title: Investigation of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin B.
abstract: 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.
authors.affiliation: School of Chemical Sciences, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Cary F C
authors.initials: CF
authors.lastname: Lam
authors.forename: Tanja
authors.initials: T
authors.lastname: Grkovic
authors.forename: A Norrie
authors.initials: AN
authors.lastname: Pearce
authors.forename: Brent R
authors.initials: BR
authors.lastname: Copp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification; D059001:Aquatic Organisms; D015394:Molecular Structure; D011161:Porifera; D015363:Quinolones / Q000737:chemistry* / Q000302:isolation & purification; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: D000970:Antineoplastic Agents; D015363:Quinolones; D013841:Thiazepines; C573536:discorhabdin B