Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives

Abstract

Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nM cytotoxicity towards multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro.

Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications

“…The promising biological activity of 65 coupled with its complex polycyclic architecture sparked considerable interest in the synthetic community, culminating in two successful enantioselective syntheses, (+)-kibdelone C completed by Porco, 20 and (−)-kibdelone C completed by Ready. 21 A key challenge for both groups was the synthesis of the chiral polyhydroxylated F ring (Scheme 3). Toward this end, for his synthesis of (+)-kibdelone C, Porco utilized 66a , which was prepared in 13 steps and 15% overall yield.…”

“…22 Ready’s approach to (−)-kibdelone C required the use of fragment 67 , which was in prepared in seven steps and 30% overall yield. 21 …”

“…Collectively, compounds belonging to this class possess an array of potentially useful biological activities that include low nanomolar GI 50 values against a panel of human cancer cell lines as well as potent antibacterial and nematocidal properties. The promising biological activity of 65 coupled with its complex polycyclic architecture sparked considerable interest in the synthetic community, culminating in two successful enantioselective syntheses, (+)-kibdelone C completed by Porco, and (−)-kibdelone C completed by Ready . A key challenge for both groups was the synthesis of the chiral polyhydroxylated F ring (Scheme ).…”

“…Hudlicky subsequently reported an enzymatic approach that provided the related F ring precursor 66b in three steps, albeit in only 2.2% overall yield . Ready’s approach to (−)-kibdelone C required the use of fragment 67 , which was prepared in seven steps and 30% overall yield …”

Synthetic Studies on the Kigamicins

“…Whereas many other tetrahydroxanthone natural products show nonselective cytotoxicity, the kigamicins are reportedly toxic only to nutrient-deprived cells . For example, kigamicin A displays LD 50 < 0.1 μM against PANC-1 pancreatic tumor cells cultured in nutrient-poor media.…”