New approaches to handle old compounds – the generation of microcystin and nodularin derivatives with “clickable” features

Lately, new crosslinking techniques have been developed to study the function of compounds in cellular processes. These techniques became known as bioorthogonal or so-called “click” reactions [1]. They are biorthogonal because they involve functional groups not found in nature. Thus, a semisynthetic approach is required to introduce the “clickable” groups into natural products – a sometimes difficult and time-consuming process.

The cyanobacterial cyclic peptides microcystins and nodularins are thoroughly studied natural products, but still their function within cyanobacteria remains unclear [2]. They have also been discussed as new, potent anti-cancer agents due to their efficient inhibition of eukaryotic protein phosphatases. However, their high toxicity potentially makes them unsuitable for clinical use [3].

Microcystin and nodularin derivatives with “clickable” features might help to gain new insights into the physiology of cyanobacteria and the biological function of these specialized molecules. Additionally, this might make them amenable for clinical use, e.g. by allowing to construct antibody-drug conjugates based on these toxins. Thus, we established rapid and feasible techniques to introduce azide- and alkyne groups into microcystins and nodularins, e.g. precursor directed biosynthesis: Supplementation of azide and alkyne functionalized tyrosine derivatives to a microcystin-YR producing Microcystis sp. strain resulted in their incorporation into this microcystin congener.

[1] Patterson DM, Nazarova LA, Prescher JA. ACS Chem. Biol. 2014; 9: 592 – 605

[2] Kaplan A, Harel M, Kaplan-Levy RN, Hadas O, Sukenik A, Dittmann E. Front. Microbiol. 2012; 3: 138

[3] McCluskey A, Sim ATR, Sakoff JA. J. Med. Chem. 2002; 45: 1151 – 1175