Design and total synthesis of Mannich derivatives of marine natural product lamellarin D as cytotoxic agents

•Novel design on lamellarin D derivatization.•Rational attempt for increasing the water-solubility of lamellarin D.•Multistep synthesis and the strategy of phenol protection.•Convincing data on Topo I inhibitory and anti-proliferative activities comparing with lamellarin D and lamellarin 501.

Enlightened by the modification route from Camptothecin (CPT) to Topotecan and based on classical drug design theory, a series of Mannich derivatives of lamellarin D were designed and synthesized in 26–27 steps starting from vanillin and isovanilin. All synthesized compounds were then biologically evaluated for their in vitro anti-cancer activities and Topo I inhibitory activities. The results showed that most target compounds exhibited Topo I inhibitory activities in equivalent level with that of lamellarin D. Compound SL-9 exhibited better Topo I inhibitory activity than that of lamellarin D. Compounds SL-2, SL-3, SL-4, SL-5 and SL-11 exhibited better anti-proliferative activity against HT-29 cells than that of lamellarin D.

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