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Org Biomol Chem. 2012 Apr 21;10(15):3092-7. doi: 10.1039/c2ob07090a. Epub 2012 Mar 7.
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.
细胞毒性海洋吡咯并[2,1-i]喹啉酮生物碱 discorhabdins 的作用机制尚不清楚。我们已经确定 discorhabdin B 作为亲电试剂作用于仿生硫醇亲核试剂，导致脱溴加合物。相比之下，效力较低的细胞毒素 discorhabdins D 和 Q 未能反应，支持细胞毒性的 SAR 模型，需要协调组合亲电性 Δ(1)碳原子中心和强活性的 N-18 胺基。discorhabdin B 的两种对映异构体表现出的立体特异性亲核试剂捕获暗示 ovothiol A 取代的 discorhabdins H、H(2)、K 和 K(2)的生物合成不一定需要酶促过程。
