In 2011 Tan and co-workers isolated lagunamide C (LagC), a depsipeptide from the cyanobacterium Lyngbya majsuclefrom the western lagoon of Pulau Hantu Besar, Singapore. It was shown to possess potent cytotoxicity against a panel of cancer cell lines: lymphoma (P388, IC50 24.4 nM), lung (A549, IC50 2.4 nM), prostate (PC3, IC50 2.6 nM), colon (HCT8, IC50 2.1 nM), and ovarian (SK-OV3, IC50 4.5 nM). In addition to its low nanomolar cytotoxicity, lagunamide C was also shown to display significant antimalarial activity with an IC50of 0.29 μM towards Plasmodium falciparum and also possess weak anti-swarming activity towards Pseudomonas aeruginosa PA01 when screened at 100 ppm. To date, no total synthesis of this potent bioactive agent has been reported, while the total synthesis of A and B have. The polyketide unit within LagC possess an extra methylene unit, which prevents the use of the routes to the polyketide units of LagA/B. Furthermore, there is structural ambiguity about two of the four stereocenters within the polyketide of LagC, limiting the possible applications of this potent bioactive agent. As such, any total synthesis campaign of LagC must also allow for structural modification of these stereocenters for final determination of its stereochemistry. Our laboratory has developed a modular route to access the assumed possible diastereomers of the polyketide unit, this approach will allow for the structural determination and also give rise to invaluable SAR analysis for mode of action studies. The synthetic studies gaining access to the polyketide, as well as the polypeptide backbone of LagC will be discussed, and potentially the first total synthesis and final structural elucidation of LagC. Biological evaluation of key intermediates of the polyketide construction will be disclosed and their unexpected cytotoxicity, which has led to a new proposed mode of action for LagC and its family of natural products.

Lagunamide C: Total synthesis efforts, final structural determination, and biological evaluation

2019 Spring National Meeting

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