Abstract

Human health benefits from consuming cruciferous vegetables that release indole-3-carbinol (I3C), but the in vivo transformation of I3C-related indoles remains underinvestigated. Here we present the post-ingestion conversion of I3C into antitumor agents, 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1) and 3,3′-diindolylmethane (DIM), by conceptualizing and materializing the reaction flux derailing (RFD) approach as a means of unraveling these stepwise transformations to be non-enzymatic but pH-dependent and gut microbe-sensitive.

In the upper (or acidic) gastrointestine, LTr1 generates through the Michael addition of 3-methyleneindolium (3MI, derived in situ from I3C) to DIM producing from I3C via the formaldehyde-releasing (major) and CO2-liberating (minor) pathways. In the large intestine, 'endogenous' I3C and DIM can form respectively from couplings of formaldehyde with one and two molecules of indole (a tryptophan catabolite). Acid-producing gut bacteria such as Lactobacillus acidophilus facilitate the H+-promotable steps. The work updates the understanding on the merits of I3C consumptions and identifies LTr1 as a drug candidate.