Total Synthesis and Antimalarial Activity of Symplostatin 4

Abstract

The first total synthesis of symplostatin 4, a marine cyanobacterium-derived natural product, is described. Notable features of the route include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings. Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED(50) of 74 nM against Plasmodium falciparum, strain 3D7).

The Antimalarial Natural Product Symplostatin 4 Is a Nanomolar Inhibitor of the Food Vacuole Falcipains

“…In the case of Sym4 treatment, we observed a red food vacuole defect, which indicates that Sym4 blocks the initial stages of hemoglobin degradation. We did not observe lysis of RBCs with either of the two compounds, which is in accordance with previously published data (Conroy et al, 2010). Finally, a dead phenotype was observed at 100 µM (Figure 2B).…”

“…The natural product symplostatin 4 ( Sym4 ) has been identified as another promising antimalarial compound (Conroy et al, 2010, 2011). To investigate the mode of action of this promising antimalarial agent, we synthesized several analogs to (1) identify its direct molecular targets and (2) characterize the underlying structure-activity relationships and correlate them to the antimalarial activities.…”

“…and Schizothrix sp., respectively (Linington et al, 2009; Taori et al, 2009). Subsequent total syntheses of these two natural products and structural characterizations revealed that both compounds are in fact identical (Conroy et al, 2010, 2011). Subsequent biological evaluations of Sym4 demonstrated their potent antimalarial properties: In fact, gallinamide A (and, therefore, Sym4 ), as well as three chemically synthesized diastereomers that differed only in the stereochemistry of their N-terminal isoleucine residue, turned out to be potent nanomolar growth inhibitors of the malaria parasite P. falciparum (strain 3D7 and W2, IC 50 s of 36–100 nM) (Conroy et al, 2010, 2011; Linington et al, 2009).…”

“…Subsequent total syntheses of these two natural products and structural characterizations revealed that both compounds are in fact identical (Conroy et al, 2010, 2011). Subsequent biological evaluations of Sym4 demonstrated their potent antimalarial properties: In fact, gallinamide A (and, therefore, Sym4 ), as well as three chemically synthesized diastereomers that differed only in the stereochemistry of their N-terminal isoleucine residue, turned out to be potent nanomolar growth inhibitors of the malaria parasite P. falciparum (strain 3D7 and W2, IC 50 s of 36–100 nM) (Conroy et al, 2010, 2011; Linington et al, 2009). Notably, no lysis of red blood cells (RBCs) was observed during Sym4 treatment even at the highest tested concentrations (>25 µM) (Conroy et al, 2010), indicating that its antiparasitic effect is not due to permeabilization of the RBC membrane.…”

Biological targets and mechanisms of action of natural products from marine cyanobacteria

“…178 Symplostatin 4 and synthetic analogs showed potent activity against drug resistant and wild-type strains of Plasmodium falciparum . 179,180 Interestingly, symplostatin 4 did not cause lysis of red blood cells, even at high-micromolar concentration. 181 Clues to the mechanism of antiplasmodial activity of symplostatin 4 were obtained from the distinct food vacuole phenotype of P. falciparum observed following symplostatin 4 treatment.…”