Indole Ring Expansion and Rearrangement-Enabled Quinoline Scaffold Formation in the Biosynthesis of the Antitumor Monoterpene Indole Alkaloid Camptothecin

Camptothecin (CAM), a well-known complex plant antitumor monoterpene indole alkaloid (MIA) with a unique pyrroloquinoline scaffold, is structurally and biosynthetically distinct from indole-type MIAs. Strictosamide (STM), a glucosylated indole-type MIA with a 6/5/6/6/6 pentacyclic scaffold, is the penultimate biosynthetic intermediate for CAM biosynthesis. Herein, we report the indole ring expansion and rearrangement of STM, rings BC opening (C2-C7 double bond cleavage), and subsequent C2-C6 double bond formation for rings BC reclosure, generating pumiloside (PUM), an MIA with a 6/6/5/6/6 framework featuring a quinoline moiety. Flavins such as flavin mononucleotide or sunlight were demonstrated to catalyze the skeletal conversion of STM to PUM. The flavin- or photocatalyzed indole ring expansion and rearrangement could be applied to a series of indole-type MIAs, producing the corresponding quinoline-containing MIAs. The present study bridged the biosynthetic gap between the indole-containing 6/5/6/6/6 pentacyclic framework and the quinoline-containing 6/6/5/6/6 pentacyclic scaffold that is involved in CAM biosynthesis. The described indole ring expansion and subsequent rearrangement enabled an alternative for ring expansion of a variety of indole-type MIAs, leading to a series of quinoline-containing complex alkaloids.