Investigation of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin B.

The mechanisms of action of the cytotoxic marine pyrroloiminoquinone alkaloids the discorhabdins are unknown. We have determined that discorhabdin B acts as an electrophile towards biomimetic thiol nucleophiles leading to debrominated adducts. In contrast, less potent cytotoxins discorhabdins D and Q failed to react, supporting an SAR model of cytotoxicity requiring an orchestrated combination of an electrophilic Δ(1) carbon centre and a nucleophilic N-18 amine for potent activity. The stereospecific nature of nucleophile trapping exhibited by both enantiomers of discorhabdin B implies the biogenesis of ovothiol A substituted discorhabdins H, H(2), K and K(2) need not be mediated by enzymatic processes.