Combining synthetic biology with synthetic electrochemistry to expand the chemical space of the indolocarbazole family

Indolocarbazoles, a class of highly privileged scaffolds, hold immense significance in medicinal chemistry due to their diverse biological activities. In this study, we have demonstrated the environmentally benign synthesis of indolocarbazoles by integrating the strengths of synthetic biology and synthetic electrochemistry. Through pathway reconstruction in <i>Escherichia coli</i>, a sustained supply of the prototype indolocarbazole k252c (1) was achieved, which could be efficiently <i>N</i>-rhamnosylated to produce k252d (2) <i>via</i> modular coculture engineering. An appreciable yield (∼20 mg L^-1) was obtained through <i>in vitro</i> enzymatic glycosylation of compounds 1 and 2, yielding derivatives 3-8 with diverse glycosyl linkages. Additionally, under exceptionally mild conditions, the electrochemical conversion of compounds 1 and 2 enabled the synthesis of derivatives 9-17 with tunable functionalization. Notably, the N-N homodimerization observed in compounds 9 and 10 is unprecedented within the structural family of indolocarbazoles. The antiproliferative activity of compounds 1-17 was assessed against twenty different human tumor cell lines. Overall, the combination of multistep biocascades with electrocatalysis represents a novel green synthetic approach to expand the repertoire of xenobiotic compounds available to chemists.