Design, Synthesis And Anti-cancer Activity Studies On Mannich Derivatives Of Marine Natural Product Lamellarm D

Lamellarin D, a benzopyrano[4’,3’:4,5]pyrrolo[2,1-α]isoquinolin-6-one derivative, is one of the marine natural products lamellarins. Being one of the most extensively studied lamellarins, Lamellarin D has been shown inhibitory activity against Topo I, potential to reverse multidrug resistance induced by P-glycoprotein mediated drug efflux, the ability to induce apoptosis through mitochondria dependent pathway and antiproliferative activities against different types of cancer cells. Thus, lamellarin D-based structural modification and derivation has been a hotspot recently.Enlightened by the modification route from CPT to Topotecan, based on classical drug design theory, a series of Mannich derivatives of lamellarin D were designed by attaching different subsitutuent to the three hydroxy groups at8-,14-, and20-position of lamellarin D.11mono-and bis-Mannich derivatives of lamellarin D were synthesized in26-27steps starting from vanillin and isovanilin with overall yields ranging from0.31-0.47%. All synthesized compounds were then biologically evaluated for their in vitro anti-cancer activities, the result of which showed that most target compounds exhibited Topo I inhibitory activity against tested cell lines in equivalent level with that of the positive control lamellarin D. Some compound, e.g. SL-9, exhibited better inhibitory ability than that of lamellarin D. Compounds SL-2, SL-3, SL-4, SL-5and SL-11exhibited better anti-proliferative activity against HT-29cells than that of lamellarin D.Preliminary SAR study revealed that mono-Mannich derivation and the introduction of a small aminomethyl group with a hydrogen bond acceptor are beneficial for antiproliferative potency against cancer cells.This study on lamellarin D-based Mannich derivation provides new insights for the development of derivatives of lamellarin D as anti-cancer agents.