Investigation of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin B |
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Authors: | Lam Cary F C Grkovic Tanja Pearce A Norrie Copp Brent R |
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Institution: | School of Chemical Sciences, Private Bag 92019, Auckland 1142, New Zealand. |
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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. |
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