huijgens, P.; Zwart, W.; Neefjes, J. Nat. Commun. 2013, 4, 1908.  Li, Y.; Yang, X.; Liu, Y.; Zhu, C.; Yang, Y.; Yu, B. Chem. - A Eur. J. 2010, 16 (6), 1871.